|
1
|
Zheng Y, Cheng H, Jiang S, Tai W. Fc Multisite Conjugation and Prolonged Delivery of the Folate-Targeted Drug Conjugate EC140. Bioconjug Chem 2025; 36:762-769. [PMID: 40178505 DOI: 10.1021/acs.bioconjchem.5c00037] [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: 04/05/2025]
Abstract
Small molecule-drug conjugate (SMDC) is a targeted drug delivery technology that develops in parallel with the antibody-drug conjugate. However, the clinical translation of SMDC faces challenges due to its limited circulating half-life in vivo. The drawback in pharmacokinetics is that it restricts the exposure time of SMDC to tumor tissues and ultimately reduces the therapeutic efficacy. In this study, we chemically conjugated a folate-targeted SMDC EC140 to the long-circulating Fc protein at multiple sites, yielding a stable and high-DAR Fc-SMDC conjugate (Fc-EC140). Fc-EC140 can bear approximately 4 molecules of EC140 per Fc protein (drug-antibody ratio = 4.1) and display enhanced potency in folate receptor (FR)-positive tumor cells compared to the SMDC comparator. In addition, Fc-EC140 retains the FcRn-mediated recycling function and displays an extended half-life of 28 h in the mice. In vivo, antitumor experiments demonstrate that intravenous administration of Fc-EC140 (Q7D × 3 at a dose of 15 mg/kg) nearly cures the KB tumors, which is far more effective than the comparator EC140 administrated at equivalent doses. This study presents a new strategy for the targeted delivery of SMDC.
Collapse
Affiliation(s)
- Yan Zheng
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
- Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| | - Hong Cheng
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Sibo Jiang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan 410219, China
| | - Wanyi Tai
- Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| |
Collapse
|
|
2
|
Wang Q, Yang N, Yan H, Zhu Y, Zhang Q, Zhu R, Yang Y, Yu L, Liu Y, Li J, Li Y. Novel Folate-Phenylfuran P-gp Inhibitor Conjugates for Overcoming Multidrug Resistance in MCF-7/ADR Cell. ChemMedChem 2025:e2500216. [PMID: 40228033 DOI: 10.1002/cmdc.202500216] [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: 03/17/2025] [Revised: 04/09/2025] [Accepted: 04/14/2025] [Indexed: 04/16/2025]
Abstract
P-glycoprotein (P-gp) functions as a critical membrane transporter that drives tumor resistance by mediating drug efflux, ultimately contributing to multidrug resistance (MDR). Recently potent inhibitors have shown significant potential in countering chemotherapeutic resistance, particularly in breast cancer. However, P-gp's presence in essential organs complicates clinical applications, underscoring the importance of developing tumor-specific targeting strategies. Given the high-level expression of folate receptors (FR) on the surface of breast cancer cells, this study conjugated a previously developed P-gp inhibitor with folic acid, with the goal of harnessing FR-mediated targeting for enhanced tumor cell specificity. In vitro evaluations reveal that the resultant conjugate maintains substantial resistance reversal efficacy against the MCF-7/ADR breast cancer-resistant cell line, comparable to the standalone inhibitor. The conjugate emerges as a highly potent and safe P-gp inhibitor in xenograft mouse, likely attributable to its enhanced tumor-targeting specificity, exhibiting superior in vivo efficacy when administered in combination with doxorubicin, relative to the original P-gp inhibitor.
Collapse
Affiliation(s)
- Qin Wang
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Ning Yang
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Hui Yan
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Yunzhu Zhu
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Qingyue Zhang
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Rongqing Zhu
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Yi Yang
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Liang Yu
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Yanyan Liu
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Jiabin Li
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
| | - Yasheng Li
- Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Infectious Diseases & Institute of Bacterial Resistance, Anhui Medical University, Hefei, 230022, China
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, 999077, China
| |
Collapse
|
|
3
|
Zhu S, Jin G, He X, Li Y, Xu F, Guo H. Mechano-assisted strategies to improve cancer chemotherapy. Life Sci 2024; 359:123178. [PMID: 39471901 DOI: 10.1016/j.lfs.2024.123178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/25/2024] [Accepted: 10/22/2024] [Indexed: 11/01/2024]
Abstract
Chemotherapy remains a cornerstone in cancer treatment; however, its effectiveness is frequently undermined by the development of drug resistance. Recent studies underscores the pivotal role of the tumor mechanical microenvironment (TMME) and the emerging field of mechanical nanomedicine in tackling chemo-resistance. This review offers an in-depth analysis of mechano-assisted strategies aimed at mitigating chemo-resistance through the modification of the TMME and the refinement of mechanical nanomedicine delivery systems. We explore the potential of targeting abnormal tumor mechanical properties as a promising avenue for enhancing the efficacy of cancer chemotherapy, which offers novel directions for advancing future cancer therapies, especially from the mechanomedicine perspective.
Collapse
Affiliation(s)
- Shanshan Zhu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Guorui Jin
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Xiaocong He
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Yuan Li
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China.
| | - Feng Xu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China.
| | - Hui Guo
- Department of Medical Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
| |
Collapse
|
|
4
|
Hong M, Wang J, Chen H, Qi J, Ji Q, Liu X, Yue Q, Li L, Cheng S. Synthesis and biological evaluation of folic acid-rotenol conjugate as a potent targeted anticancer prodrug. Eur J Pharmacol 2024; 970:176482. [PMID: 38452835 DOI: 10.1016/j.ejphar.2024.176482] [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: 11/15/2023] [Revised: 02/26/2024] [Accepted: 03/05/2024] [Indexed: 03/09/2024]
Abstract
Rotenone, a plant-based agricultural insecticide, has been shown to have anti-tumor activity through targeting mitochondrial complex I in cancer cells. However, off-target toxic side effect on nervous systems have greatly restricted the application of rotenone as anticancer drugs. Here, a folic acid-rotenol (FA-rotenol) conjugate was prepared by covalent coupling of the tumor-targeting ligand folic acid with rotenone derivative-rotenol to enhance its accumulation at tumor site. FA-rotenol conjugates present high in vitro cytotoxicties against several cell lines by inducing mitochondrial membrane potential depolarization and increasing the level of intracellular reactive oxygen species (ROS) to activate the mitochondrial pathway of apoptosis and enhance the G2/M cell cycle arrest. Because of the high affinity with over-expressed folate receptors, FA-rotenol conjugate demonstrated more effective in vivo therapeutic outcomes in 4T1 tumor-bearing mice than rotenone and rotenol. In addition, FA-rotenol conjugate can markedly inhibit the cell migration and invasion of HepG-2 cells. These studies confirm the feasibility of tumor-targeted ligand conjugated rotenone derivatives for targeted antitumor therapy; likewise, they lay the foundations for the development of other rotenol-conjugates with antitumor potential.
Collapse
Affiliation(s)
- Min Hong
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China.
| | - Juan Wang
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Haobin Chen
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Jiayu Qi
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Qinghong Ji
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Xiaoyan Liu
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Qiaoli Yue
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Lei Li
- School of Physics Science and Information Technology, Liaocheng University, Liaocheng, 252059, China.
| | - Shuang Cheng
- School of Agricultural Science and Engineering, Liaocheng University, Liaocheng, 252059, China.
| |
Collapse
|
|
5
|
Kondengadan SM, Bansal S, Yang X, Wang B. Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies. RESEARCH SQUARE 2024:rs.3.rs-4213303. [PMID: 38659849 PMCID: PMC11042441 DOI: 10.21203/rs.3.rs-4213303/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Carbon monoxide (CO) is an endogenous produced molecule and has shown efficacy in animal models of inflammation, organ injury, colitis and cancer metastasis. Because of its gaseous nature, there is a need for developing efficient CO delivery approaches, especially those capable of targeted delivery. In this study, we aim to take advantage of a previously reported approach of enrichment-triggered prodrug activation to achieve targeted delivery by targeting the folate receptor. The general idea is to exploit folate receptor-mediated enrichment as a way to accelerate a biomolecular Diels-Alder reaction for prodrug activation. In doing so, we first need to find ways to tune the reaction kinetics in order to ensure minimal rection without enrichment and optimal activation upon enrichment. In this feasibility study, we synthesized two diene-dienophile pairs and studied their reaction kinetics and ability to target the folate receptor. We found that folate conjugation significantly affects the reaction kinetics of the original diene-dienophile pairs. Such information will be very useful in future designs of similar targeted approaches of CO delivery.
Collapse
|
|
6
|
Wang Q, Li S, Xu C, Wang X, Yang T, Wang C, Xiong Y, Zhang Z, Yang X, Li Z. Glutaminolysis inhibition boosts photodynamic therapy to eliminate cancer stem cells. Biomaterials 2024; 306:122497. [PMID: 38310827 DOI: 10.1016/j.biomaterials.2024.122497] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 01/27/2024] [Accepted: 01/30/2024] [Indexed: 02/06/2024]
Abstract
High reactive oxygen species (ROS) levels provide a therapeutic opportunity to eradicate cancer stem cells (CSCs), a population of cells responsible for tumorigenesis, progression, metastasis, and recurrence. However, enhanced antioxidant systems in this population of cells attenuate ROS-inducing therapies. Here, we developed a nanoparticle-assisted combination therapy to eliminate CSCs by employing photodynamic therapy (PDT) to yield ROS while disrupting ROS defense with glutaminolysis inhibition. Specifically, we leveraged an oleic acid-hemicyanine conjugate (CyOA) as photosensitizer, a new entity molecule HYL001 as glutaminolysis inhibitor, and a biocompatible folic acid-hydroxyethyl starch conjugate (FA-HES) as amphiphilic surfactant to construct cellular and mitochondrial hierarchical targeting nanomedicine (COHF NPs). COHF NPs inhibited glutaminolysis to reduce intracellular ROS scavengers, including glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), and to blunt oxidative phosphorylation (OXPHOS) for oxygen-conserved PDT. Compared to COLF NPs without glutaminolysis inhibitor, COHF NPs exhibited higher phototoxicity to breast cancer stem cells (BCSCs) both in vitro and in vivo. More importantly, we corroborated that marketed glutaminolysis inhibitors, such as CB839 and V9302, augment the clinically used photosensitizer (Hiporfin) for BCSCs elimination. This study develops a potent CSCs targeting strategy by combining glutaminolysis inhibition with PDT and provides significant implications for cancer therapy.
Collapse
Affiliation(s)
- Qiang Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Shiyou Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Chen Xu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Xing Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Tian Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Chong Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Yuxuan Xiong
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Zhijie Zhang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Zifu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
| |
Collapse
|
|
7
|
Yan S, Na J, Liu X, Wu P. Different Targeting Ligands-Mediated Drug Delivery Systems for Tumor Therapy. Pharmaceutics 2024; 16:248. [PMID: 38399302 PMCID: PMC10893104 DOI: 10.3390/pharmaceutics16020248] [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: 01/23/2024] [Revised: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Traditional tumor treatments have the drawback of harming both tumor cells and normal cells, leading to significant systemic toxic side effects. As a result, there is a pressing need for targeted drug delivery methods that can specifically target cells or tissues. Currently, researchers have made significant progress in developing targeted drug delivery systems for tumor therapy using various targeting ligands. This review aims to summarize recent advancements in targeted drug delivery systems for tumor therapy, focusing on different targeting ligands such as folic acid, carbohydrates, peptides, aptamers, and antibodies. The review also discusses the advantages, challenges, and future prospects of these targeted drug delivery systems.
Collapse
Affiliation(s)
- Shuxin Yan
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China; (S.Y.); (J.N.)
| | - Jintong Na
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China; (S.Y.); (J.N.)
| | - Xiyu Liu
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China; (S.Y.); (J.N.)
| | - Pan Wu
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China; (S.Y.); (J.N.)
- School of Pharmacy, Guangxi Medical University, Nanning 530021, China
| |
Collapse
|
|
8
|
Ahmadi M, Ritter CA, von Woedtke T, Bekeschus S, Wende K. Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis. Chem Sci 2024; 15:1966-2006. [PMID: 38332833 PMCID: PMC10848714 DOI: 10.1039/d3sc05539f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/31/2023] [Indexed: 02/10/2024] Open
Abstract
Neoplasias pose a significant threat to aging society, underscoring the urgent need to overcome the limitations of traditional chemotherapy through pioneering strategies. Targeted drug delivery is an evolving frontier in cancer therapy, aiming to enhance treatment efficacy while mitigating undesirable side effects. One promising avenue utilizes cell membrane receptors like the folate receptor to guide drug transporters precisely to malignant cells. Based on the cellular folate receptor as a cancer cell hallmark, targeted nanocarriers and small molecule-drug conjugates have been developed that comprise different (bio) chemistries and/or mechanical properties with individual advantages and challenges. Such modern folic acid-conjugated stimuli-responsive drug transporters provide systemic drug delivery and controlled release, enabling reduced dosages, circumvention of drug resistance, and diminished adverse effects. Since the drug transporters' structure-based de novo design is increasingly relevant for precision cancer remediation and diagnosis, this review seeks to collect and debate the recent approaches to deliver therapeutics or diagnostics based on folic acid conjugated Trojan Horses and to facilitate the understanding of the relevant chemistry and biochemical pathways. Focusing exemplarily on brain and breast cancer, recent advances spanning 2017 to 2023 in conjugated nanocarriers and small molecule drug conjugates were considered, evaluating the chemical and biological aspects in order to improve accessibility to the field and to bridge chemical and biomedical points of view ultimately guiding future research in FR-targeted cancer therapy and diagnosis.
Collapse
Affiliation(s)
- Mohsen Ahmadi
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
| | - Christoph A Ritter
- Institute of Pharmacy, Section Clinical Pharmacy, University of Greifswald Greifswald Germany
| | - Thomas von Woedtke
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
- Institute for Hygiene and Environmental Medicine, Greifswald University Medical Center Ferdinand-Sauerbruch-Straße 17475 Greifswald Germany
| | - Sander Bekeschus
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
- Clinic and Policlinic for Dermatology and Venereology, Rostock University Medical Center Strempelstr. 13 18057 Rostock Germany
| | - Kristian Wende
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
| |
Collapse
|
|
9
|
Savoy EA, Olatunji FP, Fulton MD, Kesic BN, Herman JW, Romero O, Maniatopoulos M, Berkman CE. PSMA-targeted small-molecule drug-conjugates with valine-citrulline and phosphoramidate cleavable linkers. Bioorg Med Chem Lett 2024; 98:129573. [PMID: 38052377 DOI: 10.1016/j.bmcl.2023.129573] [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: 11/02/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/07/2023]
Abstract
In this study, we present a modular synthesis and evaluation of two prostate-specific membrane antigen (PSMA) targeted small molecule drug conjugates (SMDCs) incorporating the potent chemotherapeutic agent monomethyl auristatin E (MMAE). These SMDCs are distinguished by their cleavable linker modules: one utilizing the widely known valine-citrulline linker, susceptible to cleavage by cathepsin B, and the other featuring a novel acid-labile phosphoramidate-based (PhosAm) linker. Both SMDCs maintained nanomolar affinity to PSMA. Furthermore, we confirmed the selective release of the payload and observed chemotherapeutic efficacy specifically within PSMA-positive prostate cancer cells, while maintaining cell viability in PSMA-negative cells. These findings not only validate the efficacy of our approach but also highlight the potential of the innovative pH-responsive PhosAm linker. This study contributes significantly to the field and also paves the way for future advancements in targeted cancer therapy.
Collapse
Affiliation(s)
- Emily A Savoy
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA
| | - Feyisola P Olatunji
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA
| | - Melody D Fulton
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA
| | - Brittany N Kesic
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA
| | - Jacob W Herman
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA
| | - Oscar Romero
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA
| | | | - Clifford E Berkman
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630, USA.
| |
Collapse
|
|
10
|
Pratihar S, Bhagavath KK, Govindaraju T. Small molecules and conjugates as theranostic agents. RSC Chem Biol 2023; 4:826-849. [PMID: 37920393 PMCID: PMC10619134 DOI: 10.1039/d3cb00073g] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/28/2023] [Indexed: 11/04/2023] Open
Abstract
Theranostics, the integration of therapy and diagnostics into a single entity for the purpose of monitoring disease progression and treatment response. Diagnostics involves identifying specific characteristics of a disease, while therapeutics refers to the treatment of the disease based on this identification. Advancements in medicinal chemistry and technology have led to the development of drug modalities that provide targeted therapeutic effects while also providing real-time updates on disease progression and treatment. The inclusion of imaging in therapy has significantly improved the prognosis of devastating diseases such as cancer and neurodegeneration. Currently, theranostic treatment approaches are based on nuclear medicine, while nanomedicine and a wide diversity of macromolecular systems such as gels, polymers, aptamers, and dendrimer-based agents are being developed for the purpose. Theranostic agents have significant roles to play in both early-stage drug development and clinical-stage therapeutic-containing drug candidates. This review will briefly outline the pros and cons of existing and evolving theranostic approaches before comprehensively discussing the role of small molecules and their conjugates.
Collapse
Affiliation(s)
- Sumon Pratihar
- Bioorganic Chemistry Laboratory, New Chemistry Unit, and School of Advanced Materials (SAMat), Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) Jakkur P.O. Bengaluru 560064 Karnataka India
| | - Krithi K Bhagavath
- Bioorganic Chemistry Laboratory, New Chemistry Unit, and School of Advanced Materials (SAMat), Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) Jakkur P.O. Bengaluru 560064 Karnataka India
| | - Thimmaiah Govindaraju
- Bioorganic Chemistry Laboratory, New Chemistry Unit, and School of Advanced Materials (SAMat), Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) Jakkur P.O. Bengaluru 560064 Karnataka India
| |
Collapse
|
|
11
|
Hussain A, Kumar A, Uttam V, Sharma U, Sak K, Saini RV, Saini AK, Haque S, Tuli HS, Jain A, Sethi G. Application of curcumin nanoformulations to target folic acid receptor in cancer: Recent trends and advances. ENVIRONMENTAL RESEARCH 2023; 233:116476. [PMID: 37348632 DOI: 10.1016/j.envres.2023.116476] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/05/2023] [Accepted: 06/19/2023] [Indexed: 06/24/2023]
Abstract
Curcumin, derived from turmeric, has a strong anticancer potential known for millennia. The development of this phytochemical as a medicine has been hampered by several significant deficiencies, including its poor water solubility and low bioavailability. This review article discusses possibilities to overcome these bottlenecks by focusing on this natural polyphenol's nanoformulation. Moreover, preparation of curcumin conjugates containing folates as ligands for folic acid receptors can add a new important dimension in this field, allowing specific targeting of cancer cells, considering the significantly higher expression of these receptors in malignant tissues compared to normal cells. It is highly expected that simultaneous improvement of different aspects of curcumin in fighting against such a complex and multifaceted disease like cancer. Therefore, we can better comprehend cancer biology by developing a mechanistic understanding of curcumin, which will also inspire the scientific community to develop new pharmacological models, and exploration of emerging directions to revitalize application of natural products in cancer therapy.
Collapse
Affiliation(s)
- Arif Hussain
- School of Life Sciences, Manipal Academy of Higher Education, 345050, Dubai, United Arab Emirates
| | - Ajay Kumar
- University Center for Research & Development (UCRD), Chandigarh University, Mohali, 140413, Punjab, India; Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, Punjab, India
| | - Vivek Uttam
- Department of Zoology, Central University of Punjab, Ghudda, 151 401, Bathinda, Punjab, India
| | - Uttam Sharma
- Department of Zoology, Central University of Punjab, Ghudda, 151 401, Bathinda, Punjab, India
| | | | - Reena V Saini
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, 133207, India
| | - Adesh K Saini
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, 133207, India; Faculty of Agriculture, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, 133207, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, 45142, Saudi Arabia; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, 133207, India
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Ghudda, 151 401, Bathinda, Punjab, India.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| |
Collapse
|
|
12
|
Solanki R, Jangid AK, Jadav M, Kulhari H, Patel S. Folate Functionalized and Evodiamine-Loaded Pluronic Nanomicelles for Augmented Cervical Cancer Cell Killing. Macromol Biosci 2023; 23:e2300077. [PMID: 37163974 DOI: 10.1002/mabi.202300077] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/03/2023] [Indexed: 05/12/2023]
Abstract
Evodiamine (Evo) is a natural, biologically active plant alkaloid with wide range of pharmacological activities. In the present study Evo-loaded folate-conjugated Pluronic F108 nano-micelles (ENM) is synthesized to enhance the therapeutic efficacy of Evo against cervical cancer. ENM are synthesized, physicochemically characterized and in vitro anticancer activity is performed. The study demonstrates that ENM have nanoscale size (50.33 ± 3.09 nm), monodispersity of 0.122 ± 0.072, with high drug encapsulation efficiency (71.30 ± 3.76%) and controlled drug release at the tumor microenvironment. ENM showed dose-dependent and time-dependent cytotoxicity against HeLa human cervical cancer cells. The results of in vitro anticancer studies demonstrated that ENM have significant anticancer effects and greatly induce apoptosis as compared to pure Evo. The cellular uptake study suggests that increased anticancer activity of ENM is due to the improved intracellular delivery of Evo through overexpressed folate receptors. Overall, the designed ENM can be a potential targeted delivery system for hydrophobic anticancer bioactive compound like Evo.
Collapse
Affiliation(s)
- Raghu Solanki
- School of Life Sciences, Central University of Gujarat, Gandhinagar, 382030, India
| | - Ashok Kumar Jangid
- School of Nano Sciences, Central University of Gujarat, Gandhinagar, 382030, India
- Department of Chemical and Biochemical Engineering, College of Engineering, Dongguk University, 30, Pildong-ro 1-gil, Jung-gu, Seoul, 04620, South Korea
| | - Mahima Jadav
- School of Nano Sciences, Central University of Gujarat, Gandhinagar, 382030, India
| | - Hitesh Kulhari
- School of Nano Sciences, Central University of Gujarat, Gandhinagar, 382030, India
| | - Sunita Patel
- School of Life Sciences, Central University of Gujarat, Gandhinagar, 382030, India
| |
Collapse
|
|
13
|
Das S, Sakhare N, Kumar D, Mathur A, Mirapurkar S, Sheela M, Mohanty B, Chaudhari P, Chakraborty S. Design, characterization and evaluation of a new 99mTc-labeled folate derivative with affinity towards folate receptor. Bioorg Med Chem Lett 2023; 86:129240. [PMID: 36931350 DOI: 10.1016/j.bmcl.2023.129240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/09/2023] [Accepted: 03/12/2023] [Indexed: 03/17/2023]
Abstract
Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new 99mTc-labeled radiotracer for the aforementioned application following the well-established 99mTc-'4+1' chemistry. Formation of the desired [99mTc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the 99mTc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application.
Collapse
Affiliation(s)
- Soumen Das
- Radiopharmaceuticals Program, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai 400703, India; Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai 400094, India.
| | - Navin Sakhare
- Radiopharmaceuticals Program, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai 400703, India
| | - Dheeraj Kumar
- Radiopharmaceuticals Program, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai 400703, India; Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai 400094, India
| | - Anupam Mathur
- Radiopharmaceuticals Program, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai 400703, India
| | - Shubhangi Mirapurkar
- Radiopharmaceuticals Program, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai 400703, India
| | - M Sheela
- Radiopharmaceuticals Program, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai 400703, India
| | - Bhabani Mohanty
- Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Navi Mumbai 410210, India
| | - Pradip Chaudhari
- Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Navi Mumbai 410210, India
| | - Sudipta Chakraborty
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai 400094, India; Radiopharmaceutical Division, Bhabha Atomic Rweesearch Centre (BARC), Trombay, Mumbai 400085, India.
| |
Collapse
|
|
14
|
Zana A, Galbiati A, Gilardoni E, Bocci M, Millul J, Sturm T, Stucchi R, Elsayed A, Nadal L, Cirillo M, Roll W, Stegger L, Asmus I, Backhaus P, Schäfers M, Neri D, Cazzamalli S. Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors. Clin Cancer Res 2022; 28:5440-5454. [PMID: 36215129 DOI: 10.1158/1078-0432.ccr-22-1788] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/08/2022] [Accepted: 10/06/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Small molecule drug conjugates (SMDC) are modular anticancer prodrugs that include a tumor-targeting small organic ligand, a cleavable linker, and a potent cytotoxic agent. Most of the SMDC products that have been developed for clinical applications target internalizing tumor-associated antigens on the surface of tumor cells. We have recently described a novel non-internalizing small organic ligand (named OncoFAP) of fibroblast activation protein (FAP), a tumor-associated antigen highly expressed in the stroma of most solid human malignancies. EXPERIMENTAL DESIGN In this article, we describe a new series of OncoFAP-Drug derivatives based on monomethyl auristatin E (MMAE; a potent cytotoxic tubulin poison) and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. RESULTS The tumor-targeting potential of OncoFAP was confirmed in patients with cancer using nuclear medicine procedures. We used mass spectrometry methodologies to quantify the amount of prodrug delivered to tumors and normal organs, as well as the efficiency of the drug release process. Linkers previously exploited for anticancer drug conjugates were used as benchmark. We identified OncoFAP-Gly-Pro-MMAE as the best performing SMDC, which has now been prioritized for further clinical development. OncoFAP-Gly-Pro-MMAE selectively delivered more than 10% injected dose per gram of MMAE to FAP-positive tumors, with a tumor-to-kidney ratio of 16:1 at 24 hours post-injection. CONCLUSIONS The FAP-specific drug conjugates described in this article promise to be efficacious for the targeting of human malignancies. The extracellular release of potent anticancer payloads mediates durable complete remission in difficult-to-treat animal models of cancer.
Collapse
Affiliation(s)
- Aureliano Zana
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland
| | - Andrea Galbiati
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland
| | | | - Matilde Bocci
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland
| | - Jacopo Millul
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland
| | - Theo Sturm
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland
| | | | - Abdullah Elsayed
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland.,Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zürich, Switzerland
| | - Lisa Nadal
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland
| | - Martina Cirillo
- Department of Chemistry "G. Ciamician," University of Bologna, Bologna, Italy
| | - Wolfgang Roll
- Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
| | - Lars Stegger
- Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
| | - Inga Asmus
- Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
| | - Philipp Backhaus
- Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.,European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Michael Schäfers
- Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.,European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Dario Neri
- R&D Department, Philochem AG, Otelfingen, Zurich, Switzerland.,Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zürich, Switzerland.,Philogen S.p.A., Siena, Italy
| | | |
Collapse
|
|
15
|
Aung W, Tsuji AB, Hanaoka K, Higashi T. Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors. World J Clin Oncol 2022; 13:880-895. [PMID: 36483974 PMCID: PMC9724186 DOI: 10.5306/wjco.v13.i11.880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/12/2022] [Accepted: 10/18/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Photodynamic therapy (PDT) is a minimally invasive form of cancer therapy, and the development of a novel photosensitizer (PS) with optimal properties is important for enhancing PDT efficacy. Folate receptor (FR) membrane protein is frequently overexpressed in 40% of human cancer and a good candidate for tumor-specific targeting. Specific active targeting of PS to FR can be achieved by conjugation with the folate moiety. A folate-linked, near-infrared (NIR)-sensitive probe, folate-Si-rhodamine-1 (FolateSiR-1), was previously developed and is expected to be applicable to NIR-PDT.
AIM To investigate the therapeutic efficacy of NIR-PDT induced by FolateSiR-1, a FR-targeted PS, in preclinical cancer models.
METHODS FolateSiR-1 was developed by conjugating a folate moiety to the Si-rhodamine derivative through a negatively charged tripeptide linker. FR expression in the designated cell lines was examined by western blotting (WB). The selective binding of FolateSiR-1 to FR was confirmed in FR overexpressing KB cells (FR+) and tumors by fluorescence microscopy and in vivo fluorescence imaging. Low FR expressing OVCAR-3 and A4 cell lines were used as negative controls (FR-). The NIR light (635 ± 3 nm)-induced phototoxic effect of FolateSiR-1 was evaluated by cell viability imaging assays. The time-dependent distribution of FolateSiR-1 and its specific accumulation in KB tumors was determined using in vivo longitudinal fluorescence imaging. The PDT effect of FolateSiR-1 was evaluated in KB tumor-bearing mice divided into four experimental groups: (1) FolateSiR-1 (100 μmol/L) alone; (2) FolateSiR-1 (100 μmol/L) followed by NIR irradiation (50 J/cm2); (3) NIR irradiation (50 J/cm2) alone; and (4) no treatment. Tumor volume measurement and immunohistochemical (IHC) and histological examinations of the tumors were performed to analyze the effect of PDT.
RESULTS High FR expression was observed in the KB cells by WB, but not in the OVCAR-3 and A4 cells. Substantial FR-specific binding of FolateSiR-1 was observed by in vitro and in vivo fluorescence imaging. Cell viability imaging assays showed that NIR-PDT induced cell death in KB cells. In vivo longitudinal fluorescence imaging showed rapid peak accumulation of FolateSiR-1 in the KB tumors 2 h after injection. In vivo PDT conducted at this time point caused tumor growth delay. The relative tumor volumes in the PDT group were significantly reduced compared to those in the other groups [5.81 ± 1.74 (NIR-PDT) vs 12.24 ± 2.48 (Folate-SiR-1), vs 11.84 ± 3.67 (IR), vs 12.98 ± 2.78 (Untreated), at Day 16, P < 0.05]. IHC analysis revealed reduced proliferation marker Ki-67-positive cells in the PDT treated tumors, and hematoxylin-eosin staining revealed features of necrotic- and apoptotic cell death.
CONCLUSION FolateSiR-1 has potential for use in PDT, and FR-targeted NIR-PDT may open a new effective strategy for the treatment of FR-overexpressing tumors.
Collapse
Affiliation(s)
- Winn Aung
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Atsushi B Tsuji
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Kenjiro Hanaoka
- Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| |
Collapse
|
|
16
|
Parsaei M, Akhbari K. Synthesis and Application of MOF-808 Decorated with Folic Acid-Conjugated Chitosan as a Strong Nanocarrier for the Targeted Drug Delivery of Quercetin. Inorg Chem 2022; 61:19354-19368. [DOI: 10.1021/acs.inorgchem.2c03138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Mozhgan Parsaei
- School of Chemistry, College of Science, University of Tehran, Tehran14155-6455, Iran
| | - Kamran Akhbari
- School of Chemistry, College of Science, University of Tehran, Tehran14155-6455, Iran
| |
Collapse
|
|
17
|
Olatunji FP, Pun M, Herman JW, Romero O, Maniatopoulos M, Latoche JD, Parise RA, Guo J, Beumer JH, Anderson CJ, Berkman CE. Modular Smart Molecules for PSMA-Targeted Chemotherapy. Mol Cancer Ther 2022; 21:1701-1709. [PMID: 35999662 PMCID: PMC9842478 DOI: 10.1158/1535-7163.mct-22-0160] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/26/2022] [Accepted: 08/10/2022] [Indexed: 01/19/2023]
Abstract
New targeted chemotherapeutics are urgently needed to minimize off-target toxicity and reduce the high-mortality rate associated with metastatic prostate cancer. Herein, we report on the modular synthesis, pharmacokinetics, and efficacy of two small-molecule-drug conjugates (SMDC) targeted to prostate-specific membrane antigen (PSMA) incorporating either: (i) a cathepsin-B-cleavable valine-citrulline (Val-Cit), or (ii) an acid-cleavable phosphoramidate linker. Crucial components used in the design of the conjugates include: (i) CTT1298, a nanomolar affinity ligand that binds irreversibly to PSMA and has proven in past studies to rapidly internalize and shuttle payloads into PSMA-expressing prostate cancer cells, (ii) MMAE, a known potent cytotoxic payload, and (iii) an albumin-binder, proven to improve residence time of drug conjugates. At dose of 0.8 mg/kg (∼250 nmol/kg), the two SMDCs showed significant efficacy in a PSMA(+) PC3-PIP mouse model of human prostate cancer compared with controls, without inducing systemic toxicity. Though localization of the SMDCs was observed in tissues apart from the tumor, release of MMAE was observed predominantly in tumor tissue, at levels that were 2-3 orders of magnitude higher than non-target tissues. Furthermore, SMDC2, which incorporated a novel pH-responsive phosporamidate linker, demonstrated significantly improved efficacy over SMDC1 that has a Val-Cit linker, with a 100% survival over 90 days and 4 out of 8 mice showing complete tumor growth inhibition after 6 weekly doses of 0.8 mg/kg (244 nmol/kg). Our findings demonstrate the potential of irreversible PSMA inhibitors combined with pH-responsive linkers as a way to specifically deliver chemotherapeutic drugs to prostate cancer tumors with minimal toxicity.
Collapse
Affiliation(s)
| | - Michael Pun
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630,Department of Chemistry, University of Missouri, Columbia, MO 65211,Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO 65211
| | - Jacob W. Herman
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630
| | - Oscar Romero
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630
| | | | - Joseph D. Latoche
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213
| | - Robert A. Parise
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213
| | - Jianxia Guo
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213
| | - Jan H. Beumer
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213,Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA, 15261.,Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
| | - Carolyn J. Anderson
- Department of Chemistry, University of Missouri, Columbia, MO 65211,Department of Radiology, University of Missouri, Columbia, MO 65211,Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO 65211
| | - Clifford E. Berkman
- Washington State University, Department of Chemistry, Pullman, WA 99164-4630
| |
Collapse
|
|
18
|
Sahib AS, Wennas ON, Mahdi BW, Al abood RM. In vivo antitumor activity study of targeted chlorambucil-loaded nanolipid carrier for breast cancer. PHARMACIA 2022. [DOI: 10.3897/pharmacia.69.e85390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Chlorambucil (CBL) is an efficient anticancer drug. It is a lipophilic agent with serious adverse effects. The objective of this study was to formulate a CBL-loaded nanolipid carrier and target breast cancer using folic acid as a targeting probe. Characterizations of the optimum formulation were 79.9±3% EE after the addition of 4mg CBL, 119±6nm particle size which is considered appropriate for parenteral use, 0.3±0.02 PDI, -42±1mV ZP that stabilized the formulation. Tumor volume, body weight, and tumor mass weight were recorded to evaluate tumor volume doubling time, tumor growth inhibition rate, and systemic toxicity. It appeared there was a significant antitumor activity of targeted formulation compared with non-targeted one and free CBL. Moreover, the systemic toxicity was less after body weight evaluation concerning the targeted formulation when compared with other formulations.
Collapse
|
|
19
|
Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists. Int J Mol Sci 2022; 23:ijms23137160. [PMID: 35806163 PMCID: PMC9266369 DOI: 10.3390/ijms23137160] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 02/07/2023] Open
Abstract
We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody–drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA− PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.
Collapse
|
|
20
|
Effect of Trimethine Cyanine Dye- and Folate-Conjugation on the In Vitro Biological Activity of Proapoptotic Peptides. Biomolecules 2022; 12:biom12050725. [PMID: 35625652 PMCID: PMC9138991 DOI: 10.3390/biom12050725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/10/2022] [Accepted: 05/16/2022] [Indexed: 11/17/2022] Open
Abstract
Despite continuous advances, anticancer therapy still faces several technical hurdles, such as selectivity on cellular and subcellular targets of therapeutics. Toward addressing these limitations, we have combined the use of proapoptotic peptides, trimethine cyanine dye, and folate to target the mitochondria of tumor cells. A series of proapoptotic peptides and their conjugates with a cyanine dye and/or folate were synthesized in the solid phase, and their toxicity in different human cell lines was assessed. Cyanine-bearing conjugates were found to be up to 100-fold more cytotoxic than the parent peptides and to localize in mitochondria. However, the addition of a folate motif did not enhance the potency or selectivity of the resulting conjugates toward tumor cells that overexpress folate receptor α. Furthermore, while dual-labeled constructs were also found to localize within the target organelle, they were not generally selective towards folate receptor α-positive cell lines in vitro.
Collapse
|
|
21
|
Niedre M. Prospects for Fluorescence Molecular In Vivo Liquid Biopsy of Circulating Tumor Cells in Humans. FRONTIERS IN PHOTONICS 2022; 3:910035. [PMID: 39508030 PMCID: PMC11540420 DOI: 10.3389/fphot.2022.910035] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
Abstract
Our team recently developed "Diffuse in vivo Flow Cytometry" (DiFC) for detection and enumeration rare circulating tumor cells (CTCs) in mice with highly-scattered fluorescent light. We have used DiFC to study dissemination of CTCs in a number of mouse models of metastasis with fluorescent protein expressing cells. Because DiFC uses diffuse light and interrogates large blood vessels in relatively deep tissue, in principle it could be translated to larger limbs, species, and even humans clinically. In this perspective, we discuss the technical challenges of human translation of DiFC in the context of the current state of the technology, as well as potential strategies for labeling of CTCs with targeted fluorescent molecular probes. We also discuss potential advantages and disadvantages of DiFC as a clinical tool. In principle, DiFC could represent a powerful complementary technique (to liquid biopsy blood draws) for accurate and sensitive measurement of changes in CTC numbers over time.
Collapse
Affiliation(s)
- Mark Niedre
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| |
Collapse
|
|
22
|
He S, Meng Q, Zhong S, Gao Y, Cui X. Sonochemical fabrication of reduction-responsive alginate-based nanocapsules with folate targeting for drug delivery. Colloids Surf A Physicochem Eng Asp 2022. [DOI: 10.1016/j.colsurfa.2022.128349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
|
|
23
|
Daśko M, de Pascual-Teresa B, Ortín I, Ramos A. HDAC Inhibitors: Innovative Strategies for Their Design and Applications. Molecules 2022; 27:molecules27030715. [PMID: 35163980 PMCID: PMC8837987 DOI: 10.3390/molecules27030715] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/16/2022] Open
Abstract
Histone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs and imaging agents that facilitate an early diagnosis of these diseases. Thus, their selective inhibition or degradation are the basis for new therapies. This is supported by the fact that many HDAC inhibitors (HDACis) are currently under clinical research for cancer therapy, and the Food and Drug Administration (FDA) has already approved some of them. In this review, we will focus on the recent advances and latest discoveries of innovative strategies in the development and applications of compounds that demonstrate inhibitory or degradation activity against HDACs, such as PROteolysis-TArgeting Chimeras (PROTACs), tumor-targeted HDACis (e.g., folate conjugates and nanoparticles), and imaging probes (positron emission tomography (PET) and fluorescent ligands).
Collapse
Affiliation(s)
- Mateusz Daśko
- Department of Inorganic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland;
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Spain;
| | - Beatriz de Pascual-Teresa
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Spain;
| | - Irene Ortín
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Spain;
- Correspondence: (I.O.); (A.R.)
| | - Ana Ramos
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Spain;
- Correspondence: (I.O.); (A.R.)
| |
Collapse
|
|
24
|
Al-Mansoori L, Elsinga P, Goda SK. Bio-vehicles of cytotoxic drugs for delivery to tumor specific targets for cancer precision therapy. Biomed Pharmacother 2021; 144:112260. [PMID: 34607105 DOI: 10.1016/j.biopha.2021.112260] [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: 08/09/2021] [Revised: 09/22/2021] [Accepted: 09/26/2021] [Indexed: 02/09/2023] Open
Abstract
Abnormal structural and molecular changes in malignant tissues were thoroughly investigated and utilized to target tumor cells, hence rescuing normal healthy tissues and lowering the unwanted side effects as non-specific cytotoxicity. Various ligands for cancer cell specific markers have been uncovered and inspected for directional delivery of the anti-cancer drug to the tumor site, in addition to diagnostic applications. Over the past few decades research related to the ligand targeted therapy (LTT) increased tremendously aiming to treat various pathologies, mainly cancers with well exclusive markers. Malignant tumors are known to induce elevated levels of a variety of proteins and peptides known as cancer "markers" as certain antigens (e.g., Prostate specific membrane antigen "PSMA", carcinoembryonic antigen "CEA"), receptors (folate receptor, somatostatin receptor), integrins (Integrin αvβ3) and cluster of differentiation molecules (CD13). The choice of an appropriate marker to be targeted and the design of effective ligand-drug conjugate all has to be carefully selected to generate the required therapeutic effect. Moreover, since some tumors express aberrantly high levels of more than one marker, some approaches investigated targeting cancer cells with more than one ligand (dual or multi targeting). We aim in this review to report an update on the cancer-specific receptors and the vehicles to deliver cytotoxic drugs, including recent advancements on nano delivery systems and their implementation in targeted cancer therapy. We will discuss the advantages and limitations facing this approach and possible solutions to mitigate these obstacles. To achieve the said aim a literature search in electronic data bases (PubMed and others) using keywords "Cancer specific receptors, cancer specific antibody, tumor specific peptide carriers, cancer overexpressed proteins, gold nanotechnology and gold nanoparticles in cancer treatment" was carried out.
Collapse
Affiliation(s)
- Layla Al-Mansoori
- Qatar University, Biomedical Research Centre, Qatar University, Doha 2713, Qatar.
| | - Philip Elsinga
- University of Groningen, University Medical Center Groningen (UMCG), Department of Nuclear Medicine and Molecular Imaging, Groningen, the Netherlands.
| | - Sayed K Goda
- Cairo University, Faculty of Science, Giza, Egypt; University of Derby, College of Science and Engineering, Derby, UK.
| |
Collapse
|
|
25
|
Targeted delivery of mPGES-1 inhibitors to macrophages via the folate receptor-β for inflammatory pain. Bioorg Med Chem Lett 2021; 50:128313. [PMID: 34390827 DOI: 10.1016/j.bmcl.2021.128313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/27/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
Activated macrophages overexpress the folate receptor β (FR-β) that can be used for targeted delivery of drugs conjugated to folic acid. FR-expressing macrophages contribute to arthritis progression by secreting prostaglandin E2 (PGE2). Non-steroidal anti-inflammatory drugs (NSAIDs) block PGs and thromboxane by inhibiting the cyclooxygenase (COX) enzymes and are used for chronic pain and inflammation despite their well-known toxicity. New NSAIDs target an enzyme downstream of COXs, microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of mPGES-1 in inflammatory macrophages promises to retain NSAID efficacy while limiting toxicity. We conjugated a potent mPGES-1 inhibitor, MK-7285, to folate, but the construct released the drug inefficiently. Folate conjugation to the primary alcohol of MK-7285 improved the construct's stability and the release of free drug. Surprisingly, the drug-folate conjugate potentiated PGE2 in FR-positive KB cells, and reduced PGE2 in macrophages independently of the FR. Folate conjugation of NSAIDs is not an optimal strategy for targeting of macrophages.
Collapse
|
|
26
|
Patil RA, Srinivasarao M, Amiji MM, Low PS, Niedre M. Fluorescence Labeling of Circulating Tumor Cells with a Folate Receptor-Targeted Molecular Probe for Diffuse In Vivo Flow Cytometry. Mol Imaging Biol 2021; 22:1280-1289. [PMID: 32519245 DOI: 10.1007/s11307-020-01505-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE We recently developed a new instrument called "diffuse in vivo flow cytometry" (DiFC) for enumeration of rare fluorescently labeled circulating tumor cells (CTCs) in small animals without drawing blood samples. Until now, we have used cell lines that express fluorescent proteins or were pre-labeled with a fluorescent dye ex vivo. In this work, we investigated the use of a folate receptor (FR)-targeted fluorescence molecular probe for in vivo labeling of FR+ CTCs for DiFC. PROCEDURES We used EC-17, a FITC-folic acid conjugate that has been used in clinical trials for fluorescence-guided surgery. We studied the affinity of EC-17 for FR+ L1210A and KB cancer cells. We also tested FR- MM.1S cells. We tested the labeling specificity in cells in culture in vitro and in whole blood. We also studied the detectability of labeled cells in mice in vivo with DiFC. RESULTS EC-17 showed a high affinity for FR+ L1210A and KB cells in vitro. In whole blood, 85.4 % of L1210A and 80.9 % of KB cells were labeled above non-specific background with EC-17, and negligible binding to FR- MM.1S cells was observed. In addition, EC-17-labeled CTCs were readily detectable in circulation in mice with DiFC. CONCLUSIONS This work demonstrates the feasibility of labeling CTCs with a cell-surface receptor-targeted probe for DiFC, greatly expanding the potential utility of the method for pre-clinical animal models. Because DiFC uses diffuse light, this method could be also used to enumerate CTCs in larger animal models and potentially even in humans.
Collapse
Affiliation(s)
- Roshani A Patil
- Department of Bioengineering, Northeastern University, Boston, MA, 02115, USA
| | | | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, 02115, USA
| | - Philip S Low
- Department of Chemistry, Purdue University, West Lafayette, IN, 47906, USA
| | - Mark Niedre
- Department of Bioengineering, Northeastern University, Boston, MA, 02115, USA.
| |
Collapse
|
|
27
|
Deberle LM, Benešová M, Becker AE, Ratz M, Guzik P, Schibli R, Müller C. Novel Synthetic Strategies Enable the Efficient Development of Folate Conjugates for Cancer Radiotheranostics. Bioconjug Chem 2021; 32:1617-1628. [PMID: 34251183 DOI: 10.1021/acs.bioconjchem.1c00198] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The folate receptor (FR) is an interesting target for radiotheranostics due to its overexpression in several tumor types. The progress in developing novel folate radioconjugates is, however, slow due to the synthetic challenges that folate chemistry presents. The goal of this study was, thus, to establish versatile solid-phase synthetic strategies for a convenient preparation of novel folate conjugates. Two approaches were established based on an orthogonal fluorenylmethyloxycarbonyl (Fmoc)-protection strategy to enable a modular buildup of an albumin-binding DOTA conjugate (known as OxFol-1) using folic acid (oxidized folate version) as a targeting agent. The main difference between the two approaches was the sequence of conjugating the single structural units. The approach that introduced the folate entity as the last unit appeared particularly useful for the preparation of conjugates based on 6R- or 6S-5-methyltetrahydrofolic acid (5-MTHF; a reduced folate version) as targeting entity. Three types of folate conjugates were synthesized either with a p-iodophenyl-based albumin binder (OxFol-1, 6R-RedFol-1, and 6S-RedFol-1) or without an albumin-binding entity (OxFol-14, 6R-RedFol-14, and 6S-RedFol-14). All six conjugates were obtained with high chemical purity (>98%) after 9-13 synthesis steps and a single final HPLC purification. Radiolabeling with lutetium-177 was feasible at high molar activity, and the resulting radioconjugates were stable over at least 24 h. Biodistribution and SPECT/CT imaging studies confirmed the favorable effect of an albumin-binding entity to increase the tumor uptake and reduce kidney retention of folate radioconjugates. The increased tumor-to-kidney ratios obtained with [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 as compared to [177Lu]Lu-OxFol-1 indicated that 5-MTHF is the preferred FR-targeting agent for albumin-binding radioconjugates. This was, however, not the case for folate radioconjugates without an albumin binder. Thanks to the established synthesis strategy, the preparation of further folate radioconjugates will be facilitated, potentially enabling the optimization of the tissue distribution characteristics even more.
Collapse
Affiliation(s)
- Luisa M Deberle
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
| | - Martina Benešová
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Anna E Becker
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
| | - Magdalena Ratz
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
| | - Patrycja Guzik
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Cristina Müller
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| |
Collapse
|
|
28
|
Nguyen Cao TG, Kang JH, You JY, Kang HC, Rhee WJ, Ko YT, Shim MS. Safe and Targeted Sonodynamic Cancer Therapy Using Biocompatible Exosome-Based Nanosonosensitizers. ACS APPLIED MATERIALS & INTERFACES 2021; 13:25575-25588. [PMID: 34033477 DOI: 10.1021/acsami.0c22883] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Sonodynamic therapy (SDT), wherein sonosensitizers irradiated with ultrasound (US) produce cytotoxic reactive oxygen species (ROS), has garnered great attention as a promising alternative to photodynamic therapy owing to the significantly increased depth of tissue penetration. The development of nanocarriers that can selectively deposit sonosensitizers into tumor tissues without systemic toxicity is crucial to facilitate the translation of SDT to clinical use. In this study, exosomes, a class of naturally occurring nanoparticles, were utilized as nanocarriers for safe and cancer-targeted delivery of a sonosensitizer, indocyanine green (ICG). The exosomes were surface-engineered with an active cancer-targeting ligand, folic acid (FA), to increase the cancer specificity of the ICG-loaded exosomes (ExoICG). The FA-conjugated, ICG-loaded exosomes (FA-ExoICG) greatly improved aqueous stability and cellular uptake of ICG, resulting in significantly increased ROS generation in breast cancer cells. As a result, the FA-ExoICG demonstrated greater sonotoxicity against cancer cells than ExoICG and free ICG. The in vivo study revealed that compared to ExoICG, more FA-ExoICG accumulated in tumors, and their pharmacokinetic properties were superior. Notably, tumor growth in mice was significantly suppressed, without systemic toxicity, by a single intravenous injection of the FA-ExoICG and subsequent US irradiation. Therefore, this study demonstrated that active cancer-targeted FA-ExoICG could serve as effective nanosonosensitizers for safe and targeted cancer treatment.
Collapse
Affiliation(s)
- Thuy Giang Nguyen Cao
- Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Ji Hee Kang
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Jae Young You
- Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Han Chang Kang
- Department of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, and BK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Gyeonggi-do 14662, Republic of Korea
| | - Won Jong Rhee
- Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Young Tag Ko
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Min Suk Shim
- Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| |
Collapse
|
|
29
|
Wang H, Jia D, Yuan D, Yin X, Yuan F, Wang F, Shi W, Li H, Zhu LM, Fan Q. Dimeric Her2-specific affibody mediated cisplatin-loaded nanoparticles for tumor enhanced chemo-radiotherapy. J Nanobiotechnology 2021; 19:138. [PMID: 33985511 PMCID: PMC8120847 DOI: 10.1186/s12951-021-00885-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/06/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Solid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O2 production, which in turn serves as a "radiosensitizer" to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy. RESULTS Human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O2. ZHer2, produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of ZHer2. These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization. CONCLUSIONS The nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics.
Collapse
Affiliation(s)
- Haijun Wang
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.,School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, 271016, China
| | - Dianlong Jia
- Laboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, China
| | - Dandan Yuan
- Department of Digestive Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Xiaolei Yin
- School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, 271016, China
| | - Fengjiao Yuan
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, 252000, China
| | - Feifei Wang
- Laboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, China
| | - Wenna Shi
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Hui Li
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Li-Min Zhu
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China.
| | - Qing Fan
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.
| |
Collapse
|
|
30
|
Ginghină O, Hudiță A, Zaharia C, Tsatsakis A, Mezhuev Y, Costache M, Gălățeanu B. Current Landscape in Organic Nanosized Materials Advances for Improved Management of Colorectal Cancer Patients. MATERIALS (BASEL, SWITZERLAND) 2021; 14:2440. [PMID: 34066710 PMCID: PMC8125868 DOI: 10.3390/ma14092440] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022]
Abstract
Globally, colorectal cancer (CRC) ranks as one of the most prevalent types of cancers at the moment, being the second cause of cancer-related deaths. The CRC chemotherapy backbone is represented by 5-fluorouracil, oxaliplatin, irinotecan, and their combinations, but their administration presents several serious disadvantages, such as poor bioavailability, lack of tumor specificity, and susceptibility to multidrug resistance. To address these limitations, nanomedicine has arisen as a powerful tool to improve current chemotherapy since nanosized carriers hold great promise in improving the stability and solubility of the drug payload and enhancing the active concentration of the drug that reaches the tumor tissue, increasing, therefore, the safety and efficacy of the treatment. In this context, the present review offers an overview of the most recent advances in the development of nanosized drug-delivery systems as smart therapeutic tools in CRC management and highlights the emerging need for improving the existing in vitro cancer models to reduce animal testing and increase the success of nanomedicine in clinical trials.
Collapse
Affiliation(s)
- Octav Ginghină
- Department of Surgery, “Sf. Ioan” Emergency Clinical Hospital, 13 Vitan Barzesti Street, 042122 Bucharest, Romania;
- Department II, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 17-21 Calea Plevnei Street, 010232 Bucharest, Romania
| | - Ariana Hudiță
- Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei Street, 050095 Bucharest, Romania; (M.C.); (B.G.)
| | - Cătălin Zaharia
- Advanced Polymer Materials Group, Department of Bioresources and Polymer Science, University Politehnica of Bucharest, 1-7 Gh. Polizu Street, 011061 Bucharest, Romania;
| | - Aristidis Tsatsakis
- Department of Toxicology and Forensic Sciences, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece;
| | - Yaroslav Mezhuev
- Center of Biomaterials, D Mendeleev University of Chemical Technology of Russia, Miusskaya Sq. 9, 125047 Moscow, Russia;
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei Street, 050095 Bucharest, Romania; (M.C.); (B.G.)
| | - Bianca Gălățeanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei Street, 050095 Bucharest, Romania; (M.C.); (B.G.)
| |
Collapse
|
|
31
|
Rana A, Bhatnagar S. Advancements in folate receptor targeting for anti-cancer therapy: A small molecule-drug conjugate approach. Bioorg Chem 2021; 112:104946. [PMID: 33989916 DOI: 10.1016/j.bioorg.2021.104946] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/17/2021] [Accepted: 04/22/2021] [Indexed: 10/21/2022]
Abstract
Targeted delivery combined with controlled release of drugs has a crucial role in future of personalized medicine. The majority of cancer drugs are intended to interfere with one or more cellular events. Anticancer agents can also be toxic to healthy cells, as healthy cells may also need to proliferate and avoid apoptosis. The focus of this review covers the principles, advantages, drawbacks and summarize criteria that must be met for design of small molecule-drug conjugates (SMDCs) to achieve the desired therapeutic potency with minimal toxicity. SMDCs are composed of a targeting ligand, a releasable bridge, a spacer, and a therapeutic payload. We summarize the criteria for the effective design that influences the selection of tumor specific receptor and optimum elements in the design of SMDCs. We also discuss the criteria for selecting the optimal therapeutic drug payload, spacer and linker. The linker chemistries and cleavage strategies are also discussed. Finally, we review the folate receptor targeting SMDCs that are in preclinical development and in clinical trials.
Collapse
Affiliation(s)
- Abhilash Rana
- Amity Institute of Biotechnology, Amity University, Sector125, Noida, Uttar Pradesh, India.
| | - Seema Bhatnagar
- Amity Institute of Biotechnology, Amity University, Sector125, Noida, Uttar Pradesh, India.
| |
Collapse
|
|
32
|
Jin SM, Lee SN, Yoo YJ, Lim YT. Molecular and Macroscopic Therapeutic Systems for Cytokine‐Based Cancer Immunotherapy. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Seung Mo Jin
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and Biomedical Institute for Convergence at SKKU Sungkyunkwan University 2066 Seobu‐ro, Jangan‐gu Suwon Gyeonggi‐do 16419 Republic of Korea
| | - Sang Nam Lee
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and Biomedical Institute for Convergence at SKKU Sungkyunkwan University 2066 Seobu‐ro, Jangan‐gu Suwon Gyeonggi‐do 16419 Republic of Korea
| | - Yeon Jeong Yoo
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and Biomedical Institute for Convergence at SKKU Sungkyunkwan University 2066 Seobu‐ro, Jangan‐gu Suwon Gyeonggi‐do 16419 Republic of Korea
| | - Yong Taik Lim
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and Biomedical Institute for Convergence at SKKU Sungkyunkwan University 2066 Seobu‐ro, Jangan‐gu Suwon Gyeonggi‐do 16419 Republic of Korea
- Department of Chemical Engineering Sungkyunkwan University 2066 Seobu‐ro, Jangan‐gu Suwon Gyeonggi‐do 16419 Republic of Korea
| |
Collapse
|
|
33
|
Zhang XJ, Liu MH, Luo YS, Han GY, Ma ZQ, Huang F, Wang Y, Miao ZY, Zhang WN, Sheng CQ, Yao JZ. Novel dual-mode antitumor chlorin-based derivatives as potent photosensitizers and histone deacetylase inhibitors for photodynamic therapy and chemotherapy. Eur J Med Chem 2021; 217:113363. [PMID: 33744687 DOI: 10.1016/j.ejmech.2021.113363] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 02/14/2021] [Accepted: 02/27/2021] [Indexed: 12/18/2022]
Abstract
The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy.
Collapse
Affiliation(s)
- Xing-Jie Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Ming-Hui Liu
- Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Yu-Sha Luo
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Gui-Yan Han
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Zhi-Qiang Ma
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Fei Huang
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Yuan Wang
- School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhen-Yuan Miao
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Wan-Nian Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Chun-Quan Sheng
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Jian-Zhong Yao
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China; School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
| |
Collapse
|
|
34
|
Guo D, Ji X, Luo J. Rational nanocarrier design towards clinical translation of cancer nanotherapy. Biomed Mater 2021; 16. [DOI: 10.1088/1748-605x/abe35a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
|
|
35
|
Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers (Basel) 2021; 13:cancers13030417. [PMID: 33499427 PMCID: PMC7865627 DOI: 10.3390/cancers13030417] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 11/16/2022] Open
Abstract
Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand-drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule-drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body-drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.
Collapse
|
|
36
|
Manickam M, Boggu PR, Pillaiyar T, Nam YJ, Abdullah M, Lee SJ, Kang JS, Jung SH. Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine. Bioorg Med Chem Lett 2021; 31:127685. [DOI: 10.1016/j.bmcl.2020.127685] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 11/16/2022]
|
|
37
|
Patel TK, Adhikari N, Amin SA, Biswas S, Jha T, Ghosh B. Small molecule drug conjugates (SMDCs): an emerging strategy for anticancer drug design and discovery. NEW J CHEM 2021. [DOI: 10.1039/d0nj04134c] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mechanisms of how SMDCs work. Small molecule drugs are conjugated with the targeted ligand using pH sensitive linkers which allow the drug molecule to get released at lower lysosomal pH. It helps to accumulate the chemotherapeutic agents to be localized in the tumor environment upon cleaving of the pH-labile bonds.
Collapse
Affiliation(s)
- Tarun Kumar Patel
- Epigenetic Research Laboratory, Department of Pharmacy
- BITS-Pilani
- Hyderabad
- India
| | - Nilanjan Adhikari
- Natural Science Laboratory
- Division of Medicinal and Pharmaceutical Chemistry
- Department of Pharmaceutical Technology
- Jadavpur University
- Kolkata 700032
| | - Sk. Abdul Amin
- Natural Science Laboratory
- Division of Medicinal and Pharmaceutical Chemistry
- Department of Pharmaceutical Technology
- Jadavpur University
- Kolkata 700032
| | - Swati Biswas
- Epigenetic Research Laboratory, Department of Pharmacy
- BITS-Pilani
- Hyderabad
- India
| | - Tarun Jha
- Natural Science Laboratory
- Division of Medicinal and Pharmaceutical Chemistry
- Department of Pharmaceutical Technology
- Jadavpur University
- Kolkata 700032
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy
- BITS-Pilani
- Hyderabad
- India
| |
Collapse
|
|
38
|
Klein SE, Sosa JD, Castonguay AC, Flores WI, Zarzar LD, Liu Y. Green Synthesis of Zr-Based Metal-Organic Framework Hydrogel Composites and Their Enhanced Adsorptive Properties. Inorg Chem Front 2020; 7:4813-4821. [PMID: 33520236 PMCID: PMC7839982 DOI: 10.1039/d0qi00840k] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Metal-organic frameworks (MOFs) have emerged as promising candidates for a wide range of applications due to their high surface area and customizable structures, however, the minimal external hydrophilicity of MOFs has limited their biomedical implementations. Structuring of MOFs within polymer frameworks is an approach used to create hybrid materials that retain many of the MOF characteristics (e.g. high adsorption capacity) but expand the range of mechanical and surface properties as well as form factors accessible. Using this approach, hybridizing MOFs with hydrophilic hydrogels can give rise to materials with improved hydrophilicity and biocompatibility. Here, we describe the synthesis of the first Zr-based MOF-hydrogel hybrid material (composite 3) using a green chemistry approach, in which only water was used as the solvent and relatively low temperature (50 °C) was applied. Using methylene blue (MB) as a probe molecule, composite 3 exhibited greater adsorption capacity than the MOF or the hydrogel alone in aqueous solution at most tested pH values (all except pH 13). At an initial MB concentration of 0.0096 mg/mL (30.014uM) and neutral pH conditions, this new hybrid presented the highest loading of MB among similar materials (MB adsorbed = 4.361 ± 0.092 mg MB/g Zr, partition coefficient = 0.172 ± 0.004 mg/g/uM) and largely retained its adsorption capacity under varied conditions (pH 1-13 and 0.2-1.0M NaCl), rendering possible applications in drug delivery and the removal of tumor contrast agent/dye with minimal leakage due to its broad chemical stability.
Collapse
Affiliation(s)
- Shirell E Klein
- Department of Chemistry and Biochemistry, California State University Los Angeles, 5151 State University Dr, Los Angeles, CA 90032, United States
| | - Joshua D Sosa
- Department of Chemistry and Biochemistry, California State University Los Angeles, 5151 State University Dr, Los Angeles, CA 90032, United States
| | - Alexander C Castonguay
- Department of Chemistry, Pennsylvania State University, University Park, PA 16802, United States
| | - Willmer I Flores
- Department of Chemistry and Biochemistry, California State University Los Angeles, 5151 State University Dr, Los Angeles, CA 90032, United States
| | - Lauren D Zarzar
- Department of Chemistry, Pennsylvania State University, University Park, PA 16802, United States
- Department of Materials Science and Engineering, Pennsylvania State University, University Park, PA 16802, United States
- Materials Research Institute, Pennsylvania State University, University Park, PA 16802, United States
| | - Yangyang Liu
- Department of Chemistry and Biochemistry, California State University Los Angeles, 5151 State University Dr, Los Angeles, CA 90032, United States
| |
Collapse
|
|
39
|
Burt AJ, Ahmadvand P, Opp LK, Ryan AT, Kang C, Mancini RJ. A Ligand‐Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery. ChemMedChem 2020. [PMCID: PMC7702144 DOI: 10.1002/cmdc.202000655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Here we report the first use of ligand‐directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand‐directed in situ bioconjugation of a prodrug payload to a protein. The transient nature of our conjugation chemistry renders the protein a depot for time‐dependent release of active drug following hydrolysis and self‐immolation. In our model system, using an immunostimulant prodrug, biotin ligand, and avidin protein, we observe release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co‐crystalized with the nitrophenolate directing group verified the binding pose of the ligand and offered insight into the mechanism of in situ bioconjugation. Overall, this scaffold warrants further investigation for the time‐dependent delivery of therapeutics and use in protein ligand pairs beyond biotin and avidin used for this work.
Collapse
Affiliation(s)
- Anthony J. Burt
- Department of Chemistry Washington State University 1470 NE College Ave Pullman WA 99164 USA
| | - Parvaneh Ahmadvand
- Department of Chemistry Washington State University 1470 NE College Ave Pullman WA 99164 USA
| | - Larissa K. Opp
- Department of Chemistry Washington State University 1470 NE College Ave Pullman WA 99164 USA
| | - Austin T. Ryan
- Department of Chemistry Washington State University 1470 NE College Ave Pullman WA 99164 USA
| | - ChulHee Kang
- Department of Chemistry Washington State University 1470 NE College Ave Pullman WA 99164 USA
| | - Rock J. Mancini
- Department of Chemistry Washington State University 1470 NE College Ave Pullman WA 99164 USA
- The Gene & Linda Voiland School of Chemical Engineering and Bioengineering Washington State University 1470 NE College Ave Pullman WA 99164 USA
| |
Collapse
|
|
40
|
Yadav KS, Upadhya A, Misra A. Targeted drug therapy in nonsmall cell lung cancer: clinical significance and possible solutions-part II (role of nanocarriers). Expert Opin Drug Deliv 2020; 18:103-118. [PMID: 33017541 DOI: 10.1080/17425247.2021.1832989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Nonsmall cell lung cancer (NSCLC) accounts for 80-85% of the cases of lung cancer. The conventional therapeutic effective dosage forms used to treat NSCLC are associated with rigid administration schedules, adverse effects, and may be associated with acquired resistance to therapy. Nanocarriers may provide a suitable alternative to regular formulations to overcome inherent drawbacks and provide better treatment modalities for the patient. AREAS COVERED The article explores the application of drug loaded nanocarriers for lung cancer treatment. Drug-loaded nanocarriers can be modified to achieve controlled delivery at the desired tumor infested site. The type of nanocarriers employed are diverse based on polymers, liposomes, metals and a combination of two or more different base materials (hybrids). These may be designed for systemic delivery or local delivery to the lung compartment (via inhalation). EXPERT OPINION Nanocarriers can improve pharmacokinetics of the drug payload by improving its delivery to the desired location and can reduce associated systemic toxicities. Through nanocarriers, a wide variety of therapeutics can be administered and targeted to the cancerous site. Some examples of the utilities of nanocarriers are codelivery of drugs, gene delivery, and delivery of other biologics. Overall, the nanocarriers have promising potential in improving therapeutic efficacy of drugs used in NSCLC.
Collapse
Affiliation(s)
- Khushwant S Yadav
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Svkm's Nmims , Mumbai, India
| | - Archana Upadhya
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Svkm's Nmims , Mumbai, India
| | - Ambikanandan Misra
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Svkm's Nmims , Mumbai, India
| |
Collapse
|
|
41
|
Gouyou B, Millul J, Villa A, Cazzamalli S, Neri D, Matasci M. Sortase-Mediated Site-Specific Modification of Interleukin-2 for the Generation of a Tumor-Targeting Acetazolamide-Cytokine Conjugate. ACS OMEGA 2020; 5:26077-26083. [PMID: 33073134 PMCID: PMC7558062 DOI: 10.1021/acsomega.0c03592] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/15/2020] [Indexed: 05/10/2023]
Abstract
Small ligands specific to tumor-associated antigens can be used as alternatives to antibodies for the delivery of small payloads such as radionuclides, cytotoxic drugs, and fluorophores. Their use as a delivery moiety of bioactive proteins such as cytokines remains largely unexplored. Here, we describe the preparation and in vivo characterization of the first small molecule-cytokine conjugate targeting carbonic anhydrase IX (CAIX), a marker of renal cell carcinoma and hypoxia. Site-specific conjugation between interleukin-2 and acetazolamide was obtained by sortase A-mediated transpeptidation. Binding of the conjugate to the cognate CAIX antigen was confirmed by surface plasmon resonance. The in vivo targeting of structures expressing carbonic anhydrase IX was assessed by biodistribution experiments in tumor-bearing mice. Optimization of manufacturability and tumor-targeting performance of acetazolamide-cytokine products will be required in order to enable industrial applications.
Collapse
Affiliation(s)
| | - Jacopo Millul
- Philochem
AG, Libernstrasse 3, 8112 Otelfingen, Switzerland
| | | | | | - Dario Neri
- Department
of Chemistry and Applied Biosciences, Swiss
Federal Institute of Technology, 8093 Zurich, Switzerland
| | - Mattia Matasci
- Philochem
AG, Libernstrasse 3, 8112 Otelfingen, Switzerland
| |
Collapse
|
|
42
|
Design and Applications of Bifunctional Small Molecules in Biology. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1869:140534. [PMID: 32871274 DOI: 10.1016/j.bbapap.2020.140534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 12/12/2022]
|
|
43
|
Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent. Sci Rep 2020; 10:12772. [PMID: 32728172 PMCID: PMC7391724 DOI: 10.1038/s41598-020-69682-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 07/09/2020] [Indexed: 12/19/2022] Open
Abstract
Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.
Collapse
|
|
44
|
Das RP, Chakravarti S, Patel SS, Lakhamje P, Gurjar M, Gota V, Singh BG, Kunwar A. Tuning the pharmacokinetics and efficacy of irinotecan (IRI) loaded gelatin nanoparticles through folate conjugation. Int J Pharm 2020; 586:119522. [PMID: 32534159 DOI: 10.1016/j.ijpharm.2020.119522] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/05/2020] [Accepted: 06/06/2020] [Indexed: 02/07/2023]
Abstract
Gelatin based nanocarriers have major limitation of shorter circulation half-life (t1/2). Present study addressed this issue by conjugating gelatin with folate followed by nanoprecipitation in presence of polysorbate 80 to form folate attached gelatin nanoparticles (GNP-F). The folic acid was conjugated with gelatin through the formation of amide linkage with a maximum conjugation yield of ~69%. Cryo-SEM analysis indicated that unconjugated gelatin nanoparticles (GNP) and GNP-F were spherical of nearly identical size of ~200 nm. The irinotecan (IRI)-loading efficiency estimated for IRI-GNP and IRI-GNP-F was 6.6 ± 0.42% and 11.2 ± 0.73% respectively and both formulations showed faster release of IRI at acidic pH (~5) than at physiological pH (~7). Further IRI-GNP-F demonstrated significantly higher cytotoxicity in folate receptor (FR)-positive HeLa cells than the unconjugated IRI-GNP nanoparticles confirming active targeting. Subsequently the antitumor activity of above formulations in FR-positive fibrosarcoma (syngeneic) tumor-bearing mice followed the order of IRI-GNP-F > IRI-GNP > free IRI. The pharmacokinetic evaluation of IRI-GNP and IRI-GNP-F revealed that encapsulation of IRI within GNP without folate improved its plasma maximum concentration (Cmax). However, folate conjugation of GNP remarkably improved the t1/2 of IRI. Taken together, folate as a targeting ligand modulates the pharmacokinetic property of IRI loaded GNP to favor active verses passive targeting.
Collapse
Affiliation(s)
- Ram P Das
- Radiation & Photochemistry Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India
| | - Sarjak Chakravarti
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Snehal S Patel
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Pooja Lakhamje
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai 410210, India
| | - Murari Gurjar
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai 410210, India
| | - Vikram Gota
- Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India; Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai 410210, India
| | - Beena G Singh
- Radiation & Photochemistry Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India.
| | - Amit Kunwar
- Radiation & Photochemistry Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India.
| |
Collapse
|
|
45
|
Ullah R, Wazir J, Khan FU, Diallo MT, Ihsan AU, Mikrani R, Aquib M, Zhou X. Factors Influencing the Delivery Efficiency of Cancer Nanomedicines. AAPS PharmSciTech 2020; 21:132. [PMID: 32409932 DOI: 10.1208/s12249-020-01691-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/13/2020] [Indexed: 01/01/2023] Open
Abstract
The superiority of nanomedicine over conventional medicines in the treatment of cancer has gained immediate recognition worldwide. As traditional cancer therapies are nonspecific and detrimental to healthy cells, the ability of nanomedicine to release drugs to target tumor cells specifically instead of healthy cells has brought new hope to cancer patients. This review focuses on the effects of various factors of nanoparticles such as transport, concentration in cells, tumor microenvironment, interaction with protein, penetration, uptake by tumor cells, cancer cell mutations, and intracellular trafficking of the nanoparticle. Besides the history of nanomedicine, future perspectives of nanomedicines are also explored in this text.
Collapse
|
|
46
|
Shi H, van Steenbergen MJ, Lou B, Liu Y, Hennink WE, Kok RJ. Folate decorated polymeric micelles for targeted delivery of the kinase inhibitor dactolisib to cancer cells. Int J Pharm 2020; 582:119305. [PMID: 32278056 DOI: 10.1016/j.ijpharm.2020.119305] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/11/2022]
Abstract
One of the main challenges in clinical translation of polymeric micelles is retention of the drug in the nanocarrier system upon its systemic administration. Core crosslinking and coupling of the drug to the micellar backbone are common strategies to overcome these issues. In the present study, polymeric micelles were prepared for tumor cell targeting of the kinase inhibitor dactolisib which inhibits both the mammalian Target of Rapamycin (mTOR) kinase and phosphatidylinositol-3-kinase (PI3K). We employed platinum(II)-based linker chemistry to couple dactolisib to the core of poly(ethylene glycol)-b-poly(acrylic acid) (PEG-b-PAA) polymeric micelles. The formed dactolisib-PEG-PAA unimers are amphiphilic and self-assemble in an aqueous milieu into core-shell polymeric micelles. Folate was conjugated onto the surface of the micelles to yield folate-decorated polymeric micelles which can target folate receptor over-expressing tumor cells. Fluorescently labeled polymeric micelles were prepared using a lissamine-platinum complex linked in a similar manner as dactolisib. Dactolisib polymeric micelles showed good colloidal stability in water and released the coupled drug in buffers containing chloride or glutathione. Folate decorated micelles were avidly internalized by folate-receptor-positive KB cells and displayed targeted cellular cytotoxicity at 50-75 nM IC50. In conclusion, we have prepared a novel type of folate-receptor targeted polymeric micelles in which platinum(II) linker chemistry modulates drug retention and sustained release of the coupled inhibitor dactolisib.
Collapse
Affiliation(s)
- Haili Shi
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
| | - Mies J van Steenbergen
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
| | - Bo Lou
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
| | - Yanna Liu
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
| | - Wim E Hennink
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
| | - Robbert J Kok
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands.
| |
Collapse
|
|
47
|
Liu H, Bolleddula J, Nichols A, Tang L, Zhao Z, Prakash C. Metabolism of bioconjugate therapeutics: why, when, and how? Drug Metab Rev 2020; 52:66-124. [PMID: 32045530 DOI: 10.1080/03602532.2020.1716784] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Bioconjugation of therapeutic agents has been used as a selective drug delivery platform for many therapeutic areas. Bioconjugates are prepared by the covalent linkage of active compounds (small or large molecule) to a carrier molecule (lipids, proteins, peptides, carbohydrates, and polymers) through a chemical linker. The linkage of the active component to a carrier molecule enhances the therapeutic window through a targeted delivery and by reducing toxicity. Bioconjugates also possess improved pharmacokinetic properties such as a long half-life, increased stability, and cleavage by intracellular enzymes/environment. However, premature cleavage of the bioconjugates and the resulting metabolites/catabolites may produce undesirable toxic effects and, hence, it is critical to understand cleavage mechanisms, metabolism of bioconjugates, and translatability to human in the discovery stages. This article provides a comprehensive overview of linker cleavage pathways and catabolism/metabolism of antibody-drug conjugates, glycoconjugates, polymer-drug conjugates, lipid-drug conjugates, folate-targeted small molecule-drug conjugates, and drug-drug conjugates.
Collapse
Affiliation(s)
- Hanlan Liu
- KSQ Therapeutics Inc., Cambridge, MA, USA
| | | | | | | | | | | |
Collapse
|
|
48
|
Chanphai P, Thomas TJ, Tajmir-Riahi HA. Application and biomolecular study of functionalized folic acid-dendrimer nanoparticles in drug delivery. J Biomol Struct Dyn 2020; 39:787-794. [PMID: 31948357 DOI: 10.1080/07391102.2020.1717994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
We determined the loading efficacy of folic acid - PAMAM - G3 and folic acid - PAMAM - G4 nanoparticles with doxorubicin (Dox), tamoxifen (Tam) and tetracycline (Tet) in aqueous solution at pH 7.2. Thermodynamic parameters ΔH0 -16 to -4 (kJ mol-1), ΔS0 31 to -0.3 (J mol-1K-1) and ΔG0 -14 to -11 (kJ mol-1) showed drug folic acid-PAMAM bindings are via ionic, H-bonding and van der Waals interactions. As acid - PAMAM size increased the stability and loading efficacy of drug-polymer conjugates were increased. The order of stability for drug-nanoparticles was doxorubicin > tetracycline > tamoxifen. TEM analysis showed major polymer morphological changes, upon drug encapsulation. Folic acid-PAMAM conjugates are effective drug delivery tools in vitro. Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- P Chanphai
- Department of Chemistry-Biochemistry and Physics, University of Québec at Trois-Rivières, Trois-Rivières, Québec, Canada
| | - T J Thomas
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, and Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - H A Tajmir-Riahi
- Department of Chemistry-Biochemistry and Physics, University of Québec at Trois-Rivières, Trois-Rivières, Québec, Canada
| |
Collapse
|
|
49
|
Fernández M, Shamsabadi A, Chudasama V. Fine-tuning thio-pyridazinediones as SMDC scaffolds (with intracellular thiol release via a novel self-immolative linker). Chem Commun (Camb) 2020; 56:1125-1128. [PMID: 31894778 DOI: 10.1039/c9cc08744c] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Herein we report the synthesis of a library of thioalkyl- and thioaryl-pyridazinediones for thiol-based self-immolative release of cargo. A bisthioaryl-pyridazinedione is shown to be stable to serum protein albumin but unstable in intracellular conditions. A derivatised analogue underwent self-immolative degradation in cellular thiol conditions as evidenced by LC-MS/release of a turn-on fluorescence fluorophore; versatility of the thiol-pyridazinedione is demonstrated through synthesis of SMDC precursors that contain three different functional groups on the same central molecule.
Collapse
|
|
50
|
Gocheva G, Ivanova N, Iliev S, Petrova J, Madjarova G, Ivanova A. Characteristics of a Folate Receptor-α Anchored into a Multilipid Bilayer Obtained from Atomistic Molecular Dynamics Simulations. J Chem Theory Comput 2019; 16:749-764. [PMID: 31639310 DOI: 10.1021/acs.jctc.9b00872] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Thorough computational description of the properties of membrane-anchored protein receptors, which are important for example in the context of active targeting drug delivery, may be achieved by models representing as close as possible the immediate environment of these macromolecules. An all-atom bilayer, including 35 different lipid types asymmetrically distributed among the two monolayers, is suggested as a model neoplastic cell membrane. One molecule of folate receptor-α (FRα) is anchored into its outer leaflet, and the behavior of the system is explored by atomistic molecular dynamics simulations. The total number of atoms in the model is ∼185 000. Three 1-μs-long simulations are carried out, where physiological conditions (310 K and 1 bar) are maintained with three different pressure scaling schemes. To evaluate the structure and the phase state of the membrane, the density profiles of the system, the average area per lipid, and the deuterium order parameter of the lipid tails are calculated. The bilayer is in liquid ordered state, and the specific arrangement varies between the three trajectories. The changes in the structure of FRα are investigated and are found time- and ensemble-dependent. The volume of the ligand binding pocket fluctuates with time, but this variation remains independent of the more global structural alterations. The latter are mostly "waving" motions of the protein, which periodically approaches and retreats from the membrane. The semi-isotropic pressure scaling perturbs the receptor most significantly, while the isotropic algorithm induces rather slow changes. Maintaining constant nonzero surface tension leads to behavior closest to the experimentally observed one.
Collapse
Affiliation(s)
- Gergana Gocheva
- Faculty of Chemistry and Pharmacy, Laboratory of Quantum and Computational Chemistry , Sofia University "St. Kliment Ohridski" , 1 James Bourchier Boulevard , 1164 Sofia , Bulgaria
| | - Nikoleta Ivanova
- Faculty of Chemistry and Pharmacy, Laboratory of Quantum and Computational Chemistry , Sofia University "St. Kliment Ohridski" , 1 James Bourchier Boulevard , 1164 Sofia , Bulgaria
| | - Stoyan Iliev
- Faculty of Chemistry and Pharmacy, Laboratory of Quantum and Computational Chemistry , Sofia University "St. Kliment Ohridski" , 1 James Bourchier Boulevard , 1164 Sofia , Bulgaria
| | - Jasmina Petrova
- Faculty of Chemistry and Pharmacy, Laboratory of Quantum and Computational Chemistry , Sofia University "St. Kliment Ohridski" , 1 James Bourchier Boulevard , 1164 Sofia , Bulgaria
| | - Galia Madjarova
- Faculty of Chemistry and Pharmacy, Laboratory of Quantum and Computational Chemistry , Sofia University "St. Kliment Ohridski" , 1 James Bourchier Boulevard , 1164 Sofia , Bulgaria
| | - Anela Ivanova
- Faculty of Chemistry and Pharmacy, Laboratory of Quantum and Computational Chemistry , Sofia University "St. Kliment Ohridski" , 1 James Bourchier Boulevard , 1164 Sofia , Bulgaria
| |
Collapse
|