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Adhikari A, Chen IA. Antibody-Nanoparticle Conjugates in Therapy: Combining the Best of Two Worlds. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2409635. [PMID: 40051146 PMCID: PMC12001320 DOI: 10.1002/smll.202409635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/02/2025] [Indexed: 04/17/2025]
Abstract
Monoclonal antibodies (mAbs) and antibody fragments have revolutionized medicine as highly specific binding agents and inhibitors. At the same time, several types of nanomaterials, including liposomes, lipid nanoparticles (NPs), polymersomes, metal and metal oxide NPs, and protein nanostructures, are increasingly utilized and explored for therapeutic potential due to their versatility, chemical and physical properties, and tunability. However, nanomaterials alone often lack specificity, leading to relatively low efficacy and/or high toxicity. To address this problem, a rapidly emerging area is antibody-nanomaterial conjugates (ANCs), which combine the precise targeting specificity of antibodies with the effector functionality of the nanomaterial. In this review, we give a brief introduction to mAbs and major conjugation techniques, describe major classes of nanomaterials being studied for therapeutic potential, and review the literature on ANCs of each class. Special focus is given to emerging applications including ANCs addressing the blood-brain barrier, ANCs delivering nucleic acids, and light-activated ANCs. While many disease targets are related to cancer, ANCs are also under development to address autoimmune, neurological, and infectious diseases. While important challenges remain, ANCs are poised to become a next-generation therapeutic technology.
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Affiliation(s)
- Aniruddha Adhikari
- Department of Chemical and Biomolecular EngineeringDepartment of Chemistry and BiochemistryUniversity of CaliforniaLos AngelesCA90049USA
| | - Irene A. Chen
- Department of Chemical and Biomolecular EngineeringDepartment of Chemistry and BiochemistryUniversity of CaliforniaLos AngelesCA90049USA
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2
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Bresinsky M, Goepferich A. Control of biomedical nanoparticle distribution and drug release in vivo by complex particle design strategies. Eur J Pharm Biopharm 2025; 208:114634. [PMID: 39826847 DOI: 10.1016/j.ejpb.2025.114634] [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: 10/16/2024] [Revised: 01/06/2025] [Accepted: 01/14/2025] [Indexed: 01/22/2025]
Abstract
The utilization of targeted nanoparticles as a selective drug delivery system is a powerful tool to increase the amount of active substance reaching the target site. This can increase therapeutic efficacy while reducing adverse drug effects. However, nanoparticles face several challenges: upon injection, the immediate adhesion of plasma proteins may mask targeting ligands, thereby diminishing the target cell selectivity. In addition, opsonization can lead to premature clearance and the widespread presence of receptors or enzymes limits the accuracy of target cell recognition. Nanoparticles may also suffer from endosomal entrapment, and controlled drug release can be hindered by premature burst release or insufficient particle retention at the target site. Various strategies have been developed to address these adverse events, such as the implementation of switchable particle properties, regulating the composition of the formed protein corona, or using click-chemistry based targeting approaches. This has resulted in increasingly complex particle designs, raising the question of whether this development actually improves the therapeutic efficacy in vivo. This review provides an overview of the challenges in targeted drug delivery and explores potential solutions described in the literature. Subsequently, appropriate strategies for the development of nanoparticular drug delivery concepts are discussed.
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Affiliation(s)
- Melanie Bresinsky
- Department of Pharmaceutical Technology, University of Regensburg 93053 Regensburg, Bavaria, Germany
| | - Achim Goepferich
- Department of Pharmaceutical Technology, University of Regensburg 93053 Regensburg, Bavaria, Germany.
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Abdelhamid MS, Wadan AHS, Saad HA, El-Dakroury WA, Hageen AW, Mohammed DH, Mourad S, Mohammed OA, Abdel-Reheim MA, Doghish AS. Nanoparticle innovations in targeted cancer therapy: advancements in antibody-drug conjugates. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03764-7. [PMID: 39825965 DOI: 10.1007/s00210-024-03764-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 12/23/2024] [Indexed: 01/20/2025]
Abstract
Antibody-drug conjugates (ADCs) have emerged as a promising strategy in targeted cancer therapy, enabling the precise delivery of cytotoxic agents to tumor sites while minimizing systemic toxicity. However, traditional ADCs face significant limitations, including restricted drug loading capacity, where an optimal drug-to-antibody ratio (DAR) is crucial; low DARs may lead to insufficient potency, while high DARs can cause rapid clearance and increased toxicity. Additionally, ADCs often suffer from instability in circulation due to the potential for premature release of cytotoxic agents, resulting in off-target effects and reduced therapeutic efficacy. Furthermore, their large size can impede adequate penetration into solid tumors, particularly in heterogeneous environments with varying antigen expressions. This review explores the innovative use of nanoparticles as carriers for ADCs, which offers a multifaceted approach to enhance therapeutic efficacy. By leveraging the unique properties of nanoparticles, such as their small size and ability to exploit the enhanced permeability and retention (EPR) effect, researchers can improve drug stability, prolong circulation time, and achieve more effective tumor targeting. Recent studies demonstrate that nanoparticle-encapsulated ADCs can significantly enhance treatment outcomes while reducing off-target effects, as evidenced by improved targeting capabilities and reduced toxicity in preclinical models. Despite the promising advancements, challenges remain, including potential nanoparticle toxicity and manufacturing complexities. This review aims to provide a comprehensive overview of the current research on nanoparticle-encapsulated ADCs. It highlights their potential to transform cancer treatment and offers insights into future directions for optimizing these advanced therapeutic strategies.
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Affiliation(s)
| | - Al-Hassan Soliman Wadan
- Oral Biology Department, Faculty of Dentistry, Galala University, Galala Plateau, Attaka, 15888, Suez Governorate, Egypt
| | - Hager Adel Saad
- Faculty of Pharmacy, German University in Cairo (GUC), New Cairo, 11835, Cairo, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed W Hageen
- Faculty of Medicine, Tanta University, Tanta, 31527, Egypt
| | | | - Sohaila Mourad
- Faculty of Medicine, Alexandria University, Alexandria, 21526, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | | | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Lu M, Liu Y, Zhu J, Shang J, Bai L, Jin Z, Li W, Hu Y, Zheng X, Qian J. Mapping the intellectual structure and emerging trends on nanomaterials in colorectal cancer: a bibliometric analysis from 2003 to 2024. Front Oncol 2025; 14:1514581. [PMID: 39845318 PMCID: PMC11750690 DOI: 10.3389/fonc.2024.1514581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Background Colorectal cancer (CRC) is one of thes most prevalent malignant tumors worldwide. Current therapeutic strategies for CRC have limitations, while nanomaterials show significant potential for diagnosing and treating CRC. This study utilizes bibliometric analysis to evaluate the current status and trends in this field. Methods Research on nanomaterials in CRC from 2003 to 2024 was retrieved from the Web of Science Core Collection (WOSCC). Tools such as CiteSpace, VOSviewer, RStudio, GraphPad Prism, and Excel were used to analyze trends and hotspots, covering publication trends, countries, institutions, authors, journals, co-citation analysis, and keywords. Visual maps were created to forecast future developments. Results The analysis includes 3,683 publications by 17,261 authors from 3,721 institutions across 100 countries/regions, published in 840 journals. Global publications have steadily increased, particularly since 2018. China leads in publication volume and citations, with six of the top ten research institutions and seven of the ten most cited authors, while the United States excels in citation impact and academic centrality. Both countries currently dominate the field, underscoring the urgent need for enhanced international collaboration. Ramezani M and Abnous K lead in publication volume and H-index, while Siegel RL is highly cited. The International Journal of Nanomedicine has the highest publication volume, while the Journal of Controlled Release is the most cited. In addition to "colorectal cancer" and "nanoparticles," the most common keyword is "drug delivery." Emerging research areas such as "metal-organic frameworks (MOFs)" and "green synthesis" are gaining attention as leading hotspots. Conclusion This study offers an in-depth analysis of the application of nanomaterials in CRC, promoting interdisciplinary collaboration and advancing scientific progress in this field.
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Affiliation(s)
- Man Lu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yi Liu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jin Zhu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiarong Shang
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lu Bai
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhichao Jin
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenting Li
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yue Hu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xia Zheng
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jun Qian
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Tao Y, Du M, Zhu M, Wang Y, Fei Y, Zhao YQ, Ma J, Fan R, Dai F, Chen J, Yin J, Fan B, Zeng G. Antitumor Effect of Peptide-Camptothecin Conjugate Targeting CD133 Protein. Bioconjug Chem 2024; 35:1859-1869. [PMID: 39527780 DOI: 10.1021/acs.bioconjchem.4c00485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The peptide-drug conjugate (PDC) has emerged as one of the new approaches for cancer therapy, which has the advantages of improved drug target ability and reduced adverse effects compared with the traditional chemotherapy. CD133 is a surface antigen specific to cancer stem cells, which are thought to be responsible for the self-renewal, proliferation, metastasis, and chemoresistance of cancer cells. A PDC for CD133 was designed by us, and it consists of CD133 targeting peptide LS-7 (amino acid sequence LQNAPRS), a pH-sensitive linker (succinyl), and a cytotoxic payload, the cytotoxic molecule camptothecin (CPT) with potent toxicity in vivo and in vitro. An antitumor study exhibited that the conjugate LS-7-CPT has not only improved its cytotoxicity in tumor cells but also retained its anticancer effect in vivo. In addition, the acute toxicity in mice of LS-7-CPT has been improved and the maximum tolerated dose has been increased by at least 56.2-fold. Pull-down and in vivo fluorescent imaging results indicated that LS-7-CPT was enriched in mice tumors by targeting CD133 protein. As far as we know, this is the first report for a PDC molecule designed for CD133, which is important for the study of CPT drug development.
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Affiliation(s)
- Yang Tao
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Maoxin Du
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Meihua Zhu
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Yinyue Wang
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Yusong Fei
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
| | - Yu-Qiang Zhao
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
| | - Junjie Ma
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Ruifeng Fan
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Fang Dai
- School of Chemistry and Environmental Engineering, Qujing Normal University, Qujing 655011, China
| | - Jingchao Chen
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Junlin Yin
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Baomin Fan
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Guangzhi Zeng
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
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Liu R, Miao Y, Wen K, Yang Y, Xu D, Lu S, Liu Z, Qin H, Zhang X, Zhang Y. Salmonella Biomimetic Nanoparticles for Photothermal-Chemotherapy of Colorectal Cancer. NANO LETTERS 2024; 24:13851-13860. [PMID: 39432478 DOI: 10.1021/acs.nanolett.4c04609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2024]
Abstract
Nanomedicines have been widely used in colorectal cancer treatment, but their suboptimal targeting and deficient penetration capabilities remain obstacles in the delivery of therapeutics. In this study, inspired by the natural tumor tropism and intestinal invasion of Salmonella, we engineered highly biomimetic nanoparticles (SM-AuNRs) utilizing a Salmonella membrane to coat bacilliform Au nanorods. The engineered SM-AuNRs were able to mimic the germ's morphology and biological surface. SM-AuNRs containing the specific proteins inherited from the Salmonella membrane facilitated specific targeting and internalization into tumor cells. Meanwhile, SM-AuNRs with the rod-shaped morphology effectively traversed mucus barriers and tumor stroma. Due to the superior biological barrier penetrating and tumor targeting capabilities, doxorubicin-loaded SM-AuNRs with near-infrared laser irradiation displayed remarkable photothermal-chemotherapeutic antitumor effects in mouse orthotopic colorectal cancer models. Our findings pave the way for the design of bacteria-mimicking nanoparticles, presenting a promising avenue for the targeting and efficient treatment of colorectal cancer.
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Affiliation(s)
- Ruichi Liu
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Yunqiu Miao
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Keyi Wen
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Yang Yang
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Dan Xu
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Shengwei Lu
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Ziyuan Liu
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Huanlong Qin
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Xinxin Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Yang Zhang
- Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
- Department of Pharmacy, Shanghai Eighth People's Hospital, School of Medicine, Tongji University, Shanghai 200235, China
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Sipos F, Műzes G. Interconnection of CD133 Stem Cell Marker with Autophagy and Apoptosis in Colorectal Cancer. Int J Mol Sci 2024; 25:11201. [PMID: 39456981 PMCID: PMC11508732 DOI: 10.3390/ijms252011201] [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: 09/21/2024] [Revised: 10/09/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
CD133 protein expression is observable in differentiated cells, stem cells, and progenitor cells within normal tissues, as well as in tumor tissues, including colorectal cancer cells. The CD133 protein is the predominant cell surface marker utilized to detect cancer cells exhibiting stem cell-like characteristics. CD133 alters common abnormal processes in colorectal cancer, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin pathways. Autophagy is a cellular self-digestion mechanism that preserves the intracellular milieu and plays a dual regulatory role in cancer. In cancer cells, apoptosis is a critical cell death mechanism that can impede cancer progression. CD133 can modulate autophagy and apoptosis in colorectal cancer cells via several signaling pathways; hence, it is involved in the regulation of these intricate processes. This can be an explanation for why CD133 expression is associated with enhanced cellular self-renewal, migration, invasion, and survival under stress conditions in colorectal cancer. The purpose of this review article is to explain the complex relationship between the CD133 protein, apoptosis, and autophagy. We also want to highlight the possible ways that CD133-mediated autophagy may affect the apoptosis of colorectal cancer cells. Targeting the aforementioned mechanisms may have a significant therapeutic role in eliminating CD133-positive stem cell-phenotype colorectal cancer cells, which can be responsible for tumor recurrence.
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Affiliation(s)
- Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
| | - Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
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Shamsul Kamal AA, Fakiruddin KS, Bobbo KA, Ling KH, Vidyadaran S, Abdullah S. Engineered Mesenchymal Stem Cells as Treatment for Cancers: Opportunities, Clinical Applications and Challenges. Malays J Med Sci 2024; 31:56-82. [PMID: 39416732 PMCID: PMC11477465 DOI: 10.21315/mjms2024.31.5.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 06/27/2024] [Indexed: 10/19/2024] Open
Abstract
The insufficient and unspecific target of classical chemotherapies often leads to therapy resistance and cancer recurrence. Over the past decades, discoveries about mesenchymal stem cell (MSC) biology have provided new potential approaches to improve cancer therapy. Researchers have utilised the multipotent, regenerative and immunosuppressive qualities of MSCs and tropisms towards inflammatory, hypoxic and malignant sites in various therapeutic applications. Although MSC-based therapies have generally been demonstrated safe, their effectiveness remains limited when these cells are used alone. However, through genetic engineering, researchers have proven that MSCs can be modified to have specialised delivery roles to increase their therapeutic efficacy in cancer treatment. They can be made to overexpress therapeutic proteins through viral or non-viral genetic modification, which enhances their innate properties. Nevertheless, these engineering strategies must be optimised to increase therapeutic efficacy and targeting effectiveness while minimising any loss of MSC function. This review underscores the cutting-edge methods for engineering MSCs, discusses their promise and the difficulties in translating them into clinical settings, and offers some prospective suggestions for the future on achieving their full therapeutic potential.
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Affiliation(s)
- Aishah Amirah Shamsul Kamal
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Kamal Shaik Fakiruddin
- Haematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Selangor, Malaysia
| | - Khadijat Abubakar Bobbo
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - King Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Selangor, Malaysia
| | - Sharmili Vidyadaran
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysia Genome and Vaccine Institute, National Institutes of Biotechnology Malaysia, Selangor, Malaysia
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Zhao C, Zhu X, Yang H, Tan J, Gong R, Mei C, Cai X, Su Z, Kong F. Lactoferrin/CD133 antibody conjugated nanostructured lipid carriers for dual targeting of blood-brain-barrier and glioblastoma stem cells. Biomed Mater 2024; 19:055041. [PMID: 39134023 DOI: 10.1088/1748-605x/ad6e47] [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: 04/09/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024]
Abstract
The main reasons for the difficulty in curing and high recurrence rate of glioblastoma multiforme (GBM) include: 1. The difficulty of chemotherapy drugs in penetrating the blood-brain barrier (BBB) to target tumor cells; 2. The presence of glioma stem cells (GSCs) leading to chemotherapy resistance. Therefore, breaking through the limitations of the BBB and overcoming the drug resistance caused by GSCs are the main strategies to address this problem. This study presents our results on the development of lactoferrin (Lf)/CD133 antibody conjugated nanostructured lipid carriers (Lf/CD133-NLCS) for simultaneously targeting BBB and GSCs. Temozolomide (TMZ) loaded Lf/CD133-NLCS (Lf/CD133-NLCS-TMZ) exhibited high-efficiencyin vitroanti-tumor effects toward malignant glioma cells (U87-MG) and GSCs, while demonstrating no significant toxicity to normal cells at concentrations lower than 200 μg ml-1. The results of thein vitrotargeting GBM study revealed a notably higher cellular uptake of Lf/CD133-NLCS-TMZ in U87-MG cells and GSCs in comparison to Lf/CD133 unconjugated counterpart (NLCS-TMZ). In addition, increased BBB permeability were confirmed for Lf/CD133-NLCS-TMZ compared to NLCS-TMZ bothin vitroandin vivo. Taking together, Lf/CD133-NLCS-TMZ show great potential for dual targeting of BBB and GSCs, as well as GBM therapy based on this strategy.
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Affiliation(s)
- Changhong Zhao
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, People's Republic of China
- Lantian Pharmaceuticals Co., Ltd, Huangshi, Hubei 435000, People's Republic of China
| | - Xinshu Zhu
- School of Medical Science and Laboratory Medicine, Jiangsu College of Nursing, Huai'an 223005, People's Republic of China
| | - Huili Yang
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, People's Republic of China
| | - Jianmei Tan
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, People's Republic of China
| | - Ruohan Gong
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, People's Republic of China
| | - Chao Mei
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, People's Republic of China
| | - Xiang Cai
- Lantian Pharmaceuticals Co., Ltd, Huangshi, Hubei 435000, People's Republic of China
| | - Zhenhong Su
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, People's Republic of China
| | - Fei Kong
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
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10
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Sun S, Yang Q, Jiang D, Zhang Y. Nanobiotechnology augmented cancer stem cell guided management of cancer: liquid-biopsy, imaging, and treatment. J Nanobiotechnology 2024; 22:176. [PMID: 38609981 PMCID: PMC11015566 DOI: 10.1186/s12951-024-02432-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent both a key driving force and therapeutic target of tumoral carcinogenesis, tumor evolution, progression, and recurrence. CSC-guided tumor diagnosis, treatment, and surveillance are strategically significant in improving cancer patients' overall survival. Due to the heterogeneity and plasticity of CSCs, high sensitivity, specificity, and outstanding targeting are demanded for CSC detection and targeting. Nanobiotechnologies, including biosensors, nano-probes, contrast enhancers, and drug delivery systems, share identical features required. Implementing these techniques may facilitate the overall performance of CSC detection and targeting. In this review, we focus on some of the most recent advances in how nanobiotechnologies leverage the characteristics of CSC to optimize cancer diagnosis and treatment in liquid biopsy, clinical imaging, and CSC-guided nano-treatment. Specifically, how nanobiotechnologies leverage the attributes of CSC to maximize the detection of circulating tumor DNA, circulating tumor cells, and exosomes, to improve positron emission computed tomography and magnetic resonance imaging, and to enhance the therapeutic effects of cytotoxic therapy, photodynamic therapy, immunotherapy therapy, and radioimmunotherapy are reviewed.
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Affiliation(s)
- Si Sun
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qiang Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dawei Jiang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China.
| | - Yuan Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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11
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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12
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Hoover E, Ruggiero OM, Swingler RN, Day ES. FZD7-Targeted Nanoparticles to Enhance Doxorubicin Treatment of Triple-Negative Breast Cancer. ACS OMEGA 2024; 9:14323-14335. [PMID: 38559981 PMCID: PMC10976388 DOI: 10.1021/acsomega.3c10275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/01/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024]
Abstract
Doxorubicin (DOX) is a chemotherapy agent commonly used to treat triple-negative breast cancer (TNBC), but it has insufficient efficacy against the disease and considerable toxicity due to its off-target delivery. To improve the specificity of DOX for TNBC, we encapsulated it in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with antibodies against Frizzled7 (FZD7), a receptor that is overexpressed on TNBC cells and which is a key activator of the Wnt signaling pathway. In vitro studies show that DOX encapsulation does not hinder its ability to localize to the nucleus in human TNBC cell cultures and that DOX delivered via NPs induces apoptosis and DNA damage via H2A.X phosphorylation to the same degree as freely delivered DOX. FZD7-targeted NPs delivering DOX caused significantly greater inhibition of metabolic activity and led to a smaller cell population following treatment when compared to freely delivered DOX or DOX-loaded NPs coated only with poly(ethylene glycol) (PEG). The FZD7 antibodies additionally provided significant levels of Wnt pathway inhibition, as demonstrated by an increase in β-catenin phosphorylation, indicative of β-catenin destruction and downregulation. These results show that FZD7-targeted platforms have great promise for improving the therapeutic window of otherwise toxic chemotherapies like DOX in TNBC and other cancers that display the overexpression of FZD7 receptors.
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Affiliation(s)
- Elise
C. Hoover
- Department
of Biomedical Engineering, University of
Delaware, Newark, Delaware 19713, United States
| | - Olivia M. Ruggiero
- Department
of Biomedical Engineering, University of
Delaware, Newark, Delaware 19713, United States
| | - Rachel N. Swingler
- Department
of Biomedical Engineering, University of
Delaware, Newark, Delaware 19713, United States
| | - Emily S. Day
- Department
of Biomedical Engineering, University of
Delaware, Newark, Delaware 19713, United States
- Department
of Materials Science and Engineering, University
of Delaware, Newark, Delaware 19716, United States
- Helen
F. Graham Cancer Center and Research Institute, Newark, Delaware 19713, United States
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13
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Zhao Q, Zong H, Zhu P, Su C, Tang W, Chen Z, Jin S. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol 2024; 13:6. [PMID: 38254219 PMCID: PMC10802076 DOI: 10.1186/s40164-024-00474-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.
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Affiliation(s)
- Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chang Su
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenxue Tang
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jing‑ba Road, Zhengzhou, 450014, China.
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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14
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Wang L, Liu H, Liu Y, Guo S, Yan Z, Chen G, Wu Q, Xu S, Zhou Q, Liu L, Peng M, Cheng X, Yan T. Potential markers of cancer stem-like cells in ESCC: a review of the current knowledge. Front Oncol 2024; 13:1324819. [PMID: 38239657 PMCID: PMC10795532 DOI: 10.3389/fonc.2023.1324819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/01/2023] [Indexed: 01/22/2024] Open
Abstract
In patients with esophageal squamous cell carcinoma (ESCC), the incidence and mortality rate of ESCC in our country are also higher than those in the rest of the world. Despite advances in the treatment department method, patient survival rates have not obviously improved, which often leads to treatment obstruction and cancer repeat. ESCC has special cells called cancer stem-like cells (CSLCs) with self-renewal and differentiation ability, which reflect the development process and prognosis of cancer. In this review, we evaluated CSLCs, which are identified from the expression of cell surface markers in ESCC. By inciting EMTs to participate in tumor migration and invasion, stem cells promote tumor redifferentiation. Some factors can inhibit the migration and invasion of ESCC via the EMT-related pathway. We here summarize the research progress on the surface markers of CSLCs, EMT pathway, and the microenvironment in the process of tumor growth. Thus, these data may be more valuable for clinical applications.
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Affiliation(s)
- Lu Wang
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Huijuan Liu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yiqian Liu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Shixing Guo
- Clinical Laboratory Medicine Centre, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhenpeng Yan
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guohui Chen
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qinglu Wu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Songrui Xu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qichao Zhou
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lili Liu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Meilan Peng
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaolong Cheng
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ting Yan
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
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15
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [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: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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16
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Wang WD, Guo YY, Yang ZL, Su GL, Sun ZJ. Sniping Cancer Stem Cells with Nanomaterials. ACS NANO 2023; 17:23262-23298. [PMID: 38010076 DOI: 10.1021/acsnano.3c07828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.
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Affiliation(s)
- Wen-Da Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Yan-Yu Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhong-Lu Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Guang-Liang Su
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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17
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Jagasia S, Tasci E, Zhuge Y, Camphausen K, Krauze AV. Identifying patients suitable for targeted adjuvant therapy: advances in the field of developing biomarkers for tumor recurrence following irradiation. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2023; 8:33-42. [PMID: 37982134 PMCID: PMC10655913 DOI: 10.1080/23808993.2023.2276927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/25/2023] [Indexed: 11/21/2023]
Abstract
Introduction Radiation therapy (RT) is commonly used to treat cancer in conjunction with chemotherapy, immunotherapy, and targeted therapies. Despite the effectiveness of RT, tumor recurrence due to treatment resistance still lead to treatment failure. RT-specific biomarkers are currently lacking and remain challenging to investigate with existing data since, for many common malignancies, standard of care (SOC) paradigms involve the administration of RT in conjunction with other agents. Areas Covered Established clinically relevant biomarkers are used in surveillance, as prognostic indicators, and sometimes for treatment planning; however, the inability to intercept early recurrence or predict upfront resistance to treatment remains a significant challenge that limits the selection of patients for adjuvant therapy. We discuss attempts at intercepting early failure. We examine biomarkers that have made it into the clinic where they are used for treatment monitoring and management alteration, and novel biomarkers that lead the field with targeted adjuvant therapy seeking to harness these. Expert Opinion Given the growth of data correlating interventions with omic analysis toward identifying biomarkers of radiation resistance, more robust markers of recurrence that link to biology will increasingly be leveraged toward targeted adjuvant therapy to make a successful transition to the clinic in the coming years.
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Affiliation(s)
- S Jagasia
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA
| | - E Tasci
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA
| | - Ying Zhuge
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA
| | - K Camphausen
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA
| | - A V Krauze
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA
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18
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Koukourakis IM, Platoni K, Kouloulias V, Arelaki S, Zygogianni A. Prostate Cancer Stem Cells: Biology and Treatment Implications. Int J Mol Sci 2023; 24:14890. [PMID: 37834336 PMCID: PMC10573523 DOI: 10.3390/ijms241914890] [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: 09/06/2023] [Revised: 09/30/2023] [Accepted: 10/01/2023] [Indexed: 10/15/2023] Open
Abstract
Stem cells differentiate into mature organ/tissue-specific cells at a steady pace under normal conditions, but their growth can be accelerated during the process of tissue healing or in the context of certain diseases. It is postulated that the proliferation and growth of carcinomas are sustained by the presence of a vital cellular compartment resembling stem cells residing in normal tissues: 'stem-like cancer cells' or cancer stem cells (CSCs). Mutations in prostate stem cells can lead to the formation of prostate cancer. Prostate CSCs (PCSCs) have been identified and partially characterized. These express surface markers include CD44, CD133, integrin α2β1, and pluripotency factors like OCT4, NANOG, and SOX2. Several signaling pathways are also over-activated, including Notch, PTEN/Akt/PI3K, RAS-RAF-MEK-ERK and HH. Moreover, PCSCs appear to induce resistance to radiotherapy and chemotherapy, while their presence has been linked to aggressive cancer behavior and higher relapse rates. The development of treatment policies to target PCSCs in tumors is appealing as radiotherapy and chemotherapy, through cancer cell killing, trigger tumor repopulation via activated stem cells. Thus, blocking this reactive stem cell mobilization may facilitate a positive outcome through cytotoxic treatment.
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Affiliation(s)
- Ioannis M. Koukourakis
- Radiation Oncology Unit, 1st Department of Radiology, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 11528 Athens, Greece; (I.M.K.); (A.Z.)
| | - Kalliopi Platoni
- Medical Physics Unit, 2nd Department of Radiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 12462 Athens, Greece
| | - Vassilis Kouloulias
- Radiation Oncology Unit, 2nd Department of Radiology, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 12462 Athens, Greece;
| | - Stella Arelaki
- Translational Functional Cancer Genomics, National Center for Tumor Diseases, German Cancer Research Center, 69120 Heidelberg, Germany;
| | - Anna Zygogianni
- Radiation Oncology Unit, 1st Department of Radiology, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 11528 Athens, Greece; (I.M.K.); (A.Z.)
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19
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Kumari M, Acharya A, Krishnamurthy PT. Antibody-conjugated nanoparticles for target-specific drug delivery of chemotherapeutics. BEILSTEIN JOURNAL OF NANOTECHNOLOGY 2023; 14:912-926. [PMID: 37701520 PMCID: PMC10494237 DOI: 10.3762/bjnano.14.75] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 08/22/2023] [Indexed: 09/14/2023]
Abstract
Nanotechnology provides effective methods for precisely delivering chemotherapeutics to cancer cells, thereby improving efficacy and reducing off-target side effects. The targeted delivery of nanoscale chemotherapeutics is accomplished by two different approaches, namely the exploitation of leaky tumor vasculature (EPR effect) and the surface modification of nanoparticles (NPs) with various tumor-homing peptides, aptamers, oligonucleotides, and monoclonal antibodies (mAbs). Because of higher binding affinity and specificity, mAbs have received a lot of attention for the detection of selective cancer biomarkers and also for the treatment of various types of cancer. Antibody-conjugated nanoparticles (ACNPs) are an effective targeted therapy for the efficient delivery of chemotherapeutics specifically to the targeted cancer cells. ACNPs combine the benefits of NPs and mAbs to provide high drug loads at the tumor site with better selectivity and delivery efficiency. The mAbs on the NP surfaces recognize their specific receptors expressed on the target cells and release the chemotherapeutic agent in a controlled manner. Appropriately designed and synthesized ACNPs are essential to fully realize their therapeutic benefits. In blood stream, ACNPs instantly interact with biological molecules, and a protein corona is formed. Protein corona formation triggers an immune response and affects the targeting ability of the nanoformulation. In this review, we provide recent findings to highlight several antibody conjugation methods such as adsorption, covalent conjugation, and biotin-avidin interaction. This review also provides an overview of the many effects of the protein corona and the theranostic applications of ACNPs for the treatment of cancer.
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Affiliation(s)
- Mamta Kumari
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Amitabha Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (H.P.) 176061, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Praveen Thaggikuppe Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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20
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Tang C, Ke M, Yu X, Sun S, Luo X, Liu X, Zhou Y, Wang Z, Cui X, Gu C, Yang Y. GART Functions as a Novel Methyltransferase in the RUVBL1/β-Catenin Signaling Pathway to Promote Tumor Stemness in Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301264. [PMID: 37439412 PMCID: PMC10477903 DOI: 10.1002/advs.202301264] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/30/2023] [Indexed: 07/14/2023]
Abstract
Tumor stemness is associated with the recurrence and incurability of colorectal cancer (CRC), which lacks effective therapeutic targets and drugs. Glycinamide ribonucleotide transformylase (GART) fulfills an important role in numerous types of malignancies. The present study aims to identify the underlying mechanism through which GART may promote CRC stemness, as to developing novel therapeutic methods. An elevated level of GART is associated with poor outcomes in CRC patients and promotes the proliferation and migration of CRC cells. CD133+ cells with increased GART expression possess higher tumorigenic and proliferative capabilities both in vitro and in vivo. GART is identified to have a novel methyltransferase function, whose enzymatic activity center is located at the E948 site. GART also enhances the stability of RuvB-like AAA ATPase 1 (RUVBL1) through methylating its K7 site, which consequently aberrantly activates the Wnt/β-catenin signaling pathway to induce tumor stemness. Pemetrexed (PEM), a compound targeting GART, combined with other chemotherapy drugs greatly suppresses tumor growth both in a PDX model and in CRC patients. The present study demonstrates a novel methyltransferase function of GART and the role of the GART/RUVBL1/β-catenin signaling axis in promoting CRC stemness. PEM may be a promising therapeutic agent for the treatment of CRC.
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Affiliation(s)
- Chao Tang
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210008China
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Mengying Ke
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Xichao Yu
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Shanliang Sun
- School of PharmacyNanjing University of Chinese MedicineNanjing210046China
| | - Xian Luo
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Xin Liu
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Yanyan Zhou
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Ze Wang
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Xing Cui
- Department of Hematology and OncologyThe Second Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan250001China
| | - Chunyan Gu
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210008China
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
| | - Ye Yang
- School of Medicine & Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210046China
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21
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Yue M, Guo T, Nie DY, Zhu YX, Lin M. Advances of nanotechnology applied to cancer stem cells. World J Stem Cells 2023; 15:514-529. [PMID: 37424953 PMCID: PMC10324502 DOI: 10.4252/wjsc.v15.i6.514] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/01/2023] [Accepted: 04/18/2023] [Indexed: 06/26/2023] Open
Abstract
Cancer stem cells (CSCs) are a small proportion of the cells that exist in cancer tissues. They are considered to be the culprit of tumor genesis, development, drug resistance, metastasis and recurrence because of their self-renewal, proliferation, and differentiation potential. The elimination of CSCs is thus the key to cure cancer, and targeting CSCs provides a new method for tumor treatment. Due to the advantages of controlled sustained release, targeting and high biocompatibility, a variety of nanomaterials are used in the diagnosis and treatments targeting CSCs and promote the recognition and removal of tumor cells and CSCs. This article mainly reviews the research progress of nanotechnology in sorting CSCs and nanodrug delivery systems targeting CSCs. Furthermore, we identify the problems and future research directions of nanotechnology in CSC therapy. We hope that this review will provide guidance for the design of nanotechnology as a drug carrier so that it can be used in clinic for cancer therapy as soon as possible.
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Affiliation(s)
- Miao Yue
- Clinical Laboratory, Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu Province, China
| | - Ting Guo
- Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Deng-Yun Nie
- Clinical Laboratory, Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu Province, China
| | - Yin-Xing Zhu
- Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Mei Lin
- Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China.
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22
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Dianat-Moghadam H, Abbasspour-Ravasjani S, Hamishehkar H, Rahbarghazi R, Nouri M. LXR inhibitor SR9243-loaded immunoliposomes modulate lipid metabolism and stemness in colorectal cancer cells. Med Oncol 2023; 40:156. [PMID: 37093287 DOI: 10.1007/s12032-023-02027-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/13/2023] [Indexed: 04/25/2023]
Abstract
Reprogrammed metabolism and active stemness contribute to cancer stem cells' (CSCs) survival and tumorigenesis. LXR signaling regulates the metabolism of different cancers. A selective LXR inhibitor, SR9243 (SR), can target and eradicate non-CSC tumor cells. CD133 is a stem marker in solid tumors-associated CSCs within the active lipogenesis, and anti-CD133 mAb targeting liposomal drug delivery systems expected to increase drug internalization and improve the therapeutic efficacy of poor-in water solubility drugs, e, g., SR. In this study, anti-CD133 mAbs-targeted Immunoliposomes (ILipo) were developed for specific delivery of SR into MACS-enriched CD133 + CSCs and induce their functional effects. Results have shown that ILipo having an average size of 64.79 nm can encapsulate SR in maximum proportion, and cell association studies have shown cationic ILipo and targeting CD133 provide the CSCs binding. Also, FCM analysis of RhoB has demonstrated that the ILipo uptake was higher in CD133 + CSCs than in the non-targeted liposomes. ILipo-SR was significantly more toxic in CD133 + CSCs compared to the free SR and non-targeted ones. More efficient than Lipo-SR, ILipo-SR improved the reduction of clonogenicity, stemness, and lipogenesis in CD133 + CSCs in vitro, boosted ROS generation, and induced apoptosis. Our study revealed the dual targeting of CD133 and LXR appears to be a promising strategy for targeting CD133 + CSCs-presenting dynamic metabolism and self-renewal potentials.
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Affiliation(s)
- Hassan Dianat-Moghadam
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Hamed Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahammad Nouri
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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23
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Gillespie MS, Ward CM, Davies CC. DNA Repair and Therapeutic Strategies in Cancer Stem Cells. Cancers (Basel) 2023; 15:1897. [PMID: 36980782 PMCID: PMC10047301 DOI: 10.3390/cancers15061897] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.
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Affiliation(s)
- Matthew S. Gillespie
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK; (M.S.G.)
- School of Cancer Sciences, University of Southampton, Southampton SO16 6YD, UK
| | - Ciara M. Ward
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK; (M.S.G.)
| | - Clare C. Davies
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK; (M.S.G.)
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24
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An J, Hu X, Liu F. Current understanding of cancer stem cells: Immune evasion and targeted immunotherapy in gastrointestinal malignancies. Front Oncol 2023; 13:1114621. [PMID: 36910604 PMCID: PMC9996315 DOI: 10.3389/fonc.2023.1114621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
As a relatively rare population of cancer cells existing in the tumor microenvironment, cancer stem cells (CSCs) possess properties of immune privilege to evade the attack of immune system, regulated by the microenvironment of CSCs, the so-called CSCs niche. The bidirectional interaction of CSCs with tumor microenvironment (TME) components favors an immunosuppressive shelter for CSCs' survival and maintenance. Gastrointestinal cancer stem cells (GCSCs) are broadly regarded to be intimately involved in tumor initiation, progression, metastasis and recurrence, with elevated tumor resistance to conventional therapies, which pose a major hindrance to the clinical efficacy for treated patients with gastrointestinal malignancies. Thus, a multitude of efforts have been made to combat and eradicate GCSCs within the tumor mass. Among diverse methods of targeting CSCs in gastrointestinal malignancies, immunotherapy represents a promising strategy. And the better understanding of GCSCs immunomodulation and immunoresistance mechanisms is beneficial to guide and design novel GCSCs-specific immunotherapies with enhanced immune response and clinical efficacy. In this review, we have gathered available and updated information to present an overview of the immunoevasion features harbored by cancer stem cells, and we focus on the description of immune escape strategies utilized by CSCs and microenvironmental regulations underlying CSCs immuno-suppression in the context of gastrointestinal malignancies. Importantly, this review offers deep insights into recent advances of CSC-targeting immunotherapeutic approaches in gastrointestinal cancers.
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Affiliation(s)
- Junyi An
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohua Hu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Swetha KL, Maravajjala KS, Li SD, Singh MS, Roy A. Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation. Drug Deliv Transl Res 2023; 13:105-134. [PMID: 35697894 DOI: 10.1007/s13346-022-01194-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 12/13/2022]
Abstract
Most of the current antitumor therapeutics were developed targeting the cancer cells only. Unfortunately, in the majority of tumors, this single-dimensional therapy is found to be ineffective. Advanced research has shown that cancer is a multicellular disorder. The tumor microenvironment (TME), which is made by a complex network of the bulk tumor cells and other supporting cells, plays a crucial role in tumor progression. Understanding the importance of the TME in tumor growth, different treatment modalities have been developed targeting these supporting cells. Recent clinical results suggest that simultaneously targeting multiple components of the tumor ecosystem with drug combinations can be highly effective. This type of "multidimensional" therapy has a high potential for cancer treatment. However, tumor-specific delivery of such multi-drug combinations remains a challenge. Nanomedicine could be utilized for the tumor-targeted delivery of such multidimensional therapeutics. In this review, we first give a brief overview of the major components of TME. We then highlight the latest developments in nanoparticle-based combination therapies, where one drug targets cancer cells and other drug targets tumor-supporting components in the TME for a synergistic effect. We include the latest preclinical and clinical studies and discuss innovative nanoparticle-mediated targeting strategies.
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Affiliation(s)
- K Laxmi Swetha
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India
| | - Kavya Sree Maravajjala
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India
| | - Shyh-Dar Li
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Westbrook Mall, Vancouver, BC, Canada
| | - Manu Smriti Singh
- Department of Biotechnology, Bennett University, Greater Noida, Uttar Pradesh, 201310, India. .,Center of Excellence for Nanosensors and Nanomedicine, Bennett University, Greater Noida, Uttar Pradesh, 201310, India.
| | - Aniruddha Roy
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India.
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26
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Design of Nanoparticles in Cancer Therapy Based on Tumor Microenvironment Properties. Pharmaceutics 2022; 14:pharmaceutics14122708. [PMID: 36559202 PMCID: PMC9785496 DOI: 10.3390/pharmaceutics14122708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/23/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and battling cancer has always been a challenging subject in medical sciences. All over the world, scientists from different fields of study try to gain a deeper knowledge about the biology and roots of cancer and, consequently, provide better strategies to fight against it. During the past few decades, nanoparticles (NPs) have attracted much attention for the delivery of therapeutic and diagnostic agents with high efficiency and reduced side effects in cancer treatment. Targeted and stimuli-sensitive nanoparticles have been widely studied for cancer therapy in recent years, and many more studies are ongoing. This review aims to provide a broad view of different nanoparticle systems with characteristics that allow them to target diverse properties of the tumor microenvironment (TME) from nanoparticles that can be activated and release their cargo due to the specific characteristics of the TME (such as low pH, redox, and hypoxia) to nanoparticles that can target different cellular and molecular targets of the present cell and molecules in the TME.
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27
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Cepero A, Luque C, Cabeza L, Perazzoli G, Quiñonero F, Mesas C, Melguizo C, Prados J. Antibody-Functionalized Nanoformulations for Targeted Therapy of Colorectal Cancer: A Systematic Review. Int J Nanomedicine 2022; 17:5065-5080. [PMID: 36345508 PMCID: PMC9635983 DOI: 10.2147/ijn.s368814] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 08/21/2022] [Indexed: 11/06/2022] Open
Abstract
The failure of chemotherapeutic treatment in colorectal cancer (CRC), the second most mortal cancer worldwide, is associated with several drug limitations, such as non-selective distribution, short half-life, and development of multiple resistances. One of the most promising strategies in CRC therapy is the development of delivery systems based on nanomaterials that can transport antitumor agents to the tumor site more efficiently, increasing accumulation within the tumor and thus the antitumor effect. In addition to taking advantage of the increased permeability and retention effect (EPR) of solid tumors, these nanoformulations can be conjugated with monoclonal antibodies that recognize molecular markers that are specifically over-expressed on CRC cells. Active targeting of nanoformulations reduces the adverse effects associated with the cytotoxic activity of drugs in healthy tissues, which will be of interest for improving the quality of life of cancer patients in the future. This review focuses on in vitro and in vivo studies of drug delivery nanoformulations functionalized with monoclonal antibodies for targeted therapy of CRC.
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Affiliation(s)
- Ana Cepero
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain
| | - Cristina Luque
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain
| | - Laura Cabeza
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain
| | - Francisco Quiñonero
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain
| | - Cristina Mesas
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain,Correspondence: Consolación Melguizo, Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain, Tel +34-958-249833, Email
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain,Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain,Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Granada, 18014, Spain
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28
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Abdou Hassan W, Muqresh MA, Omar M. The Potential Role of CD44 and CD133 in Colorectal Stem Cell Cancer. Cureus 2022; 14:e30509. [DOI: 10.7759/cureus.30509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2022] [Indexed: 11/05/2022] Open
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29
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Sun Y, Li B, Cao Q, Liu T, Li J. Targeting cancer stem cells with polymer nanoparticles for gastrointestinal cancer treatment. Stem Cell Res Ther 2022; 13:489. [PMID: 36182897 PMCID: PMC9526954 DOI: 10.1186/s13287-022-03180-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 09/24/2022] [Indexed: 11/10/2022] Open
Abstract
Nanomaterials are developing rapidly in the medical field, bringing new hope for treating various refractory diseases. Among them, polymer nanomaterials, with their excellent properties, have been used to treat various diseases, such as malignant tumors, diabetes, and nervous system diseases. Gastrointestinal cancer is among the cancers with the highest morbidity and mortality worldwide. Cancer stem cells are believed to play an important role in the occurrence and development of tumors. This article summarizes the characteristics of gastrointestinal cancer stem cells and reviews the latest research progress in treating gastrointestinal malignant tumors using polymer nanoparticles to target cancer stem cells. In addition, the review article highlights the potential of polymer nanoparticles in targeting gastrointestinal cancer stem cells.
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Affiliation(s)
- Yao Sun
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China
| | - Bo Li
- Department of Rehabilitation Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130000, China
| | - Qian Cao
- Department of Education, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China.
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30
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Firdous S, Ghosh A, Saha S. BCSCdb: a database of biomarkers of cancer stem cells. Database (Oxford) 2022; 2022:6725752. [PMID: 36169329 PMCID: PMC9517164 DOI: 10.1093/database/baac082] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/06/2022] [Accepted: 09/02/2022] [Indexed: 06/14/2023]
Abstract
Cancer stem cells (CSCs) are a small heterogeneous population present within the tumor cells exhibiting self-renewal properties. CSCs have been demonstrated to elicit an important role in cancer recurrence, metastasis and drug resistance. CSCs are distinguished from cancer cell populations based on their molecular profiling or expression of distinct CSC biomarker(s). Recently, a huge amount of omics data have been generated for the characterization of CSCs, which enables distinguishing CSCs in different cancers. Here, we report biomarkers of the Cancer Stem Cells database (BCSCdb), a repository of information about CSC biomarkers. BCSCdb comprises CSC biomarkers collected from PubMed literature where these are identified using high-throughput and low-throughput methods. Each biomarker is provided with two different scores: the first is a confidence score to give confidence to reported CSC biomarkers based on the experimental method of detection in CSCs. The second is the global score to identify the global CSC biomarkers across 10 different types of cancer. This database contains three tables containing information about experimentally validated CSC biomarkers or genes, therapeutic target genes of CSCs and CSC biomarkers interactions. It contains information on three types of markers: high-throughput marker (HTM-8307), high-throughput marker validated by the low-throughput method (283) and low-throughput marker (LTM-525). A total of 171 low-throughput biomarkers were identified in primary tissue referred to as clinical biomarkers. Moreover, it contains 445 target genes for CSC therapeutics, 10 biomarkers targeted by clinical trial drugs in CSCs and 5 different types of interaction data for CSC biomarkers. BCSCdb is an online resource for CSC biomarkers, which will be immensely helpful in the cancer research community and is freely available. Database URL: http://dibresources.jcbose.ac.in/ssaha4/bcscdb.
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Affiliation(s)
- Shazia Firdous
- Division of Bioinformatics, Bose Institute, Unified Campus Salt Lake, College More, EN Block, Sector V, Kolkata, West Bengal 700091, India
| | - Abhirupa Ghosh
- Division of Bioinformatics, Bose Institute, Unified Campus Salt Lake, College More, EN Block, Sector V, Kolkata, West Bengal 700091, India
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31
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Buyana B, Naki T, Alven S, Aderibigbe BA. Nanoparticles Loaded with Platinum Drugs for Colorectal Cancer Therapy. Int J Mol Sci 2022; 23:11261. [PMID: 36232561 PMCID: PMC9569963 DOI: 10.3390/ijms231911261] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is a common cancer in both men and women. Numerous studies on the therapeutic effectiveness of nanoparticles against colorectal cancer have been reported. Platinum treatments as well as other medications comprising of nanoparticles have been utilized. Drug resistance restricts the use of platinum medicines, despite their considerable efficacy against a variety of cancers. This review reports clinically licensed platinum medicines (cisplatin, carboplatin, and oxaliplatin) combined with various nanoparticles that have been evaluated for their therapeutic efficacy in the treatment of colorectal cancer, including their mechanism of action, resistance, and limitations.
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Affiliation(s)
| | | | | | - Blessing Atim Aderibigbe
- Department of Chemistry, University of Fort Hare, Alice 5700, Eastern Cape Province, South Africa
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32
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Malindi Z, Barth S, Abrahamse H. The Potential of Antibody Technology and Silver Nanoparticles for Enhancing Photodynamic Therapy for Melanoma. Biomedicines 2022; 10:2158. [PMID: 36140259 PMCID: PMC9495799 DOI: 10.3390/biomedicines10092158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Melanoma is highly aggressive and is known to be efficient at resisting drug-induced apoptotic signals. Resection is currently the gold standard for melanoma management, but it only offers local control of the early stage of the disease. Metastatic melanoma is prone to recurrence, and has a poor prognosis and treatment response. Thus, the need for advanced theranostic alternatives is evident. Photodynamic therapy has been increasingly studied for melanoma treatment; however, it relies on passive drug accumulation, leading to off-target effects. Nanoparticles enhance drug biodistribution, uptake and intra-tumoural concentration and can be functionalised with monoclonal antibodies that offer selective biorecognition. Antibody-drug conjugates reduce passive drug accumulation and off-target effects. Nonetheless, one limitation of monoclonal antibodies and antibody-drug conjugates is their lack of versatility, given cancer's heterogeneity. Monoclonal antibodies suffer several additional limitations that make recombinant antibody fragments more desirable. SNAP-tag is a modified version of the human DNA-repair enzyme, O6-alkylguanine-DNA alkyltransferase. It reacts in an autocatalytic and covalent manner with benzylguanine-modified substrates, providing a simple protein labelling system. SNAP-tag can be genetically fused with antibody fragments, creating fusion proteins that can be easily labelled with benzylguanine-modified payloads for site-directed delivery. This review aims to highlight the benefits and limitations of the abovementioned approaches and to outline how their combination could enhance photodynamic therapy for melanoma.
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Affiliation(s)
- Zaria Malindi
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 55 Beit Street, Doornfontein, Johannesburg 2028, South Africa
| | - Stefan Barth
- Medical Biotechnology and Immunotherapy Research Unit, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road Observatory, Cape Town 7925, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 55 Beit Street, Doornfontein, Johannesburg 2028, South Africa
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33
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CRISPR screening in cancer stem cells. Essays Biochem 2022; 66:305-318. [PMID: 35713228 DOI: 10.1042/ebc20220009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are a subpopulation of tumor cells with self-renewal ability. Increasing evidence points to the critical roles of CSCs in tumorigenesis, metastasis, therapy resistance, and cancer relapse. As such, the elimination of CSCs improves cancer treatment outcomes. However, challenges remain due to limited understanding of the molecular mechanisms governing self-renewal and survival of CSCs. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screening has been increasingly used to identify genetic determinants in cancers. In this primer, we discuss the progress made and emerging opportunities of coupling advanced CRISPR screening systems with CSC models to reveal the understudied vulnerabilities of CSCs.
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34
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Shrestha S, Banstola A, Jeong JH, Seo JH, Yook S. Targeting Cancer Stem Cells: Therapeutic and diagnostic strategies by the virtue of nanoparticles. J Control Release 2022; 348:518-536. [PMID: 35709876 DOI: 10.1016/j.jconrel.2022.06.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) are the subpopulation of cells present within a tumor with the properties of self-renewing, differentiating, and proliferating. Owing to the presence of ATP-binding cassette drug pumps and increased expression of anti-apoptotic proteins, the conventional chemotherapeutic agents have failed to eliminate CSCs resulting in relapse and resistance of cancer. Therefore, to obtain long-lasting clinical responses and avoid the recurrence of cancer, it is crucial to develop an efficient strategy targeting CSCs by either employing a differentiation therapy or specifically delivering drugs to CSCs. Several intracellular and extracellular cancer specific biomarkers are overexpressed by CSCs and are utilized as targets for the development of new approaches in the diagnosis and treatment of CSCs. Moreover, several nanostructured particles, alone or in combination with current treatment approaches, have been used to improve the detection, imaging, and targeting of CSCs, thus addressing the limitations of cancer therapies. Targeting CSC surface markers, stemness-related signaling pathways, and tumor microenvironmental signals has improved the detection and eradication of CSCs and, therefore, tumor diagnosis and treatment. This review summarizes a variety of promising nanoparticles targeting the surface biomarkers of CSCs for the detection and eradication of tumor-initiating stem cells, used in combination with other treatment regimens.
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Affiliation(s)
- Samjhana Shrestha
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea
| | - Asmita Banstola
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea; Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ji Hae Seo
- Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea.
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Wu SY, Wu FG, Chen X. Antibody-Incorporated Nanomedicines for Cancer Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2109210. [PMID: 35142395 DOI: 10.1002/adma.202109210] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 02/06/2022] [Indexed: 06/14/2023]
Abstract
Antibody-based cancer therapy, one of the most significant therapeutic strategies, has achieved considerable success and progress over the past decades. Nevertheless, obstacles including limited tumor penetration, short circulation half-lives, undesired immunogenicity, and off-target side effects remain to be overcome for the antibody-based cancer treatment. Owing to the rapid development of nanotechnology, antibody-containing nanomedicines that have been extensively explored to overcome these obstacles have already demonstrated enhanced anticancer efficacy and clinical translation potential. This review intends to offer an overview of the advancements of antibody-incorporated nanoparticulate systems in cancer treatment, together with the nontrivial challenges faced by these next-generation nanomedicines. Diverse strategies of antibody immobilization, formats of antibodies, types of cancer-associated antigens, and anticancer mechanisms of antibody-containing nanomedicines are provided and discussed in this review, with an emphasis on the latest applications. The current limitations and future research directions on antibody-containing nanomedicines are also discussed from different perspectives to provide new insights into the construction of anticancer nanomedicines.
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Affiliation(s)
- Shun-Yu Wu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China
| | - Fu-Gen Wu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China
| | - Xiaoyuan Chen
- Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119077, Singapore
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Shih YH, Peng CL, Chiang PF, Shieh MJ. Dual-Functional Polymeric Micelles Co-Loaded with Antineoplastic Drugs and Tyrosine Kinase Inhibitor for Combination Therapy in Colorectal Cancer. Pharmaceutics 2022; 14:pharmaceutics14040768. [PMID: 35456602 PMCID: PMC9030189 DOI: 10.3390/pharmaceutics14040768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/18/2022] [Accepted: 03/26/2022] [Indexed: 12/24/2022] Open
Abstract
The aim of this research was to evaluate the receptor tyrosine kinase inhibitor Sunitinib combined with SN-38 in polymeric micelles for antitumor efficacy in colorectal cancer. First, SN-38 and Sunitinib co-loaded micelles were developed and characterized. We studied cell viability and cellular uptake in HCT-116 cells. Then, subcutaneous HCT-116 xenograft tumors were used for ex vivo biodistribution, antitumor efficacy, and histochemical analysis studies. Results of cellular uptake and ex vivo biodistribution of SN-38/Sunitinib micelles showed the highest accumulation in tumors compared with other normal organs. In the antitumor effect studies, mice bearing HCT-116 tumors were smallest at day 28 after injection of SN-38/Sunitinib micelles, compared with other experiment groups (p < 0.01). As demonstrated by the results of inhibition on multi-receptors by Sunitinib, we confirmed that SN-38/Sunitinib co-loaded micelles to be a treatment modality that could inhibit VEGF and PDGF receptors and enhance the antitumor effect of SN-38 (p < 0.05). In summary, we consider that this micelle is a potential formulation for the combination of SN-38 and Sunitinib in the treatment of colorectal cancer.
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Affiliation(s)
- Ying-Hsia Shih
- Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan 32546, Taiwan; (Y.-H.S.); (P.-F.C.)
| | - Cheng-Liang Peng
- Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan 32546, Taiwan; (Y.-H.S.); (P.-F.C.)
- Correspondence: (C.-L.P.); (M.-J.S.)
| | - Ping-Fang Chiang
- Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan 32546, Taiwan; (Y.-H.S.); (P.-F.C.)
| | - Ming-Jium Shieh
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 100, Taiwan
- Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan
- Correspondence: (C.-L.P.); (M.-J.S.)
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Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers. Cancers (Basel) 2022; 14:cancers14041028. [PMID: 35205776 PMCID: PMC8869923 DOI: 10.3390/cancers14041028] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Late-stage colorectal cancer treatment often involves chemotherapy and radiation that can cause dose-limiting toxicity, and therefore there is great interest in developing targeted therapies for this disease. Immunotherapy is a targeted therapy that uses peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer. Here, we discuss the preclinical and clinical development of immunotherapy for treatment of colorectal cancer and provide an overview of predictive biomarkers for such treatments. We also consider open questions including optimal combination treatments and sensitization of colorectal cancer patients with proficient mismatch repair enzymes. Abstract Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy.
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Wang Y, Gong X, Li J, Wang H, Xu X, Wu Y, Wang J, Wang S, Li Y, Zhang Z. M2 macrophage microvesicle-inspired nanovehicles improve accessibility to cancer cells and cancer stem cells in tumors. J Nanobiotechnology 2021; 19:397. [PMID: 34838042 PMCID: PMC8627085 DOI: 10.1186/s12951-021-01143-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/14/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer cells and cancer stem cells (CSCs) are the major players of cancer malignancy and metastasis, but they are extremely difficult to access. Inspired by the vital role of macrophages and microvesicle-mediated cell–cell communication in tumors, we herein designed M2 macrophage microvesicle-inspired nanovehicle of cabazitaxel (M-CFN) to promote accessibility to cancer cells and CSCs in tumors. In the 4T1 tumor model, M-CFN flexibly permeated the tumor mass, accessed cancer cells and CD90-positive cells, and significantly promoted their entry into CSC fractions in tumors. Moreover, M-CFN treatment profoundly eliminated aldehyde dehydrogenase (ALDH)-expressing CSCs in 4T1 and MCF-7 tumors, produced notable depression of tumor growth and caused 93.86% suppression of lung metastasis in 4T1 models. Therefore, the M2 macrophage microvesicle-inspired nanovehicle provides an encouraging strategy to penetrate the tumor tissues and access these insult cells in tumors for effective cancer therapy. ![]()
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Affiliation(s)
- Yuqi Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.,State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiang Gong
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jie Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hong Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiaoxuan Xu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yao Wu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jiaoying Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Siling Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Zhiwen Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. .,Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
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Fabrication of supramolecular nano-assembly irinotecan prodrug into polymeric nanomaterials for delivery in cervical carcinoma therapy. Process Biochem 2021. [DOI: 10.1016/j.procbio.2021.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Ying K, Bai B, Gao X, Xu Y, Wang H, Xie B. Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer. Front Bioeng Biotechnol 2021; 9:670124. [PMID: 34307319 PMCID: PMC8293278 DOI: 10.3389/fbioe.2021.670124] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drugs have low water solubility and are unstable in the gastrointestinal tract (GIT), poor intestinal permeability, and are susceptible to P-glycoprotein (P-gp) efflux, resulting in limited therapeutic outcomes. Orally administrable nanoformulations hold the great potential for improving the bioavailability of poorly permeable and poorly soluble therapeutics, but there are still limitations associated with these regimes. This review focuses on the barriers for oral drug delivery and various oral therapeutic nanoparticles for the management of CRC.
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Affiliation(s)
- Kangkang Ying
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC), Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bingjun Bai
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xing Gao
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuzi Xu
- Department of Oral Implantology and Prosthodontics, The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Hangxiang Wang
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC), Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
| | - Binbin Xie
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC), Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Ertas YN, Abedi Dorcheh K, Akbari A, Jabbari E. Nanoparticles for Targeted Drug Delivery to Cancer Stem Cells: A Review of Recent Advances. NANOMATERIALS 2021; 11:nano11071755. [PMID: 34361141 PMCID: PMC8308126 DOI: 10.3390/nano11071755] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022]
Abstract
Cancer stem cells (CSCs) are a subpopulation of cells that can initiate, self-renew, and sustain tumor growth. CSCs are responsible for tumor metastasis, recurrence, and drug resistance in cancer therapy. CSCs reside within a niche maintained by multiple unique factors in the microenvironment. These factors include hypoxia, excessive levels of angiogenesis, a change of mitochondrial activity from aerobic aspiration to aerobic glycolysis, an upregulated expression of CSC biomarkers and stem cell signaling, and an elevated synthesis of the cytochromes P450 family of enzymes responsible for drug clearance. Antibodies and ligands targeting the unique factors that maintain the niche are utilized for the delivery of anticancer therapeutics to CSCs. In this regard, nanomaterials, specifically nanoparticles (NPs), are extremely useful as carriers for the delivery of anticancer agents to CSCs. This review covers the biology of CSCs and advances in the design and synthesis of NPs as a carrier in targeting cancer drugs to the CSC subpopulation of cancer cells. This review includes the development of synthetic and natural polymeric NPs, lipid NPs, inorganic NPs, self-assembling protein NPs, antibody-drug conjugates, and extracellular nanovesicles for CSC targeting.
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Affiliation(s)
- Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey;
- ERNAM—Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Keyvan Abedi Dorcheh
- Department of Biomedical Engineering, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran 14115, Iran;
| | - Ali Akbari
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia 57147, Iran;
| | - Esmaiel Jabbari
- Biomaterials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, SC 29208, USA
- Correspondence:
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Sang R, Stratton B, Engel A, Deng W. Liposome technologies towards colorectal cancer therapeutics. Acta Biomater 2021; 127:24-40. [PMID: 33812076 DOI: 10.1016/j.actbio.2021.03.055] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/05/2021] [Accepted: 03/23/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth most common deadly cancer worldwide. After treatment with curative intent recurrence rates vary with staging 0-13% in Stage 1, 11-61% in S2 and 28-73% in Stage 3. The toxicity to healthy tissues from chemotherapy and radiotherapy and drug resistance severely affect the quality of life and cancer specific outcomes of CRC patients. To overcome some of these limitations, many efforts have been made to develop nanomaterial-based drug delivery systems. Among these nanocarriers, liposomes represented one of the most successful candidates in delivering targeted oncological treatment, improving safety profile and therapeutic efficacy of encapsulated drugs. In this review we will discuss liposome design with a particular focus on the targeting feature and triggering functions. We will also summarise the recent advances in liposomal delivery system for CRC treatment in both the preclinical and clinical studies. We will finally provide our perspectives on the liposome technology development for the future clinical translation. STATEMENT OF SIGNIFICANCE: Conventional treatments for colorectal cancer (CRC) severely affect the therapeutic effects for advanced patients. With the development of nanomedicines, liposomal delivery system appears to be one of the most promising nanocarriers for CRC treatment. In last three years several reviews in this area have been published focusing on the preclinical research and drug delivery function, which is a fairly narrow focus in the field of liposome technology for CRC therapy. Our review presented the most recent advances of the liposome technology (both clinical and preclinical applications) for CRC with strong potential for further clinical translation. We believe it will attract lots of attention from various audiences, including researchers, clinicians and the industry.
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Mohd-Zahid MH, Zulkifli SN, Che Abdullah CA, Lim J, Fakurazi S, Wong KK, Zakaria AD, Ismail N, Uskoković V, Mohamud R, Z A I. Gold nanoparticles conjugated with anti-CD133 monoclonal antibody and 5-fluorouracil chemotherapeutic agent as nanocarriers for cancer cell targeting. RSC Adv 2021; 11:16131-16141. [PMID: 35481195 PMCID: PMC9030463 DOI: 10.1039/d1ra01093j] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/25/2021] [Indexed: 12/17/2022] Open
Abstract
The enhanced permeability and retention effect allows for passive targeting of solid tumours by nanoparticles carrying anticancer drugs. However, active targeting by incorporation of various ligands onto nanoparticles can provide for a more selective and enhanced chemotherapeutic effect and complement the deficiencies of the passive targeting approach. Here we report on the design of the carboxyl-terminated PEGylated gold nanoparticles (AuNPs), their functionalization with anti-CD133 monoclonal antibody (mAb) via a crosslinking reaction, and subsequent 5-fluorouracil (5-FU) drug loading. The synthesized products in the form of stable colloids were characterised using a range of physicochemical techniques, including X-ray diffraction (XRD), UV-Vis spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Conjugation of anti-CD133 mAb onto PEGylated AuNPs was confirmed with the use of UV-Vis, BCA protein assay and fluorescence microscopy. HCT116 colorectal cancer cells abundantly expressed CD133: 92.4 ± 1.3%, as measured by flow cytometry. Whereas PEGylated AuNPs not conjugated with anti-CD133 mAb accumulated mainly at the cellular membrane, nanoparticles conjugated with anti-CD133 mAb were contained within the nuclear region of the cells. Anti-CD133 mAb conjugation facilitated the specific intracellular uptake due to specific antigen-antibody binding interaction. In vitro cytotoxicity studies on HCT116 cells showed that PEGylated AuNPs and PEGylated AuNPs-CD133 did not elicit any toxicity at any of the tested concentrations. Meanwhile, 5-FU-PEGylated AuNPs-CD133 significantly reduced the cell viability relative to the treatment with 5-FU-PEGylated AuNPs without anti-CD133 mAb conjugates (p < 0.0001). This study shows that the conjugation of nanocarriers with the anti-CD133 antibody improves the specific targeting of 5-FU against colorectal cancer cells. These results demonstrate that simultaneous functionalisation of PEGylated AuNPs with antibodies and chemotherapeutic drugs is a viable strategy to combat cancer through targeted drug delivery.
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Affiliation(s)
- Manali Haniti Mohd-Zahid
- Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
| | - Siti Nadiah Zulkifli
- Material Synthesis and Characterization Laboratory, Institute of Advanced Technology, Universiti Putra Malaysia Serdang 43400 Selangor Malaysia
| | - Che Azurahanim Che Abdullah
- Material Synthesis and Characterization Laboratory, Institute of Advanced Technology, Universiti Putra Malaysia Serdang 43400 Selangor Malaysia
- Department of Physics, Faculty of Science, Universiti Putra Malaysia Serdang 43400 Selangor Malaysia
| | - JitKang Lim
- School of Chemical Engineering, Universiti Sains Malaysia 14300 Nibong Tebal Penang Malaysia
| | - Sharida Fakurazi
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia Serdang 43400 Selangor Malaysia
| | - Kah Keng Wong
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
| | - Andee Dzulkarnaen Zakaria
- Department of Surgery, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
| | - Norzila Ismail
- Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
| | - Vuk Uskoković
- Advanced Materials and Nanobiotechnology Laboratory, TardigradeNano LLC Irvine CA 92604 USA
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
| | - Iskandar Z A
- Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
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Notabi MK, Arnspang EC, Andersen MØ. Antibody conjugated lipid nanoparticles as a targeted drug delivery system for hydrophobic pharmaceuticals. Eur J Pharm Sci 2021; 161:105777. [PMID: 33647401 DOI: 10.1016/j.ejps.2021.105777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/10/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
Cancer remains a significant health issue worldwide. The most common group of chemotherapeutic agents are small-molecule drugs, which often are associated with toxic side-effects and non-specific delivery, leading to limited therapeutic effect. This paper describes the development of a targeted drug delivery system based on lipid nanoparticles for cancer therapy. The lipid nanoparticles consist of a lipid core conjugated to an albumin stealth coating and targeting antibodies through thiol chemistry synthesized utilizing a one-step method. Applying the developed method, lipid nanoparticles with diameters down to 87 nm, capable of encapsulating small molecule compounds were synthesized. Cellular uptake studies of the lipid nanoparticles loaded with the model drug Nile red demonstrated that stealth-coating reduced non-specific cell uptake by up to a 1000-fold compared to free drug. Moreover, antibody-conjugation led to a significant cellular retargeting. Finally, it was shown that the lipid nanoparticles undergo cellular uptake through the endocytic pathway. The lipid nanoparticles are simple to synthesize, stabile in serum and have the potential to be versatile targeted towards receptors selectively expressed by diseased cells using antibodies. Thus, the system may reduce the toxic side-effects of cancer drugs while improving their delivery to cancer cells, increasing the therapeutic effect.
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Affiliation(s)
- Martine K Notabi
- SDU Biotechnology, Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Campusvej 55, Odense M DK-5230, Denmark
| | - Eva C Arnspang
- SDU Biotechnology, Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Campusvej 55, Odense M DK-5230, Denmark
| | - Morten Ø Andersen
- SDU Biotechnology, Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Campusvej 55, Odense M DK-5230, Denmark.
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Yan S, Tang D, Hong Z, Wang J, Yao H, Lu L, Yi H, Fu S, Zheng C, He G, Zou H, Hou X, He Q, Xiong L, Li Q, Deng X. CD133 peptide-conjugated pyropheophorbide-a as a novel photosensitizer for targeted photodynamic therapy in colorectal cancer stem cells. Biomater Sci 2021; 9:2020-2031. [PMID: 33439161 DOI: 10.1039/d0bm01874k] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer around the world. Recent findings suggest that cancer stem cells (CSCs) play a pivotal role in the resistance to current therapeutic modalities, including surgery and chemotherapy. Photodynamic therapy (PDT) is a promising non-invasive therapeutic strategy for advanced metastatic CRC. Traditional photosensitizers such as pyropheophorbide-a (Pyro) lack tumor selectivity, causing unwanted treatment-related toxicity to the surrounding normal tissue. In order to enhance the targeting properties of Pyro, we synthesize a novel photosensitizer, CD133-Pyro, via the conjugation of Pyro to a peptide domain targeting CD133, which is highly expressed on CRC CSCs and correlated with poor prognosis of CRC patients. We demonstrate that CD133-Pyro possesses the targeted delivery capacity both in CRC CSCs derived from HT29 and SW620 cell lines and in a xenograft mouse model of tumor growth. CD133-Pyro PDT can promote the production of reactive oxygen species (ROS), suppress the stemness properties, and induce autophagic cell death in CRC CSCs. Furthermore, CD133-Pyro PDT has a potent inhibitory effect on CRC CSC-derived xenograft tumors in nude mice. These findings may offer a useful and important strategy for the treatment of CRC through targeting CSCs.
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Affiliation(s)
- Shichao Yan
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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Duan H, Liu Y, Gao Z, Huang W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharm Sin B 2021; 11:55-70. [PMID: 33532180 PMCID: PMC7838023 DOI: 10.1016/j.apsb.2020.09.016] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/25/2020] [Accepted: 07/12/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.
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Key Words
- ABC, ATP binding cassette
- AFN, apoferritin
- ALDH, aldehyde dehydrogenase
- BM-MSCs-derived Exos, bone marrow mesenchymal stem cells-derived exosomes
- Biomarker
- CAFs, cancer-associated fibroblasts
- CL-siSOX2, cationic lipoplex of SOX2 small interfering RNA
- CMP, carbonate-mannose modified PEI
- CQ, chloroquine
- CSCs, cancer stem cells
- Cancer stem cells
- Cancer treatment
- Cellular level
- DCLK1, doublecortin-like kinase 1
- DDSs, drug delivery systems
- DLE, drug loading efficiency
- DOX, doxorubicin
- DQA-PEG2000-DSPE, dequlinium and carboxyl polyethylene glycol-distearoylphosphatidylethanolamine
- Dex, dexamethasone
- Drug delivery systems
- ECM, extracellular matrix
- EMT, epithelial–mesenchymal transition
- EPND, nanodiamond-Epirubicin drug complex
- EpCAM, epithelial cell adhesion molecule
- GEMP, gemcitabine monophosphate
- GLUT1, glucose ligand to the glucose transporter 1
- Glu, glucose
- HCC, hepatocellular carcinoma
- HH, Hedgehog
- HIF1α, hypoxia-inducible factor 1-alpha
- HNSCC, head and neck squamous cell carcinoma
- IONP, iron oxide nanoparticle
- LAC, lung adenocarcinoma
- LNCs, lipid nanocapsules
- MAPK, mitogen-activated protein kinase
- MB, methylene blue
- MDR, multidrug resistance
- MNP, micellar nanoparticle
- MSNs, mesoporous silica nanoparticles
- Molecular level
- NF-κB, nuclear factor-kappa B
- Nav, navitoclax
- Niche
- PBAEs, poly(β-aminoester)
- PDT, photodynamic therapy
- PEG-PCD, poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol)
- PEG-PLA, poly(ethylene glycol)-b-poly(d,l-lactide)
- PEG-b-PLA, poly(ethylene glycol)-block-poly(d,l-lactide)
- PLGA, poly(ethylene glycol)-poly(d,l-lactide-co-glycolide)
- PTX, paclitaxel
- PU-PEI, polyurethane-short branch-polyethylenimine
- SLNs, solid lipid nanoparticles
- SSCs, somatic stem cells
- Sali-ABA, 4-(aminomethyl) benzaldehyde-modified Sali
- TNBC, triple negative breast cancer
- TPZ, tirapazamine
- Targeting strategies
- cRGD, cyclic Arg-Gly-Asp
- iTEP, immune-tolerant, elastin-like polypeptide
- mAbs, monoclonal antibodies
- mPEG-b-PCC-g-GEM-g-DC-g-CAT, poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-graft-cationic ligands)
- ncRNA, non-coding RNAs
- uPAR, urokinase plasminogen activator receptor
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Affiliation(s)
- Hongxia Duan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yanhong Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Wei Huang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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Kharkar PS. Cancer Stem Cell (CSC) Inhibitors in Oncology-A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives. J Med Chem 2020; 63:15279-15307. [PMID: 33325699 DOI: 10.1021/acs.jmedchem.0c01336] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.
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Affiliation(s)
- Prashant S Kharkar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
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48
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Li W, Peng A, Wu H, Quan Y, Li Y, Lu L, Cui M. Anti-Cancer Nanomedicines: A Revolution of Tumor Immunotherapy. Front Immunol 2020; 11:601497. [PMID: 33408716 PMCID: PMC7779686 DOI: 10.3389/fimmu.2020.601497] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/20/2020] [Indexed: 12/17/2022] Open
Abstract
Immunotherapies have been accelerating the development of anti-cancer clinical treatment, but its low objective responses and severe off-target immune-related adverse events (irAEs) limit the range of application. Strategies to remove these obstacles primarily focus on the combination of different therapies and the exploitation of new immunotherapeutic agents. Nanomedicine potentiates the effects of activating immune cells selectively and reversing tumor induced immune deficiency microenvironment through multiple mechanisms. In the last decade, a variety of nano-enabled tumor immunotherapies was under clinical investigation. As time goes by, the advantages of nanomedicine are increasingly prominent. With the continuous development of nanotechnology, nanomedicine will offer more distinctive perspectives in imaging diagnosis and treatment of tumors. In this Review, we wish to provide an overview of tumor immunotherapy and the mechanisms of nanomaterials that aim to enhance the efficacy of tumor immunotherapy under development or in clinic treatment.
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Affiliation(s)
- Wei Li
- Department of General Surgery, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Anghui Peng
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Huajun Wu
- Department of General Surgery, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Yingyao Quan
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.,Faculty of Health Sciences, University of Macau, Macau, China
| | - Yong Li
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Ligong Lu
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Min Cui
- Department of General Surgery, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
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Pan Y, Zhou S, Li Y, Parshad B, Li W, Haag R. Novel dendritic polyglycerol-conjugated, mesoporous silica-based targeting nanocarriers for co-delivery of doxorubicin and tariquidar to overcome multidrug resistance in breast cancer stem cells. J Control Release 2020; 330:1106-1117. [PMID: 33189788 DOI: 10.1016/j.jconrel.2020.11.015] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/23/2020] [Accepted: 11/09/2020] [Indexed: 12/18/2022]
Abstract
Multidrug resistance (MDR) of cancer stem cells (CSCs) is a major hurdle to chemotherapy, and it is very important to develop CSCs-specific targeted nanocarriers for the treatment of drug resistant CSCs. In this work, we developed CSCs-specific targeted mSiO2-dPG nanocarriers simultaneous delivery chemotherapy drug DOX along with the P-glycoprotein (P-gp) inhibitor tariquidar (Tar) for enhanced chemotherapy to overcome MDR in breast CSCs. The mSiO2-dPG nanocarriers possess a high loading capability, excellent pH stimuli-responsive performance, and good biocompatibility. With the help of CSCs-specific targeting and P-gp inhibitor Tar, the accumulation of DOX delivered by the mSiO2-dPG nanocarriers could be greatly increased in drug resistant three-dimensional mammosphere of breast CSCs, and the chemotherapeutic efficacy against breast CSCs was enhanced. Moreover, the expression of stemness-associated gene and tumorspheres' formation ability was also significantly suppressed, which indicates the excellent capability for overcoming MDR of breast CSCs. Taken together, we developed a CSCs-specific targeted mSiO2-dPG nanocarriers for co-delivery DOX and Tar, which provide a promising approach to effectively eliminate the CSCs and overcome the MDR of breast CSCs.
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Affiliation(s)
- Yuanwei Pan
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany
| | - Suqiong Zhou
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany
| | - Yan Li
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany
| | - Badri Parshad
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany
| | - Wenzhong Li
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany.
| | - Rainer Haag
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany.
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50
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Song C, Xu W, Wu H, Wang X, Gong Q, Liu C, Liu J, Zhou L. Photodynamic therapy induces autophagy-mediated cell death in human colorectal cancer cells via activation of the ROS/JNK signaling pathway. Cell Death Dis 2020; 11:938. [PMID: 33130826 PMCID: PMC7603522 DOI: 10.1038/s41419-020-03136-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/02/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
Evidence has shown that m-THPC and verteporfin (VP) are promising sensitizers in photodynamic therapy (PDT). In addition, autophagy can act as a tumor suppressor or a tumor promoter depending on the photosensitizer (PS) and the cancer cell type. However, the role of autophagy in m-THPC- and VP-mediated PDT in in vitro and in vivo models of human colorectal cancer (CRC) has not been reported. In this study, m-THPC-PDT or VP-PDT exhibited significant phototoxicity, inhibited proliferation, and induced the generation of large amounts of reactive oxygen species (ROS) in CRC cells. From immunoblotting, fluorescence image analysis, and transmission electron microscopy, we found extensive autophagic activation induced by ROS in cells. In addition, m-THPC-PDT or VP-PDT treatment significantly induced apoptosis in CRC cells. Interestingly, the inhibition of m-THPC-PDT-induced autophagy by knockdown of ATG5 or ATG7 substantially inhibited the apoptosis of CRC cells. Moreover, m-THPC-PDT treatment inhibited tumorigenesis of subcutaneous HCT116 xenografts. Meanwhile, antioxidant treatment markedly inhibited autophagy and apoptosis induced by PDT in CRC cells by inactivating JNK signaling. In conclusion, inhibition of autophagy can remarkably alleviate PDT-mediated anticancer efficiency in CRC cells via inactivation of the ROS/JNK signaling pathway. Our study provides evidence for the therapeutic application of m-THPC and VP in CRC.
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Affiliation(s)
- Changfeng Song
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China
| | - Wen Xu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China
| | - Hongkun Wu
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, P.R. China
| | - Xiaotong Wang
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China
| | - Qianyi Gong
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China
| | - Chang Liu
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, P.R. China
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China.
| | - Lin Zhou
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, P.R. China.
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