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Dong L, Lou W, Wang J. β-Carotene-loaded cationic nanoparticles ameliorate MASLD via modulating lipid homeostasis and gut microbiome. Food Res Int 2025; 205:115816. [PMID: 40032486 DOI: 10.1016/j.foodres.2025.115816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/19/2025] [Accepted: 01/19/2025] [Indexed: 03/05/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is, increasingly, a major threat to human health, yet without any approved drug. β-carotene (BC) contributes to alleviating several metabolic diseases. However, the bioavailability of BC is hindered by hydrophobicity and environmental sensitivity. Herein, we explore the utilization of cationic lipid-assisted nanoparticles to achieve efficient delivery of BC. In the MASLD model, NP-BC ameliorated the development of metabolic disorders, insulin resistance, inflammatory injury and hepatic steatosis. Transcriptomic analysis showed that NP-BA rectifies various pathways involved in steatosis development by inhibiting the PI3K/AKT/mTOR pathway and PPARγ gene expression. Meanwhile, NP-BC also reshaped the composition of gut microbiota in MASLD mice by reducing the Firmicutes/Bacteroidetes ratio and increasing the abundance of beneficial bacteria. Taken together, our study demonstrates that NP-BC can improve MASLD and may be a promising candidate for treating MASLD.
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Affiliation(s)
- Lu Dong
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Wenyong Lou
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Juan Wang
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
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2
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Guo T, Wang Y, Wang D, Ge R, Du Z, Zhang Z, Qin Y, Liu X, Deng Y, Song Y. Sialic acid-modified docetaxel cationic liposomes: double targeting of tumor-associated macrophages and tumor endothelial cells. J Liposome Res 2025; 35:29-43. [PMID: 39138909 DOI: 10.1080/08982104.2024.2388140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/15/2024]
Abstract
Taxane drugs are clinically used for the treatment of many types of cancers due to their excellent antitumor effects. However, the surfactants contained in the injections currently used in the clinic may have serious toxic side effects on the organism, making it necessary to develop new dosage forms. Cationic liposomes have been widely used in antitumor research because of their advantage of preferentially targeting tumor neovascularization, but antitumor by targeting tumor vasculature alone does not necessarily provide good results. Malignant tumors represent complex ecosystems, tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) in the tumor microenvironment play crucial roles in tumor growth. Therefore, given the ability to achieve active targeting of TAMs and TECs by using sialic acid (SA) as a targeting material, the potential of cationic nanoformulations to preferentially target neovascularization at the tumor site, and the excellent antitumor effects of the taxane drugs docetaxel (DOC), in the present study, sialic acid-cholesterol coupling (SA-CH) was selected as a targeting material to prepare a DOC cationic liposome (DOC-SAL) for tumor therapy. The results of the study showed that DOC-SAL had the strongest drug accumulation in tumor tissues compared with the common DOC formulations, and was able to effectively reduce the colonization of TAMs, inhibit the proliferation of tumor cells, and have the best tumor-suppressing effect. In addition, DOC-SAL was able to improve the internal microenvironment of tumors by modulating cytokines. In summary, this drug delivery system has good anti-tumor effects and provides a new option for tumor therapy.
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Affiliation(s)
- Tiantian Guo
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yu Wang
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Dazhi Wang
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Ruirui Ge
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Zhouchunxiao Du
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Zhirong Zhang
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yushi Qin
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Xinrong Liu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yihui Deng
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yanzhi Song
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
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Haggstrom L, Chan WY, Nagrial A, Chantrill LA, Sim HW, Yip D, Chin V. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database Syst Rev 2024; 12:CD011044. [PMID: 39635901 PMCID: PMC11619003 DOI: 10.1002/14651858.cd011044.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
BACKGROUND Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018. OBJECTIVES To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer. SEARCH METHODS We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023. SELECTION CRITERIA We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes. AUTHORS' CONCLUSIONS Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.
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Affiliation(s)
- Lucy Haggstrom
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
| | - Wei Yen Chan
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia
| | - Adnan Nagrial
- The Crown Princess Mary Cancer Centre, Westmead, Australia
- Medical School, The University of Sydney, Sydney, Australia
| | - Lorraine A Chantrill
- Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, Australia
- University of Wollongong, Wollongong, Australia
| | - Hao-Wen Sim
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
| | - Desmond Yip
- Department of Medical Oncology, The Canberra Hospital, Garran, Australia
- ANU Medical School, Australian National University, Acton, Australia
| | - Venessa Chin
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
- Medical Oncology, Garvan Institute of Medical Research, Sydney, Australia
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4
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Löhr JM. Pancreas 2000. My journey with the central organ. Pancreatology 2024; 24:671-676. [PMID: 38641487 DOI: 10.1016/j.pan.2024.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 03/27/2024] [Indexed: 04/21/2024]
Abstract
The European Pancreatic Club Lifetime Achievement Award is a distinction awarded for research on the pancreas and service to European Pancreatology. It comes with the obligation to submit a review article to our society's journal, Pancreatology. It was awarded to me 2023 and I take this opportunity to highlight my journey with the central organ AKA the pancreas, that is inseparatable from "Pancreas 2000" - an educational program for future pancreatologists, inaugurated by Karolinska Institutet.
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Affiliation(s)
- J-Matthias Löhr
- Karolinska Institutet, Alfred Nobels Allé 8, S-141 86, Stockholm, Sweden.
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5
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Askarizadeh A, Mashreghi M, Mirhadi E, Mehrabian A, Heravi Shargh V, Badiee A, Alavizadeh SH, Arabi L, Kamali H, Jaafari MR. Surface-modified cationic liposomes with a matrix metalloproteinase-degradable polyethylene glycol derivative improved doxorubicin delivery in murine colon cancer. J Liposome Res 2024; 34:221-238. [PMID: 37647288 DOI: 10.1080/08982104.2023.2247079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/27/2023] [Accepted: 08/04/2023] [Indexed: 09/01/2023]
Abstract
PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake.
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Affiliation(s)
- Anis Askarizadeh
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mashreghi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elaheh Mirhadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amin Mehrabian
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Heravi Shargh
- Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Ali Badiee
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Hoda Alavizadeh
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Arabi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Kamali
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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6
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Silli EK, Li M, Shao Y, Zhang Y, Hou G, Du J, Liang J, Wang Y. Liposomal nanostructures for Gemcitabine and Paclitaxel delivery in pancreatic cancer. Eur J Pharm Biopharm 2023; 192:13-24. [PMID: 37758121 DOI: 10.1016/j.ejpb.2023.09.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/01/2023] [Accepted: 09/24/2023] [Indexed: 10/03/2023]
Abstract
Pancreatic cancer (PC) is an incurable disease with a high death rate in the world nowadays. Gemcitabine (GEM) and Paclitaxel (PTX) are considered as references of chemotherapeutic treatments and are commonly used in clinical applications. Factors related to the tumor microenvironment such as insufficient tumor penetration, toxicity, and drug resistance can limit the effectiveness of these therapeutic anticancer drugs. The use of different liposomal nanostructures is a way that can optimize the drug's effectiveness and reduce toxicity. Given the development of PC therapy, this review focuses on advances in Nano-formulation, characterization, and delivery systems of loaded GEM and PTX liposomes using chemotherapy, nucleic acid delivery, and stroma remodeling therapy. As a result, the review covers the literature dealing with the applications of liposomes in PC therapy.
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Affiliation(s)
- Epiphane K Silli
- School of Life Sciences and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Mengfei Li
- School of Life Sciences and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Yuting Shao
- College of Engineering, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Yiran Zhang
- College of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Guilin Hou
- College of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Jiaqian Du
- College of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Jingdan Liang
- College of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Ying Wang
- School of Life Sciences and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
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7
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Go EJ, Yang H, Park W, Lee SJ, Han JH, Kong SJ, Lee WS, Han DK, Chon HJ, Kim C. Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2300544. [PMID: 37381624 DOI: 10.1002/smll.202300544] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/13/2023] [Indexed: 06/30/2023]
Abstract
Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.
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Affiliation(s)
- Eun-Jin Go
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Hannah Yang
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Wooram Park
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Seoburo 2066, Suwon, Gyeonggi, 16419, Republic of Korea
| | - Seung Joon Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Jun-Hyeok Han
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Seoburo 2066, Suwon, Gyeonggi, 16419, Republic of Korea
| | - So Jung Kong
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Won Suk Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
| | - Chan Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi, 13496, Republic of Korea
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8
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Raza F, Evans L, Motallebi M, Zafar H, Pereira-Silva M, Saleem K, Peixoto D, Rahdar A, Sharifi E, Veiga F, Hoskins C, Paiva-Santos AC. Liposome-based diagnostic and therapeutic applications for pancreatic cancer. Acta Biomater 2023; 157:1-23. [PMID: 36521673 DOI: 10.1016/j.actbio.2022.12.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 12/02/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is one of the harshest and most challenging cancers to treat, often labeled as incurable. Chemotherapy continues to be the most popular treatment yet yields a very poor prognosis. The main barriers such as inefficient drug penetration and drug resistance, have led to the development of drug carrier systems. The benefits, ease of fabrication and modification of liposomes render them as ideal future drug delivery systems. This review delves into the versatility of liposomes to achieve various mechanisms of treatment for pancreatic cancer. Not only are there benefits of loading chemotherapy drugs and targeting agents onto liposomes, as well as mRNA combined therapy, but liposomes have also been exploited for immunotherapy and can be programmed to respond to photothermal therapy. Multifunctional liposomal formulations have demonstrated significant pre-clinical success. Functionalising drug-encapsulated liposomes has resulted in triggered drug release, specific targeting, and remodeling of the tumor environment. Suppressing tumor progression has been achieved, due to their ability to more efficiently and precisely deliver chemotherapy. Currently, no multifunctional surface-modified liposomes are clinically approved for pancreatic cancer thus we aim to shed light on the trials and tribulations and progress so far, with the hope for liposomal therapy in the future and improved patient outcomes. STATEMENT OF SIGNIFICANCE: Considering that conventional treatments for pancreatic cancer are highly associated with sub-optimal performance and systemic toxicity, the development of novel therapeutic strategies holds outmost relevance for pancreatic cancer management. Liposomes are being increasingly considered as promising nanocarriers for providing not only an early diagnosis but also effective, highly specific, and safer treatment, improving overall patient outcome. This manuscript is the first in the last 10 years that revises the advances in the application of liposome-based formulations in bioimaging, chemotherapy, phototherapy, immunotherapy, combination therapies, and emergent therapies for pancreatic cancer management. Prospective insights are provided regarding several advantages resulting from the use of liposome technology in precision strategies, fostering new ideas for next-generation diagnosis and targeted therapies of pancreatic cancer.
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Affiliation(s)
- Faisal Raza
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Lauren Evans
- Pure and Applied Chemistry, University of Strathclyde, 99 George Street, Glasgow, G1 1RD, UK
| | - Mahzad Motallebi
- Immunology Board for Transplantation And Cell-based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 7616911319, Iran; Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hajra Zafar
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Miguel Pereira-Silva
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal; LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal
| | - Kalsoom Saleem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 45320, Pakistan
| | - Diana Peixoto
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal; LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol 98613-35856, Iran
| | - Esmaeel Sharifi
- Cancer Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Francisco Veiga
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal; LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal
| | - Clare Hoskins
- Pure and Applied Chemistry, University of Strathclyde, 99 George Street, Glasgow, G1 1RD, UK
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal; LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal.
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9
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Gautier L. Nanotechnology and cancer therapeutics: delivering on the hype? Biotechniques 2023; 74:63-67. [PMID: 36856138 DOI: 10.2144/btn-2022-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
Nanoparticle drug delivery systems are a promising development in cancer therapy for reducing toxicity and drug resistance, whilst improving precision targeting. Several types of nanotechnology are in development, with some receiving market approval and others proving difficult to translate to the bedside. [Formula: see text].
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10
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Askarizadeh A, Mashreghi M, Mirhadi E, Mirzavi F, Shargh VH, Badiee A, Alavizadeh SH, Arabi L, Jaafari MR. Doxorubicin-loaded liposomes surface engineered with the matrix metalloproteinase-2 cleavable polyethylene glycol conjugate for cancer therapy. Cancer Nanotechnol 2023; 14:18. [PMID: 36910721 PMCID: PMC9988605 DOI: 10.1186/s12645-023-00169-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/15/2023] [Indexed: 03/09/2023] Open
Abstract
Background Colorectal cancer is one of the prominent leading causes of fatality worldwide. Despite recent advancements within the field of cancer therapy, the cure rates and long-term survivals of patients suffering from colorectal cancer have changed little. The application of conventional chemotherapeutic agents like doxorubicin is limited by some drawbacks such as cardiotoxicity and hematotoxicity. Therefore, nanotechnology has been exploited as a promising solution to address these problems. In this study, we synthesized and compared the anticancer efficacy of doxorubicin-loaded liposomes that were surface engineered with the 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-matrix metalloproteinase-2 (MMP-2) cleavable peptide-polyethylene glycol (PEG) conjugate. The peptide linker was used to cleave in response to the upregulated MMP-2 in the tumor microenvironment, thus exposing a positive charge via PEG-deshielding and enhancing liposomal uptake by tumor cells/vasculature. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell binding and uptake, and cytotoxicity. Results The formulations had particle sizes of ~ 100-170 nm, narrow distribution (PDI ˂ 0.2), and various surface charges (- 10.2 mV to + 17.6 mV). MMP-2 overexpression was shown in several cancer cell lines (C26, 4T1, and B16F10) as compared to the normal NIH-3T3 fibroblast cells by gelatin zymography and qRT-PCR. In vitro results demonstrated enhanced antitumor efficacy of the PEG-cleavable cationic liposomes (CLs) as compared to the commercial Caelyx® (up to fivefold) and the chick chorioallantoic membrane assay showed their great antiangiogenesis potential to target and suppress tumor neovascularization. The pharmacokinetics and efficacy studies also indicated higher tumor accumulation and extended survival rates in C26 tumor-bearing mice treated with the MMP-2 cleavable CLs as compared to the non-cleavable CLs with no remarkable sign of toxicity in healthy tissues. Conclusion Altogether, the MMP-2-cleavable CLs have great potency to improve tumor-targeted drug delivery and cellular/tumor-vasculature uptake which merits further investigation. Supplementary Information The online version contains supplementary material available at 10.1186/s12645-023-00169-8.
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Affiliation(s)
- Anis Askarizadeh
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mashreghi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elaheh Mirhadi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Science, Birjand, Iran
| | - Vahid Heravi Shargh
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Ali Badiee
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Hoda Alavizadeh
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Arabi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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11
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Slapak EJ, el Mandili M, Bijlsma MF, Spek CA. Mesoporous Silica Nanoparticle-Based Drug Delivery Systems for the Treatment of Pancreatic Cancer: A Systematic Literature Overview. Pharmaceutics 2022; 14:390. [PMID: 35214121 PMCID: PMC8876630 DOI: 10.3390/pharmaceutics14020390] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/02/2022] [Accepted: 02/07/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic cancer is a devastating disease with the worst outcome of any human cancer. Despite significant improvements in cancer treatment in general, little progress has been made in pancreatic cancer (PDAC), resulting in an overall 5-year survival rate of less than 10%. This dismal prognosis can be attributed to the limited clinical efficacy of systemic chemotherapy due to its high toxicity and consequent dose reductions. Targeted delivery of chemotherapeutic drugs to PDAC cells without affecting healthy non-tumor cells will largely reduce collateral toxicity leading to reduced morbidity and an increased number of PDAC patients eligible for chemotherapy treatment. To achieve targeted delivery in PDAC, several strategies have been explored over the last years, and especially the use of mesoporous silica nanoparticles (MSNs) seem an attractive approach. MSNs show high biocompatibility, are relatively easy to surface modify, and the porous structure of MSNs enables high drug-loading capacity. In the current systematic review, we explore the suitability of MSN-based targeted therapies in the setting of PDAC. We provide an extensive overview of MSN-formulations employed in preclinical PDAC models and conclude that MSN-based tumor-targeting strategies may indeed hold therapeutic potential for PDAC, although true clinical translation has lagged behind.
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Affiliation(s)
- Etienne J. Slapak
- Center of Experimental and Molecular Medicine, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (M.e.M.); (C.A.S.)
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - Mouad el Mandili
- Center of Experimental and Molecular Medicine, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (M.e.M.); (C.A.S.)
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - C. Arnold Spek
- Center of Experimental and Molecular Medicine, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (M.e.M.); (C.A.S.)
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12
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Dorman K, Heinemann V, Kobold S, von Bergwelt-Baildon M, Boeck S. Novel systemic treatment approaches for metastatic pancreatic cancer. Expert Opin Investig Drugs 2022; 31:249-262. [PMID: 35114868 DOI: 10.1080/13543784.2022.2037552] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) has a 5-year overall survival rate of 10 %, emphasizing the need for more effective therapies, especially in metastatic disease. The immunosuppressive tumor microenvironment, poor vascularization, and dense tumor stroma typical for PDAC are hurdles that need to be overcome by novel drugs. Investigations are moving towards more targeted treatments including immunotherapy and cell-based approaches. AREAS COVERED This article reviews emerging drugs in clinical development for metastatic PDAC, focusing on cellular therapies and novel treatments targeting metabolism, tumor stroma, oncogenic pathways and immunosuppression. With immunotherapy and CAR T cell therapy on the rise in hematological malignancies, the transfer to solid tumors remains intriguing. Multiple exciting clinical trials investigating innovative therapeutic strategies for PDAC are currently ongoing and reviewed herein. ClinicalTrials.gov, conference abstracts and PubMed were searched in August 2021 and assessed for information on ongoing and published clinical studies. EXPERT OPINION With many challenges to overcome, the optimal therapy for patients with metastatic PDAC is likely to consist of a combination of different agents. We are slowly moving from entity-dependent approaches to ones more focused on molecular and pathological features. Increasingly personalized treatment plans tailored to each patient may be the future of PDAC therapy.
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Affiliation(s)
- Klara Dorman
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Volker Heinemann
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Sebastian Kobold
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.,Center for Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Stefan Boeck
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
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13
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Phillips MC, Mousa SA. Clinical application of nano-targeting for enhancing chemotherapeutic efficacy and safety in cancer management. Nanomedicine (Lond) 2022; 17:405-421. [PMID: 35118878 DOI: 10.2217/nnm-2021-0361] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Despite improvements in treatment, cancer remains a leading cause of death worldwide. While chemotherapy is effective, it also damages healthy tissue, leading to severe, dose-limiting side effects that can impair efficacy and even contribute to chemoresistance. Nano-based drug-delivery systems can potentially target the delivery of chemotherapy to improve efficacy and reduce adverse effects. A number of nanocarriers have been investigated for the delivery of chemotherapy, and many of the most promising agents have advanced to clinical trials. This review examines the safety and efficacy of nanoformulated chemotherapeutic agents in clinical trials, with particular emphasis on anthracyclines, taxanes and platinum compounds. It also briefly discusses the role nano-targeting might play in the prevention and treatment of chemoresistance.
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Affiliation(s)
- Matthew C Phillips
- Pharmaceutical Research Institute, Albany College of Pharmacy & Health Sciences, Rensselaer, NY 12144, USA
| | - Shaker A Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy & Health Sciences, Rensselaer, NY 12144, USA
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14
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Costoya J, Surnar B, Kalathil AA, Kolishetti N, Dhar S. Controlled release nanoplatforms for three commonly used chemotherapeutics. Mol Aspects Med 2022; 83:101043. [PMID: 34920863 PMCID: PMC10074549 DOI: 10.1016/j.mam.2021.101043] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 12/11/2022]
Abstract
In order to combat an evolving, multidimensional disease such as cancer, research has been aimed at synthesizing more efficient and effective versions of popular chemotherapeutic drugs. Despite these efforts, there remains a necessity for the development of suitable delivery vehicles that can both harness the chemotherapeutic effects meanwhile reducing some of the known issues when using these drugs such as unwanted side-effects, acquired drug resistance, and associated difficulties with drug delivery. Synthetic drug discovery approaches focusing on modification of the native structure of these chemotherapeutic drugs often face challenges such as loss of efficacy, as well as a potential worsening of side-effects. Synthetic chemists are then left with increasingly narrow choices for possible chemistry they could implement to achieve the desired therapy. The emergence of targeted therapies using controlled-release nanomaterials can provide many opportunities for conventional chemotherapeutic drugs to be delivered to specific target sites, ultimately leading to reduced side-effects and improved efficacy. Logically, it may prove advantageous to consider nano-delivery systems as a likely candidate for circumventing some of the barriers associated with creating viable drug therapies. In this review, we summarize controlled release nanoformulations of the three most widely used and approved chemotherapeutics, doxorubicin, paclitaxel, and cisplatin as an alternative therapeutic approach against different cancer types.
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Affiliation(s)
- Joel Costoya
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Bapurao Surnar
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Akil A Kalathil
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Nagesh Kolishetti
- Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Shanta Dhar
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
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15
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Wang W, Joyce P, Bremmell K, Milne R, Prestidge CA. Liposomal 5-Fluorouracil Polymer Complexes Facilitate Tumor-Specific Delivery: Pharmaco-Distribution Kinetics Using Microdialysis. Pharmaceutics 2022; 14:pharmaceutics14020221. [PMID: 35213954 PMCID: PMC8878722 DOI: 10.3390/pharmaceutics14020221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 02/04/2023] Open
Abstract
Liposomes are widely used as carriers for anticancer drugs due to their ability to prolong the retention of encapsulated drugs in blood plasma while directing their distribution increasingly into tumor tissue. We report on the development of stealth liposomal formulations for the common chemotherapy drug 5-fluorouracil, where pharmacokinetic studies were undertaken using a microdialysis probe to specifically quantify drug accumulation in tumor, which was contrasted to drug exposure to healthy tissue. Greater accumulation of the drug into the tumor than into healthy subcutaneous tissue was observed for neutral and cationic liposomal 5-fluorouracil polymer complexes in comparison to the conventional delivery by an injected solution. Increased drug accumulation in tumor also correlated to reduced tumor growth. This research has generated new mechanistic insight into liposomal-specific delivery to tumors with potential to improve the efficacy and reduce the toxicity of chemotherapy.
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16
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Ahmed Khalil A, Rauf A, Alhumaydhi FA, Aljohani ASM, Javed MS, Khan MA, Khan IA, El-Esawi MA, Bawazeer S, Bouyahya A, Rebezov M, Shariati MA, Thiruvengadam M. Recent Developments and Anticancer Therapeutics of Paclitaxel: An Update. Curr Pharm Des 2022; 28:3363-3373. [PMID: 36330627 DOI: 10.2174/1381612829666221102155212] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/06/2022]
Abstract
Plants are a source of diverse classes of secondary metabolites with anticancer properties. Paclitaxel (Taxol) is an anticancer drug isolated from various Taxus species and is used as a chemotherapeutic agent against various cancers. The biosynthesis of paclitaxel is a complex pathway, making its total chemical synthesis commercially non-viable; hence, alternative novel sources - like plant cell culture and heterologous expression systems, are being investigated to overcome this issue. Advancements in the field of genetic engineering, microbial fermentation engineering, and recombinant techniques have significantly increased the achievable yields of paclitaxel. Indeed, paclitaxel selectively targets microtubules and causes cell cycle arrest in the G2/M phase, inducing a cytotoxic effect in a concentration and time-dependent manner. Innovative drug delivery formulations, like the development of albumin-bound nanoparticles, nano-emulsions, nano-suspensions, liposomes, and polymeric micelles, have been applied to enhance the delivery of paclitaxel to tumor cells. This review focuses on the production, biosynthesis, mechanism of action, and anticancer effects of paclitaxel.
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Affiliation(s)
- Anees Ahmed Khalil
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Pakistan
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar-23561, K.P.K, Pakistan
| | - Fahad A Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Abdullah S M Aljohani
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Muhammad Sameem Javed
- Institute of Food Science and Nutrition, Bahauddin Zakariya University, Multan, Pakistan
| | | | - Imtiaz Ali Khan
- Department of Entomology, University of Peshawar, KP, Pakistan
| | - Mohamed A El-Esawi
- Botany Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Sami Bawazeer
- Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University, Makkah, P.O. Box 42, Saudi Arabia
| | - Abdelhakim Bouyahya
- Department of Biology, Laboratory of Human Pathologies Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, 10106 Morocco
| | - Maksim Rebezov
- V.M. Gorbatov Federal Research Center for Food Systems of Russian Academy of Sciences, Moscow, Russian Federation
- Prokhorov General Physics Institute, Russian Academy of Sciences, Moscow, Russian Federation
| | - Mohammad Ali Shariati
- K.G. Razumovsky Moscow State University of Technologies and management (the First Cossack University), Moscow, Russian Federation
| | - Muthu Thiruvengadam
- Department of Applied Bioscience, College of Life and Environmental Sciences, Konkuk University, Seoul 05029, South Korea
- Department of Microbiology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 600077, India
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17
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Ali N, Srivastava N. Recent Advancements for the Management of Pancreatic Cancer: Current Insights. CURRENT CANCER THERAPY REVIEWS 2021. [DOI: 10.2174/1573394717666210625153256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
One of the most fatal forms of cancer includes cancer of the pancreas And the most
rapid malignancy is observed in PDAC (pancreatic ductal adenocarcinoma). The high lethality rate
is generally due to very late diagnosis and resistance to traditional chemotherapeutic agents. Desmoplastic
stromal barrier results in resistance to immunotherapy. Other reasons for the high lethality
rate include the absence of effective treatment and standard screening tests. Hence, there is a
need for effective novel carrier systems. “A formulation, method, or device that allows the desired
therapeutic substance to reach its site of action in such a manner that nontarget cells experience
minimum effect is referred to as a drug delivery system”. The delivery system is responsible for introducing
the active component into the body. They are also liable for boosting the efficacy and desirable
targeted action on the tumorous tissues. Several studies, researches, and developments have
yielded various advanced drug delivery systems, which include liposomes, nanoparticles, carbon
nanotubules, renovoCath, etc. These systems control rate and location of the release. They are designed
while taking into consideration characteristic properties of the tumor and tumor stroma. These
delivery systems overcome the barriers in drug deliverance in pancreatic cancer. Alongside providing
palliative benefits, these delivery systems also aim to correct the underlying reason for the
defect. The following review article aims and focuses to bring out a brief idea about systems, methods,
and technologies for futuristic drug deliverance in pancreatic cancer therapy.
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Affiliation(s)
- Naureen Ali
- Amity Institute of Pharmacy, Amity University, Uttar Pradesh, Lucknow Campus, Lucknow,India
| | - Nimisha Srivastava
- Amity Institute of Pharmacy, Amity University, Uttar Pradesh, Lucknow Campus, Lucknow,India
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18
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Allahou LW, Madani SY, Seifalian A. Investigating the Application of Liposomes as Drug Delivery Systems for the Diagnosis and Treatment of Cancer. Int J Biomater 2021; 2021:3041969. [PMID: 34512761 PMCID: PMC8426107 DOI: 10.1155/2021/3041969] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/15/2021] [Accepted: 08/23/2021] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy is the routine treatment for cancer despite the poor efficacy and associated off-target toxicity. Furthermore, therapeutic doses of chemotherapeutic agents are limited due to their lack of tissue specificity. Various developments in nanotechnology have been applied to medicine with the aim of enhancing the drug delivery of chemotherapeutic agents. One of the successful developments includes nanoparticles which are particles that range between 1 and 100 nm that may be utilized as drug delivery systems for the treatment and diagnosis of cancer as they overcome the issues associated with chemotherapy; they are highly efficacious and cause fewer side effects on healthy tissues. Other nanotechnological developments include organic nanocarriers such as liposomes which are a type of nanoparticle, although they can deviate from the standard size range of nanoparticles as they may be several hundred nanometres in size. Liposomes are small artificial spherical vesicles ranging between 30 nm and several micrometres and contain one or more concentric lipid bilayers encapsulating an aqueous core that can entrap both hydrophilic and hydrophobic drugs. Liposomes are biocompatible and low in toxicity and can be utilized to encapsulate and facilitate the intracellular delivery of chemotherapeutic agents as they are biodegradable and have reduced systemic toxicity compared with free drugs. Liposomes may be modified with PEG chains to prolong blood circulation and enable passive targeting. Grafting of targeting ligands on liposomes enables active targeting of anticancer drugs to tumour sites. In this review, we shall explore the properties of liposomes as drug delivery systems for the treatment and diagnosis of cancer. Moreover, we shall discuss the various synthesis and functionalization techniques associated with liposomes including their drug delivery, current clinical applications, and toxicology.
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Affiliation(s)
- Latifa W. Allahou
- School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK
| | - Seyed Yazdan Madani
- School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK
- School of Pharmacy, University of Nottingham Malaysia, Semenyih, Selangor, Malaysia
| | - Alexander Seifalian
- Nanotechnology and Regenerative Medicine Commercialisation Centre (NanoRegMed Ltd.) London BioScience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
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19
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Subhan MA, Yalamarty SSK, Filipczak N, Parveen F, Torchilin VP. Recent Advances in Tumor Targeting via EPR Effect for Cancer Treatment. J Pers Med 2021; 11:571. [PMID: 34207137 PMCID: PMC8234032 DOI: 10.3390/jpm11060571] [Citation(s) in RCA: 262] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer causes the second-highest rate of death world-wide. A major shortcoming inherent in most of anticancer drugs is their lack of tumor selectivity. Nanodrugs for cancer therapy administered intravenously escape renal clearance, are unable to penetrate through tight endothelial junctions of normal blood vessels and remain at a high level in plasma. Over time, the concentration of nanodrugs builds up in tumors due to the EPR effect, reaching several times higher than that of plasma due to the lack of lymphatic drainage. This review will address in detail the progress and prospects of tumor-targeting via EPR effect for cancer therapy.
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, Shah Jalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Satya Siva Kishan Yalamarty
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
| | - Nina Filipczak
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
| | - Farzana Parveen
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
- Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Punjab 63100, Pakistan
| | - Vladimir P. Torchilin
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
- Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
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20
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Petrini M, Lokerse WJM, Mach A, Hossann M, Merkel OM, Lindner LH. Effects of Surface Charge, PEGylation and Functionalization with Dipalmitoylphosphatidyldiglycerol on Liposome-Cell Interactions and Local Drug Delivery to Solid Tumors via Thermosensitive Liposomes. Int J Nanomedicine 2021; 16:4045-4061. [PMID: 34163158 PMCID: PMC8214027 DOI: 10.2147/ijn.s305106] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/24/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Previous studies demonstrated the possibility of targeting tumor-angiogenic endothelial cells with positively charged nanocarriers, such as cationic liposomes. We investigated the active targeting potential of positively charged nanoparticles in combination with the heat-induced drug release function of thermosensitive liposomes (TSL). This novel dual-targeted approach via cationic TSL (CTSL) was thoroughly explored using either a novel synthetic phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2) or a conventional polyethylene glycol (PEG) surface modification. Anionic particles containing either DPPG2 or PEG were also included in the study to highlight difference in tumor enrichment driven by surface charge. With this study, we aim to provide a deep insight into the main differences between DPPG2- and PEG-functionalized liposomes, focusing on the delivery of a well-known cytotoxic drug (doxorubicin; DOX) in combination with local hyperthermia (HT, 41–43°C). Materials and Methods DPPG2- and PEG-based cationic TSLs (PG2-CTSL/PEG-CTSL) were thoroughly analyzed for size, surface charge, and heat-triggered DOX release. Cancer cell targeting and DOX delivery was evaluated by FACS, fluorescence imaging, and HPLC. In vivo particle behavior was analyzed by assessing DOX biodistribution with local HT application in tumor-bearing animals. Results The absence of PEG in PG2-CTSL promoted more efficient liposome–cell interactions, resulting in a higher DOX delivery and cancer cell toxicity compared with PEG-CTSL. By exploiting the dual-targeting function of CTSLs, we were able to selectively trigger DOX release in the intracellular compartment by HT. When tested in vivo, local HT promoted an increase in intratumoral DOX levels for all (C)TSLs tested, with DOX enrichment factors ranging from 3 to 14-fold depending on the type of formulation. Conclusion Cationic particles showed lower hemocompatibility than their anionic counterparts, which was partially mitigated when PEG was grafted on the liposome surface. DPPG2-based anionic TSL showed optimal local drug delivery compared to all other formulations tested, demonstrating the potential advantages of using DPPG2 lipid in designing liposomes for tumor-targeted applications.
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Affiliation(s)
- Matteo Petrini
- Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich, Germany.,Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilian University, Munich, Germany
| | - Wouter J M Lokerse
- Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich, Germany
| | - Agnieszka Mach
- Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich, Germany
| | | | - Olivia M Merkel
- Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilian University, Munich, Germany
| | - Lars H Lindner
- Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich, Germany
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21
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Rachamalla HK, Bhattacharya S, Ahmad A, Sridharan K, Madamsetty VS, Mondal SK, Wang E, Dutta SK, Jan BL, Jinka S, Chandra Sekhar Jaggarapu MM, Yakati V, Mukhopadhyay D, Alkharfy KM, Banerjee R. Enriched pharmacokinetic behavior and antitumor efficacy of thymoquinone by liposomal delivery. Nanomedicine (Lond) 2021; 16:641-656. [PMID: 33769068 DOI: 10.2217/nnm-2020-0470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: Thymoquinone (TQ) has potential anti-inflammatory, immunomodulatory and anticancer effects but its clinical use is limited by its low solubility, poor bioavailability and rapid clearance. Aim: To enhance systemic bioavailability and tumor-specific toxicity of TQ. Materials & methods: Cationic liposomal formulation of TQ (D1T) was prepared via ethanol injection method and their physicochemical properties, anticancer effects in orthotopic xenograft pancreatic tumor model and pharmacokinetic behavior of D1T relative to TQ were evaluated. Results: D1T showed prominent inhibition of pancreatic tumor progression, significantly greater in vivo absorption, approximately 1.5-fold higher plasma concentration, higher bioavailability, reduced volume of distribution and improved clearance relative to TQ. Conclusion: Encapsulation of TQ in cationic liposomal formulation enhanced its bioavailability and anticancer efficacy against xenograft pancreatic tumor.
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Affiliation(s)
- Hari Krishnareddy Rachamalla
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, Telangana 500007, India
| | - Santanu Bhattacharya
- Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA.,Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kathyayani Sridharan
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, Telangana 500007, India
| | - Vijay Sagar Madamsetty
- Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA
| | - Sujan Kumar Mondal
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.,UPMC Hilman Cancer Center, Pittsburgh, PA 15232, USA
| | - Enfeng Wang
- Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA
| | - Shamit K Dutta
- Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA
| | - Basit L Jan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sudhakar Jinka
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, Telangana 500007, India
| | | | - Venu Yakati
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, Telangana 500007, India
| | - Debabrata Mukhopadhyay
- Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA.,Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine & Science, Jacksonville, FL, USA
| | - Khalid M Alkharfy
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Rajkumar Banerjee
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, Telangana 500007, India
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22
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Zhang Z, Song J, Xie C, Pan J, Lu W, Liu M. Pancreatic Cancer: Recent Progress of Drugs in Clinical Trials. AAPS JOURNAL 2021; 23:29. [PMID: 33580411 DOI: 10.1208/s12248-021-00556-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 01/06/2021] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer is a highly malignant tumor and one of the primary causes of cancer-related death. Because pancreatic cancer is difficult to diagnose in the early course of the disease, most patients present with advanced lesions at the time of diagnosis, and only 20% of patients are eligible for surgery. Consequently, drug treatment has become extremely important. At present, the main treatment regimens for pancreatic cancer are gemcitabine and the FORFIRINOX and MPACT regimens. However, none of these regimens substantially improves the prognosis of patients with pancreatic cancer. Extensive efforts have been dedicated to the study of pancreatic cancer in recent years. With the development and clinical application of biological targeted drugs, the biological targeted treatment of tumors has been widely accepted. Therefore, this article used relevant clinical trial data to summarize the research progress of traditional chemotherapy drugs and biological targeted drugs for the treatment of pancreatic cancer.
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Affiliation(s)
- Zhiyi Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Jie Song
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Cao Xie
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Jun Pan
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Weiyue Lu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Min Liu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China.
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23
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Yeh C, Bates SE. Two decades of research toward the treatment of locally advanced and metastatic pancreatic cancer: Remarkable effort and limited gain. Semin Oncol 2021; 48:34-46. [PMID: 33712267 DOI: 10.1053/j.seminoncol.2021.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/20/2021] [Indexed: 01/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is diagnosed at the locally advanced or metastatic stage in approximately 80% of cases. Relative to other tumor types, progress in the treatment of this disease has been painfully slow. While agents targeting DNA repair have proven successful in a subset of patients, the majority of PDACs do not exhibit validated molecular targets. Hence, conventional chemotherapy remains at the forefront of therapy for this disease. In this review, we study two decades of efforts to improve upon the gemcitabine backbone - 67 phase II and III trials enrolling 16,446 patients - that culminated in the approvals of gemcitabine/nab-paclitaxel (Gem/NabP) and FOLFIRINOX. Today, these remain gold standards for the first-line treatment of locally advanced unresectable and metastatic PDAC, while ongoing efforts focus on improving upon the Gem/NabP backbone. Because real world data often do not reflect the data of randomized controlled trials (RCTs), we also summarize the retrospective evidence comparing the efficacy of Gem/NabP and FOLFIRINOX in the first-line setting - 29 studies reporting a median overall survival of 10.7 and 9.1 months for FOLFIRINOX and Gem/NabP, respectively. These values are surprisingly comparable to those reported by the pivotal RCTs at 11.1 and 8.5 months. Finally, there is a paucity of RCT data regarding the efficacy of second-line therapy. Hence, we conclude this review by summarizing the data that ultimately demonstrate a small but significant survival benefit of second-line therapy with Gem/NabP or FOLFIRINOX. Collectively, these studies describe the long journey, the steady effort, and the myriad lessons to be learned from 20 years of PDAC trials to inform strategies for success in clinical trials moving forward.
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Affiliation(s)
- Celine Yeh
- Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Susan E Bates
- James J. Peters VA Medical Center, Bronx, NY; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY.
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24
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Lambert A, Conroy T, Ducreux M. Future directions in drug development in pancreatic cancer. Semin Oncol 2021; 48:47-56. [PMID: 33674067 DOI: 10.1053/j.seminoncol.2021.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is still one of the most lethal cancers with a reported 5-year relative survival rate of approximatively 9% and medical treatment remains a major challenge. Systemic treatment is recommended in every setting: resectable, borderline resectable, locally advanced and metastatic. Yet, few groundbreaking changes in practice have occurred in the last 30 years compared to other cancers and new treatments options are highly desirable. Most treatment approaches using chemotherapy have failed to improve patients' life expectancy and the few therapies finally found to have statistically significant benefit actually have modest clinical impact. It is becoming imperative to find new paths for improvement, such as encapsulated agents, new generation targeted therapies and treatments directed against the tumor microenvironment. We report here the new drugs of interest in pancreatic cancer and analyze the most recent failures.
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Affiliation(s)
- Aurélien Lambert
- Medical Oncology Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; Université de Lorraine, Nancy, France.
| | - Thierry Conroy
- Medical Oncology Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; Université de Lorraine, Nancy, France
| | - Michel Ducreux
- Gastrointestinal Oncology Department, Gustave Roussy, Villejuif, France; Université Paris-Saclay, Saint-Aubin, France
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25
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Mi P, Miyata K, Kataoka K, Cabral H. Clinical Translation of Self‐Assembled Cancer Nanomedicines. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000159] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Peng Mi
- Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center West China Hospital, Sichuan University No. 17 People's South Road Chengdu 610041 China
| | - Kanjiro Miyata
- Department of Materials Engineering, Graduate School of Engineering The University of Tokyo 7‐3‐1 Hongo, Bunkyo‐ku Tokyo 113‐8656 Japan
| | - Kazunori Kataoka
- Institute for Future Initiatives The University of Tokyo 7‐3‐1 Hongo, Bunkyo‐ku Tokyo 113‐0033 Japan
- Innovation Center of NanoMedicine Kawasaki Institute of Industrial Promotion 3‐25‐14, Tonomachi, Kawasaki‐ku Kawasaki 210‐0821 Japan
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering The University of Tokyo 7‐3‐1 Hongo, Bunkyo‐ku Tokyo 113‐8656 Japan
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26
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Katayama ES, Hue JJ, Bajor DL, Ocuin LM, Ammori JB, Hardacre JM, Winter JM. A comprehensive analysis of clinical trials in pancreatic cancer: what is coming down the pike? Oncotarget 2020; 11:3489-3501. [PMID: 33014285 PMCID: PMC7517959 DOI: 10.18632/oncotarget.27727] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Pancreatic cancer is the most aggressive common cancer and is desperately in need of novel therapies. Unlike many other common cancers, there have been no new paradigm-changing therapies in the past 40 years beyond multi-agent chemotherapy. In this study, we perform the first comprehensive analysis of the current clinical trial landscape in pancreatic cancer to better understand the pipeline of new therapies. MATERIALS AND METHODS We queried https://clinicaltrials.gov/ for registered pancreatic cancer clinical trials. Studies were curated and categorized according to phase of study, clinical stage of the study population, type of the intervention under investigation, and biologic mechanism targeted by the therapy under study. RESULTS As of May 18, 2019, there were 430 total active therapeutic interventional trials testing 590 interventions. The vast minority of trials (n = 37, 8.6%) are in phase III testing. 189 (31%) interventions are immunotherapies, 69 (11%) target cell signaling pathways, 154 (26%) target cell cycle or DNA biology, and 35 (6%) target metabolic pathways. Of the late phase trials, only 14 are currently testing novel interventions. Rather, 23 phase III trials examine new ways to deliver existing FDA-approved drugs, procedures, or pain management. CONCLUSIONS A large number of novel therapeutic strategies are currently under investigation. They include a broad range of therapies targeting diverse biologic processes. However, only a small number of novel therapies are in late-stage testing, suggesting that future progress is likely several years away, and dependent on the success of early-stage trials.
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Affiliation(s)
- Erryk S Katayama
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Jonathan J Hue
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Surgery, University Hospitals Seidman Cancer Center and Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - David L Bajor
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Division of Hematology and Oncology, University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA
| | - Lee M Ocuin
- Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina, USA
| | - John B Ammori
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Surgery, University Hospitals Seidman Cancer Center and Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Jeffrey M Hardacre
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Surgery, University Hospitals Seidman Cancer Center and Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Jordan M Winter
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Surgery, University Hospitals Seidman Cancer Center and Case Comprehensive Cancer Center, Cleveland, Ohio, USA
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27
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Young CC, Vedadghavami A, Bajpayee AG. Bioelectricity for Drug Delivery: The Promise of Cationic Therapeutics. Bioelectricity 2020; 2:68-81. [PMID: 32803148 DOI: 10.1089/bioe.2020.0012] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Biological systems overwhelmingly comprise charged entities generating electrical activity that can have significant impact on biological structure and function. This intrinsic bio-electrical activity can also be harnessed for overcoming the tissue matrix and cell membrane barriers, which have been outstanding challenges for targeted drug delivery, by using rationally designed cationic carriers. The weak and reversible long-range electrostatic interactions with fixed negatively charged groups facilitate electro-diffusive transport of cationic therapeutics through full-tissue thickness to effectively reach intra-tissue, cellular, and intracellular target sites. This article presents a perspective on the promise of using rationally designed cationic biomaterials in targeted drug delivery, the underlying charge-based mechanisms, and bio-transport phenomena while addressing outstanding concerns around toxicity and methods to mitigate them. We also discuss electrically charged drugs that are currently being evaluated in clinical trials and identify areas of further development that have the potential to usher in new treatments.
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Affiliation(s)
- Cameron C Young
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts, USA
| | - Armin Vedadghavami
- Department of Bioengineering, Northeastern University, Boston, Massachusetts, USA
| | - Ambika G Bajpayee
- Department of Bioengineering, Northeastern University, Boston, Massachusetts, USA.,Department of Mechanical and Industrial Engineering, Northeastern University, Boston, Massachusetts, USA
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28
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Beltrán-Gracia E, López-Camacho A, Higuera-Ciapara I, Velázquez-Fernández JB, Vallejo-Cardona AA. Nanomedicine review: clinical developments in liposomal applications. Cancer Nanotechnol 2019. [DOI: 10.1186/s12645-019-0055-y] [Citation(s) in RCA: 286] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Abstract
Background
In recent years, disease treatment has evolved strategies that require increase in pharmaceutical agent’s efficacy and selectivity while decreasing their toxicity in normal tissues. These requirements have led to the development of nanoscale liposome systems for drug release. This review focuses on lipid features, pharmacological properties of liposomal formulations and the clinical studies of their application.
Main body
Several lipids are available, but their properties could affect pharmacological or clinical efficiency of drug formulations. Many liposomal formulations have been developed and are currently on the market. Proper selection of lipid is essential for the pharmacological effect to be improved. Most of the formulations use mainly zwitterionic, cationic or anionic lipids, PEG and/or cholesterol, which have different effects on stability, pharmacokinetics and delivery of the drug formulation. Clinical trials have shown that liposomes are pharmacologically and pharmacokinetically more efficient than drug-alone formulations in treating acute myeloid leukemia, hepatitis A, pain management, ovary, gastric breast and lung cancer, among others.
Conclusion
Liposomal formulations are less toxic than drugs alone and have better pharmacological parameters. Although they seem to be the first choice for drug delivery systems for various diseases, further research about dosage regimen regarding dose and time needs to be carried out.
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29
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Network Meta-Analysis of Efficacy and Safety of Chemotherapy and Target Therapy in the First-Line Setting of Advanced Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11111746. [PMID: 31703359 PMCID: PMC6895788 DOI: 10.3390/cancers11111746] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/29/2019] [Accepted: 11/02/2019] [Indexed: 12/13/2022] Open
Abstract
Both gemcitabine and fluoropyrimidine are recommended backbones in the first-line treatment of pancreatic ductal adenocarcinoma (PDAC). To compare the efficacy and safety of these two therapeutic backbones, and to investigate the optimal therapies, we conducted a network meta-analysis. By retrospective analysis of randomized controlled trials (RCT), the most preferred therapeutic regimen may be predicted. The eligible RCTs of the gemcitabine-based therapies and fluoropyrimidine-based therapies were searched up to 31 August 2019. In a frequentist network meta-analysis, treatments were compared and ranked according to overall survival (OS) and progression-free survival (PFS). Thirty-two trials with 10,729 patients were included. The network meta-analyses results for overall survival and progression-free survival showed that fluoropyrimidine-based therapy seems to be the most effective treatment choice. Compared to gemcitabine combined with taxanes or immunotherapy, fluoropyrimidine-based therapy had comparable treatment effects (PFS: 0.67, p-Value = 0.11; 0.76, p-Value = 0.32; OS: 0.80, p-Value = 0.16; 0.77, p-Value = 0.21). Moreover, the combination of immunotherapy and gemcitabine had tolerable toxicities. Based on current evidence, fluoropyrimidine-based therapies and the combination of gemcitabine and taxanes were the most effective therapies in the advanced pancreatic cancer, and the combination of immunotherapy and gemcitabine can be developed into a new form of therapy.
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30
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Abstract
OBJECTIVES We evaluated how well phase II trials in locally advanced and metastatic pancreatic cancer (LAMPC) meet current recommendations for trial design. METHODS We conducted a systematic review of phase II first-line treatment trial for LAMPC. We assessed baseline characteristics, type of comparison, and primary end point to examine adherence to the National Cancer Institute recommendations for trial design. RESULTS We identified 148 studies (180 treatment arms, 7505 participants). Forty-seven (32%) studies adhered to none of the 5 evaluated National Cancer Institute recommendations, 62 (42%) followed 1, 31 (21%) followed 2, and 8 (5%) followed 3 recommendations. Studies varied with respect to the proportion of patients with good performance status (range, 0%-80%) and locally advanced disease (range, 14%-100%). Eighty-two (55%) studies concluded that investigational agents should progress to phase III testing; of these, 24 (16%) had documented phase III trials. Three (8%) phase III trials demonstrated clinically meaningful improvements for investigational agents. One of 38 phase II trials that investigated biological investigational agents was enriched for a biomarker. CONCLUSIONS Phase II trials do not conform well to current recommendations for trial design in LAMPC.
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31
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Lu Z, Weniger M, Jiang K, Boeck S, Zhang K, Bazhin A, Miao Y, Werner J, D'Haese JG. Therapies Targeting the Tumor Stroma and the VEGF/VEGFR Axis in Pancreatic Ductal Adenocarcinoma: a Systematic Review and Meta-Analysis. Target Oncol 2019; 13:447-459. [PMID: 30062609 DOI: 10.1007/s11523-018-0578-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Abundant tumor stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and is suggested to play a role in the resistance of this deadly disease to systemic treatment. Despite promising results from preclinical studies, clinical trials with therapies targeting the tumor stroma and the vascular endothelial growth factor (VEGF) and its receptor VEGFR yielded conflicting results. With this systematic review and meta-analysis, we aim to summarize the existing evidence in this important field with a special focus on anti-VEGF/VEGFR therapy. A total of 24 clinical studies were included in the qualitative synthesis, and six randomized controlled trials (RCTs) investigating anti-VEGF/VEGFR agents were further included in the quantitative synthesis. The qualitative synthesis revealed a treatment advantage of combined therapy with nab-paclitaxel, while the meta-analysis on anti-VEGF/VEGFR drugs demonstrated marginal improvement of objective response rates and progression-free survival, but not overall survival. Stroma targeting is a promising and rapidly-developing treatment strategy in PDAC. However, novel drugs balancing stroma depletion and modulation are needed.
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Affiliation(s)
- Zipeng Lu
- Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
- Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany
| | - Maximilian Weniger
- Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany
| | - Kuirong Jiang
- Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Stefan Boeck
- Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Kai Zhang
- Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Alexander Bazhin
- Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany
| | - Yi Miao
- Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Jens Werner
- Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany
| | - Jan G D'Haese
- Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany
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32
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Xu CF, Iqbal S, Shen S, Luo YL, Yang X, Wang J. Development of "CLAN" Nanomedicine for Nucleic Acid Therapeutics. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1900055. [PMID: 30884095 DOI: 10.1002/smll.201900055] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 02/19/2019] [Indexed: 05/17/2023]
Abstract
Nucleic acid-based macromolecules have paved new avenues for the development of therapeutic interventions against a spectrum of diseases; however, their clinical translation is limited by successful delivery to the target site and cells. Therefore, numerous systems have been developed to overcome delivery challenges to nucleic acids. From the viewpoint of clinical translation, it is highly desirable to develop systems with clinically validated materials and controllability in synthesis. With this in mind, a cationic lipid assisted PEG-b-PLA nanoparticle (CLAN) is designed that is capable of protecting nucleic acids via encapsulation inside the aqueous core, and delivers them to target cells, while maintaining or improving nucleic acid function. The system is formulated from clinically validated components (PEG-b-PLA and its derivatives) and can be scaled-up for large scale manufacturing, offering potential for its future use in clinical applications. Here, the development and working mechanisms of CLANs, the ways to improve its delivery efficacy, and its application in various disease treatments are summarized. Finally, a prospective for the further development of CLAN is also discussed.
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Affiliation(s)
- Cong-Fei Xu
- Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangdong, 510006, Guangzhou, China
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510006, P. R. China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, P. R. China
- Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, P. R. China
| | - Shoaib Iqbal
- School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
| | - Song Shen
- Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangdong, Guangzhou, 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, 510006, P. R. China
| | - Ying-Li Luo
- Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangdong, 510006, Guangzhou, China
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510006, P. R. China
| | - Xianzhu Yang
- Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangdong, Guangzhou, 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, 510006, P. R. China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China
| | - Jun Wang
- Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangdong, 510006, Guangzhou, China
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510006, P. R. China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, P. R. China
- Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, P. R. China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China
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33
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Zhang S, Xie W, Zou Y, Xie S, Zhang J, Yuan W, Ma J, Zhao J, Zheng C, Chen Y, Wang C. First-line chemotherapy regimens for locally advanced and metastatic pancreatic adenocarcinoma: a Bayesian analysis. Cancer Manag Res 2018; 10:5965-5978. [PMID: 30538546 PMCID: PMC6254987 DOI: 10.2147/cmar.s162980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Background Systemic chemotherapy is the standard treatment for locally advanced and metastatic pancreatic cancer, but there is no consensus on the optimum regimen. We aimed to compare and rank the locally advanced and metastatic pancreatic adenocarcinoma chemotherapy regimens evaluated in randomized controlled trials (RCTs) in the past 15 years. Materials and methods PubMed, Embase, Cochrane Collaboration database, and ClinicalTrials.gov were searched for RCTs comparing chemotherapy regimens as first-line treatment for locally advanced and metastatic pancreatic adenocarcinomas. By using Bayesian network meta-analysis, we compared and ranked all included chemotherapy regimens in terms of overall survival, progression-free survival, response rate, and hematological toxicity. Results The analysis included 68 RCTs, with 14,908 patients and 63 treatment strategies. For overall survival, NSC-631570 (hazard ratio [HR] vs gemcitabine monotherapy 0.44, 95% credible interval: 0.24–0.76) and gemcitabine+NSC-631570 (HR 0.45, 0.24–0.86) were the two top-ranked chemotherapy regimens. For progression-free survival, PEFG (cisplatin + epirubicin + fluorouracil + gemcitabine) ranked first (HR 0.51, 0.34–0.77). PG (gemcitabine + pemetrexed) (odds ratio [OR] 4.68, 2.24–9.64) and FLEC (fluorouracil + leucovorin + epirubicin + carboplatin) (OR 4.52, 1.14–24.00) were ranked the most hematologically toxic, with gastrazole having the least toxicity (OR 0.03, 0.00–0.46). Conclusion The chemotherapy regimens NSC-631570 and gemcitabine+NSC-631570 were ranked the most efficacious for locally advanced and metastatic pancreatic adenocarcinomas in terms of overall survival, which warrants further confirmation in large-scale RCTs.
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Affiliation(s)
- Shuisheng Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ; .,Department of General Surgery, Peking University Third Hospital
| | - Weimin Xie
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital
| | - Yinghua Zou
- Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital
| | - Shuanghua Xie
- Department of Cancer Epidemiology and Health Statistics
| | - Jianwei Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| | - Wei Yuan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Clinical Immunology Center, Chinese Academy of Medical Science
| | - Jie Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Clinical Immunology Center, Chinese Academy of Medical Science.,Department of Biotherapy, Beijing Hospital, National Center of Gerontology, Beijing
| | - Jiuda Zhao
- Department of Medical Oncology, Affiliated Hospital of Qinghai University, Xining
| | - Cuiling Zheng
- Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| | - Chengfeng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
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Malik P, Mukherjee TK. Recent advances in gold and silver nanoparticle based therapies for lung and breast cancers. Int J Pharm 2018; 553:483-509. [DOI: 10.1016/j.ijpharm.2018.10.048] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/20/2018] [Accepted: 10/20/2018] [Indexed: 02/06/2023]
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Nanda B, Manjappa AS, Chuttani K, Balasinor NH, Mishra AK, Ramachandra Murthy RS. Acylated chitosan anchored paclitaxel loaded liposomes: Pharmacokinetic and biodistribution study in Ehrlich ascites tumor bearing mice. Int J Biol Macromol 2018; 122:367-379. [PMID: 30342146 DOI: 10.1016/j.ijbiomac.2018.10.071] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 10/04/2018] [Accepted: 10/14/2018] [Indexed: 10/28/2022]
Abstract
Acylated chitosan (Myristoyl and Octanoyl) coated paclitaxel-loaded liposomal formulation was developed with an aim to overcome the cremophor EL related toxicities. They were evaluated for drug entrapment, in vitro drug release, and cytotoxicity and cell uptake behavior using A549 cells. The 99mTc radio-labeled formulations were also evaluated in vivo in Ehrlich Ascites Tumor (EAT) bearing mice for biodistribution and tumor uptake. The mean particle size of both coated and uncoated liposomal formulations was found to be in the range of 180-200 nm with high drug entrapment efficiency (>90% in case of uncoated liposomes and 80 ± 5% in case of coated liposomes). The uncoated liposomes displayed negative zeta potential (-10.5 ± 4.9 mV) whereas coated liposomes displayed positive zeta potential in the range of +21 to +27 mV. Slower drug release was observed in case of liposomes coated with acylated chitosans as compared to uncoated and native chitosan coated liposomes. All liposomal formulations were found less cytotoxic than paclitaxel injection (Celtax™, Celon Labs, India). In vitro cell uptake and intracellular distribution studies confirmed the cytosolic delivery of uncoated and coated liposomes. The myristoyl chitosan coated liposomal system (LMC) exhibited improved pharmacokinetic, biodistribution and tumor uptake characteristics over other formulations. These obtained results confirmed the potential application of acylated chitosn coated liposomal delivery systems (LMC) in tumor targeting of paclitaxel and other drugs.
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Affiliation(s)
- Biswarup Nanda
- TIFAC Centre of Relevance and Excellence in NDDS, Pharmacy Department, Faculty of Technology & Engineering, The M.S. University of Baroda, Vadodara, India.
| | - A S Manjappa
- TIFAC Centre of Relevance and Excellence in NDDS, Pharmacy Department, Faculty of Technology & Engineering, The M.S. University of Baroda, Vadodara, India; Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur, Maharashtra, India
| | - Krishna Chuttani
- Division of Radiopharmaceuticals & Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, India
| | - N H Balasinor
- Neuroendocrinology Department, National Institute for Research in Reproductive Health (ICMR), Mumbai, India
| | - Anil K Mishra
- Division of Radiopharmaceuticals & Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, India
| | - Rayasa S Ramachandra Murthy
- TIFAC Centre of Relevance and Excellence in NDDS, Pharmacy Department, Faculty of Technology & Engineering, The M.S. University of Baroda, Vadodara, India; Nanomedicine Centre, ISF College of Pharmacy, Moga, Punjab, India
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Mishra DK, Shandilya R, Mishra PK. Lipid based nanocarriers: a translational perspective. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2018; 14:2023-2050. [PMID: 29944981 DOI: 10.1016/j.nano.2018.05.021] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 05/28/2018] [Indexed: 12/11/2022]
Abstract
Over the recent couple of decades, pharmaceutical field has embarked most phenomenal noteworthy achievements in the field of medications as well as drug delivery. The rise of Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic, remedial applications and patient monitoring. The convincing usage of nanotechnology in the conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-liposomal systems has been discussed. Present review deals with the late advances and updates in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical applications alongside commercially available products and products under clinical trials. This exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice for the formulation of pharmaceutical products, the challenges looked by the translational process of lipid-based nanocarriers and the combating methodologies to guarantee the headway of these nanocarriers from bench to bedside.
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Affiliation(s)
- Dinesh K Mishra
- NMIMS, School of Pharmacy & Technology Management, Shirpur (Maharashtra), India.
| | - Ruchita Shandilya
- Department of Molecular Biology ICMR-National Institute for Research in Environmental Health, Bhopal (MP), India
| | - Pradyumna K Mishra
- Department of Molecular Biology ICMR-National Institute for Research in Environmental Health, Bhopal (MP), India
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Ostwal V, Sahu A, Zanwar S, Nayak L, Shrikhande SV, Shetty N, Gupta S, Ramaswamy A. Experience with non-cremophor-based paclitaxel-gemcitabine regimen in advanced pancreatic cancer: Results from a single tertiary cancer centre. Indian J Med Res 2018; 148:284-290. [PMID: 30425218 PMCID: PMC6251278 DOI: 10.4103/ijmr.ijmr_249_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND & OBJECTIVES Gemcitabine combined with non-cremophor-based paclitaxel is one of the standards of care in advanced inoperable pancreatic cancer. This study was undertaken to retrospectively evaluate real world non-trial outcomes with this combination. METHODS Patients with histologically proven advanced inoperable pancreatic adenocarcinoma (PDAC), treated with non-cremophor-based paclitaxel-gemcitabine combination (PG) (gemcitabine-nanoxel or gemcitabine-abraxane) between January 2012 and June 2015, were retrospectively analyzed. Response assessment was done every 8-12 wk with computed tomography scan and responses were measured as per the Response Evaluation Criteria in Solid Tumours 1.1 criteria where feasible. Toxicity was recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS A total of 78 patients with PDAC were treated with the combination. Of these, 83.3 per cent of patients had metastatic disease. The median number of chemotherapy cycles administered was three. The objective response rate for the whole group was 30.8 per cent. Grade III/IV toxicities were seen in 35.9 per cent of patients. Median PFS was 5.6 months and median OS was 11.6 months. INTERPRETATION & CONCLUSIONS Non-cremophor-based paclitaxel in combination with gemcitabine appeared efficacious for advanced pancreatic cancers in routine clinical practice. Within the confines of a single-centre retrospective analysis, gemcitabine-nanoxel and gemcitabine-abraxane appeared to have similar efficacy and toxicity in advanced pancreatic cancers.
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Affiliation(s)
- Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
| | - Arvind Sahu
- Department of Medicine, H. M. Patel Center for Medical Care & Education, Anand, India
| | - Saurabh Zanwar
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
| | - Lingaraj Nayak
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
| | | | - Nitin Shetty
- Department of Interventional Radiology, Tata Memorial Hospital, Mumbai, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
| | - Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
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Chin V, Nagrial A, Sjoquist K, O'Connor CA, Chantrill L, Biankin AV, Scholten RJPM, Yip D, Cochrane Upper GI and Pancreatic Diseases Group. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database Syst Rev 2018; 3:CD011044. [PMID: 29557103 PMCID: PMC6494171 DOI: 10.1002/14651858.cd011044.pub2] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease. OBJECTIVES To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life. SEARCH METHODS We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017. SELECTION CRITERIA All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments. DATA COLLECTION AND ANALYSIS Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study. MAIN RESULTS We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy.We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone.Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing.When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL.We did not find any survival advantages when comparing 5FU combinations to 5FU alone. AUTHORS' CONCLUSIONS Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.
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Affiliation(s)
- Venessa Chin
- Garvan Institute of Medical ResearchThe Kinghorn Cancer Centre384 Victoria Street DarlinghurstSydneyNSWAustralia2010
- St Vincent's HospitalSydneyNSWAustralia
| | - Adnan Nagrial
- Garvan Institute of Medical ResearchThe Kinghorn Cancer Centre384 Victoria Street DarlinghurstSydneyNSWAustralia2010
- The Crown Princess Mary Cancer CentreDarcy RoadWestmeadNSWAustralia2145
| | - Katrin Sjoquist
- University of SydneyNHMRC Clinical Trials CentreK25 ‐ Medical Foundation BuildingSydneyNSWAustralia2006
- Cancer Care Centre, St George HospitalMedical OncologySt George Hospital, Gray StKogarahAustraliaNSW 2217
| | - Chelsie A O'Connor
- St Vincent's HospitalSydneyNSWAustralia
- Genesis Cancer CareSydneyNSWAustralia
- Macquarie University HospitalSydneyAustralia
| | - Lorraine Chantrill
- The Kinghorn Cancer Centre, Garvan Institute of Medical ResearchDepartment of Pancreatic Cancer382 Victoria Street DarlinghurstSydneyNSWAustralia2010
| | - Andrew V Biankin
- University of GlasgowInstitute of Cancer SciencesWolfson Wohl Cancer Research CentreGarscube Estate, Switchback RoadGlasgowUKG61 1QH
- University of New South WalesSouth Western Sydney Clinical School, Faculty of MedicineLiverpoolNSWAustralia2170
- West of Scotland Pancreatic Unit and Glasgow Royal InfirmaryGlasgowUK
| | - Rob JPM Scholten
- Julius Center for Health Sciences and Primary Care / University Medical Center UtrechtCochrane NetherlandsRoom Str. 6.126P.O. Box 85500UtrechtNetherlands3508 GA
| | - Desmond Yip
- The Canberra HospitalDepartment of Medical OncologyYamba DriveGarranACTAustralia2605
- Australian National UniversityANU Medical SchoolActonACTAustralia0200
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Zhang XW, Ma YX, Sun Y, Cao YB, Li Q, Xu CA. Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis. Target Oncol 2018; 12:309-321. [PMID: 28353074 DOI: 10.1007/s11523-017-0486-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC). OBJECTIVE The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single-agent gemcitabine in the first-line treatment of unresectable LA/MPC. METHODS We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016. RESULTS Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine-based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue. CONCLUSIONS Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine-based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC.
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Affiliation(s)
- Xiu-Wei Zhang
- Department of Pathology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Yu-Xiang Ma
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yang Sun
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yu-Bo Cao
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Qin Li
- Center for Translational Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Chong-An Xu
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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Matkar PN, Singh KK, Rudenko D, Kim YJ, Kuliszewski MA, Prud'homme GJ, Hedley DW, Leong-Poi H. Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma. Oncotarget 2018; 7:69489-69506. [PMID: 27542226 PMCID: PMC5342493 DOI: 10.18632/oncotarget.11060] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/18/2016] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness. Endothelial cells have been shown to display cellular plasticity in the form of endothelial-to-mesenchymal transition (EndMT) that serves as an important source of fibroblasts in pathological disorders, including cancer. Angiogenic co-receptor, neuropilin-1 (NRP-1) actively binds TGFβ1, the primary mediator of EndMT and is involved in oncogenic processes like epithelial-to-mesenchymal transition (EMT). NRP-1 and TGFβ1 signaling have been shown to be aberrantly up-regulated in PDAC. We report herein a positive correlation between NRP-1 levels, EndMT and fibrosis in human PDAC xenografts. Loss of NRP-1 in HUVECs limited TGFβ1-induced EndMT as demonstrated by gain of endothelial and loss of mesenchymal markers, while maintaining endothelial cell architecture. Knockdown of NRP-1 down-regulated TGFβ canonical signaling (pSMAD2) and associated pro-fibrotic genes. Overexpression of NRP-1 exacerbated TGFβ1-induced EndMT and up-regulated TGFβ signaling and expression of pro-fibrotic genes. In vivo, loss of NRP-1 attenuated tumor perfusion and size, accompanied by reduction in EndMT and fibrosis. This study defines a previously unrecognized role of NRP-1 in regulating TGFβ1-induced EndMT and fibrosis, and advocates NRP-1 as a therapeutic target to reduce tumor fibrosis and PDAC progression.
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Affiliation(s)
- Pratiek N Matkar
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Krishna Kumar Singh
- Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.,Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Dmitriy Rudenko
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Yu Jin Kim
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Michael A Kuliszewski
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Gerald J Prud'homme
- Division of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - David W Hedley
- Division of Medical Oncology and Hematology, Ontario Cancer Institute, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Canada
| | - Howard Leong-Poi
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
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Matera R, Saif MW. New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies. Expert Opin Emerg Drugs 2017; 22:223-233. [PMID: 28783977 DOI: 10.1080/14728214.2017.1362388] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options. Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future. Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.
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Affiliation(s)
- Robert Matera
- a Department of Hematology and Oncology , Tufts University School of Medicine , Boston , MA , USA
| | - Muhammad Wasif Saif
- a Department of Hematology and Oncology , Tufts University School of Medicine , Boston , MA , USA
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Luo D, Geng J, Li N, Carter KA, Shao S, Atilla-Gokcumen GE, Lovell JF. Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes. Mol Cancer Ther 2017; 16:2452-2461. [PMID: 28729400 DOI: 10.1158/1535-7163.mct-17-0276] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/02/2017] [Accepted: 07/05/2017] [Indexed: 11/16/2022]
Abstract
Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm2 NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm2 NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. Mol Cancer Ther; 16(11); 2452-61. ©2017 AACR.
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Affiliation(s)
- Dandan Luo
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York
| | - Jumin Geng
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York
| | - Nasi Li
- Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York
| | - Kevin A Carter
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York
| | - Shuai Shao
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York
| | - G Ekin Atilla-Gokcumen
- Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York
| | - Jonathan F Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York.
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Hamada T, Nakai Y, Isayama H, Yasunaga H, Matsui H, Takahara N, Mizuno S, Kogure H, Matsubara S, Yamamoto N, Tada M, Koike K. Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer. Eur J Cancer 2016; 65:11-20. [PMID: 27451020 DOI: 10.1016/j.ejca.2016.05.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 04/24/2016] [Accepted: 05/15/2016] [Indexed: 02/09/2023]
Abstract
BACKGROUND Overall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer. METHODS Based on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer. Correlation analyses were performed between surrogate end-points and OS, and between improvements in surrogates and those in OS. RESULTS Fifty trials (II/II-III/III, 17/2/31) with 111 treatment arms were identified, and 15,906 patients were analysed. PFS was most strongly correlated with OS (correlation coefficient, 0.76). Weighted linear regression models revealed the greatest determinant coefficient of 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of PFS and that of OS. The approximate equation was log HROS = 0.01 + 0.77 × log HRPFS, indicating that risk reduction of OS via chemotherapy would translate into a 77% risk reduction of PFS. The surrogacy of PFS for OS was robust throughout our subgroup analyses: e.g., biologic versus non-biologic regimens, locally advanced versus metastatic disease. CONCLUSIONS The surrogacy of PFS for OS in pancreatic cancer was validated. Therefore, the use of PFS as the primary end-point in clinical trials could facilitate the early introduction of new effective chemotherapy regimens into clinical practice.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan.
| | - Hiroki Matsui
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan.
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Saburo Matsubara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Natsuyo Yamamoto
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Minoru Tada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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Hsueh CT, Selim JH, Tsai JY, Hsueh CT. Nanovectors for anti-cancer drug delivery in the treatment of advanced pancreatic adenocarcinoma. World J Gastroenterol 2016; 22:7080-7090. [PMID: 27610018 PMCID: PMC4988316 DOI: 10.3748/wjg.v22.i31.7080] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/13/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovector-based anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma.
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Rovira J, Diekmann F, Campistol JM, Ramírez-Bajo MJ. Therapeutic application of extracellular vesicles in acute and chronic renal injury. Nefrologia 2016; 37:126-137. [PMID: 27462016 DOI: 10.1016/j.nefro.2016.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/14/2016] [Accepted: 04/28/2016] [Indexed: 12/31/2022] Open
Abstract
A new cell-to-cell communication system was discovered in the 1990s, which involves the release of vesicles into the extracellular space. These vesicles shuttle bioactive particles, including proteins, mRNA, miRNA, metabolites, etc. This particular communication has been conserved throughout evolution, which explains why most cell types are capable of producing vesicles. Extracellular vesicles (EVs) are involved in the regulation of different physiological processes, as well as in the development and progression of several diseases. EVs have been widely studied over recent years, especially those produced by embryonic and adult stem cells, blood cells, immune system and nervous system cells, as well as tumour cells. EV analysis from bodily fluids has been used as a diagnostic tool for cancer and recently for different renal diseases. However, this review analyses the importance of EVs generated by stem cells, their function and possible clinical application in renal diseases and kidney transplantation.
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Affiliation(s)
- Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España
| | - Fritz Diekmann
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España; Departamento de Nefrología y Trasplante Renal, Institut Clínic de Nefrologia i Urologia (ICNU), Hospital Clínic, Barcelona, España.
| | - Josep M Campistol
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España; Departamento de Nefrología y Trasplante Renal, Institut Clínic de Nefrologia i Urologia (ICNU), Hospital Clínic, Barcelona, España
| | - María José Ramírez-Bajo
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España
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46
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Yingchoncharoen P, Kalinowski DS, Richardson DR. Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come. Pharmacol Rev 2016; 68:701-87. [PMID: 27363439 PMCID: PMC4931871 DOI: 10.1124/pr.115.012070] [Citation(s) in RCA: 466] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles.
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Affiliation(s)
- Phatsapong Yingchoncharoen
- Molecular Pharmacology and Pathology Program, Department of Pathology, Faculty of Medicine, Bosch Institute, The University of Sydney, Sydney, NSW, Australia
| | - Danuta S Kalinowski
- Molecular Pharmacology and Pathology Program, Department of Pathology, Faculty of Medicine, Bosch Institute, The University of Sydney, Sydney, NSW, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology, Faculty of Medicine, Bosch Institute, The University of Sydney, Sydney, NSW, Australia
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Lemstrova R, Melichar B, Mohelnikova-Duchonova B. Therapeutic potential of taxanes in the treatment of metastatic pancreatic cancer. Cancer Chemother Pharmacol 2016; 78:1101-1111. [DOI: 10.1007/s00280-016-3058-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/09/2016] [Indexed: 02/07/2023]
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Nasongkla N, Nittayacharn P, Rotjanasitthikit A, Pungbangkadee K, Manaspon C. Paclitaxel-loaded polymeric depots as injectable drug delivery system for cancer chemotherapy of hepatocellular carcinoma. Pharm Dev Technol 2016; 22:652-658. [PMID: 27056587 DOI: 10.3109/10837450.2016.1163389] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this work, paclitaxel-encapsulated polymeric depots were prepared and characterized as drug delivery system for cancer chemotherapy against hepatocellular carcinoma. Effects of different parameters, including drug-loading content, polymer concentration and depot weight on depot formation, percentage of sustained-release taxol and drug release profile were evaluated. Paclitaxel-loaded depots were successfully formed at the polymer concentration above 25% w/v. For all formulations, paclitaxel could be encapsulated with very high percentage of sustained-release taxol (>90%). The release rate of paclitaxel from depots could be controlled by the amount of drug-loading content, polymer concentration and depot weight. Cytotoxicity against liver cancer cell line, HepG2, was evaluated by medium extraction method. Paclitaxel releasing from depots showed cytotoxic effect against HepG2 at different incubation times, whereas blank depots exhibited no cytotoxicity.
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Affiliation(s)
- Norased Nasongkla
- a Department of Biomedical Engineering, Faculty of Engineering , Mahidol University , Nakorn Pathom , Thailand
| | - Pinunta Nittayacharn
- a Department of Biomedical Engineering, Faculty of Engineering , Mahidol University , Nakorn Pathom , Thailand
| | - Apichada Rotjanasitthikit
- a Department of Biomedical Engineering, Faculty of Engineering , Mahidol University , Nakorn Pathom , Thailand
| | - Korawich Pungbangkadee
- a Department of Biomedical Engineering, Faculty of Engineering , Mahidol University , Nakorn Pathom , Thailand
| | - Chawan Manaspon
- a Department of Biomedical Engineering, Faculty of Engineering , Mahidol University , Nakorn Pathom , Thailand
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49
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Indolfi L, Ligorio M, Ting DT, Xega K, Tzafriri AR, Bersani F, Aceto N, Thapar V, Fuchs BC, Deshpande V, Baker AB, Ferrone CR, Haber DA, Langer R, Clark JW, Edelman ER. A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma. Biomaterials 2016; 93:71-82. [PMID: 27082874 DOI: 10.1016/j.biomaterials.2016.03.044] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 03/06/2016] [Accepted: 03/28/2016] [Indexed: 02/09/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer.
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Affiliation(s)
- Laura Indolfi
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Matteo Ligorio
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Health Sciences, University of Genoa, Genoa, Italy
| | - David T Ting
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Kristina Xega
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Francesca Bersani
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Nicola Aceto
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Vishal Thapar
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Bryan C Fuchs
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Aaron B Baker
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Cristina R Ferrone
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniel A Haber
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Robert Langer
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jeffrey W Clark
- Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Elazer R Edelman
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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50
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Kristensen A, Vagnildhaug OM, Grønberg BH, Kaasa S, Laird B, Solheim TS. Does chemotherapy improve health-related quality of life in advanced pancreatic cancer? A systematic review. Crit Rev Oncol Hematol 2016; 99:286-98. [PMID: 26819138 DOI: 10.1016/j.critrevonc.2016.01.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 12/18/2015] [Accepted: 01/12/2016] [Indexed: 01/05/2023] Open
Abstract
Chemotherapy is increasingly being used in advanced pancreatic cancer, but side-effects are common. The aim of this systematic review was to assess whether chemotherapy improves health-related quality of life (HRQoL), pain or cachexia. Thirty studies were reviewed. Four of 23 studies evaluating HRQoL, 7 of 24 studies evaluating pain and 0 of 8 studies evaluating cachexia found differences between treatment arms. Change in HRQoL from baseline was evaluated in 14 studies: five studies reported an improvement in at least one treatment arm; three a worsening and the remaining stable scores. Change in pain intensity from baseline was evaluated in eight studies, and improvement was observed in seven. Of the four studies reporting improved survival, three reported improved HRQoL or pain. In conclusion, chemotherapy can stabilize HRQoL and improve pain control. Effects on cachexia are hard to elucidate. Improved survival does not come at the expense of HRQoL or pain control.
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Affiliation(s)
- A Kristensen
- European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
| | - O M Vagnildhaug
- European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - B H Grønberg
- European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - S Kaasa
- European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - B Laird
- European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - T S Solheim
- European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
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