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Wang D, Yin F, Li Z, Zhang Y, Shi C. Current progress and remaining challenges of peptide-drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)? J Nanobiotechnology 2025; 23:305. [PMID: 40259322 PMCID: PMC12013038 DOI: 10.1186/s12951-025-03277-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 02/24/2025] [Indexed: 04/23/2025] Open
Abstract
Drug conjugates have emerged as a promising alternative delivery system designed to deliver an ultra-toxic payload directly to the target cancer cells, maximizing therapeutic efficacy while minimizing toxicity. Among these, antibody-drug conjugates (ADCs) have garnered significant attention from both academia and industry due to their great potential for cancer therapy. However, peptide-drug conjugates (PDCs) offer several advantages over ADCs, including more accessible industrial synthesis, versatile functionalization, high tissue penetration, and rapid clearance with low immunotoxicity. These factors position PDCs as up-and-coming drug candidates for future cancer therapy. Despite their potential, PDCs face challenges such as poor pharmacokinetic properties and low bioactivity, which hinder their clinical development. How to design PDCs to meet clinical needs is a big challenge and urgent to resolve. In this review, we first carefully analyzed the general consideration of successful PDC design learning from ADCs. Then, we summarised the basic functions of each component of a PDC construct, comprising of peptides, linkers and payloads. The peptides in PDCs were categorized into three types: tumor targeting peptides, cell penetrating peptide and self-assembling peptide. We then analyzed the potential of these peptides for drug delivery, such as overcoming drug resistance, controlling drug release and improving therapeutic efficacy with reduced non-specific toxicity. To better understand the potential druggability of PDCs, we discussed the pharmacokinetics of PDCs and also briefly introduced the current PDCs in clinical trials. Lastly, we discussed the future perspectives for the successful development of an oncology PDC. This review aimed to provide useful information for better construction of PDCs in future clinical applications.
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Affiliation(s)
- Dongyuan Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Feng Yin
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China
- Shenzhen Bay Laboratory, Pingshan Translational Medicine Center, Shenzhen, 518118, China
| | - Zigang Li
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
- Shenzhen Bay Laboratory, Pingshan Translational Medicine Center, Shenzhen, 518118, China.
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China.
| | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China.
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Liu H, Zou J, Li X, Ge Y, He W. Drug delivery for platinum therapeutics. J Control Release 2025; 380:503-523. [PMID: 39923853 DOI: 10.1016/j.jconrel.2025.02.006] [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: 07/02/2024] [Revised: 01/18/2025] [Accepted: 02/04/2025] [Indexed: 02/11/2025]
Abstract
Cancer remains a severe threat to human health. Platinum drugs, such as cisplatin (CDDP), oxaliplatin, and carboplatin, are extensively utilized for treating various cancers and have become the primary drugs in first-line treatments for numerous solid tumors due to their effective anticancer properties. However, their side effects, including drug resistance, nephrotoxicity and ototoxicity, limit the clinical application. Therefore, there is an urgent need to develop targeted delivery and controlled release systems for platinum drugs to address the disadvantages, enhancing tumor accumulation and improving therapeutic effects. In this review, we first review the progress of platinum drugs, their anticancer mechanism, clinical applications and limitations. Then, we comprehensively summarize the platinum-based delivery using drug carriers and responsive strategies. We especially highlight the platinum-delivery formulations in ongoing clinical trials. Finally, we provide perspectives for this field. The review could provide an increasingly in-depth understanding of platinum therapeutics and motivate increasing delivery tactics to overcome the limitations of platinum application.
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Affiliation(s)
- Hui Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Jiahui Zou
- School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Xiaotong Li
- School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Yizhi Ge
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, PR China.
| | - Wei He
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, PR China.
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3
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Wang Y, Xu W, Zhang B, Wang X, Gou S. Concept of Targeted Drug Conjugate and Its Application in Reversing Drug Resistance. J Med Chem 2025; 68:7353-7366. [PMID: 40170467 DOI: 10.1021/acs.jmedchem.4c03006] [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: 04/03/2025]
Abstract
Small-molecule targeted drugs have become the mainstream cancer treatment due to their specific therapy. However, drug resistance inevitably happens to cancer patients. Herein, we propose the "targeted drug conjugate (TDC)" concept to design drugs that enhance antitumor activity, reduce toxicity, and reverse resistance. Upon this idea, compounds Lapa-603 and Lapa-604 were obtained by modifying Pt(II) units with Lapatinib's pharmacophore. Research has found that Lapa-604 can potently inhibit the proliferation of the tested cancer cells and reverse multiple cancer cell resistance by targeting the EGFR protein and causing severe DNA damage. More importantly, Lapa-604 presented higher tumor growth inhibitory efficacy than Lapatinib, Cisplatin, or their physical mixtures in both MDA-MB-231 and BT474 xenograft tumor models. Our research has provided promise for the design and development of novel drugs based on the TDC concept that can effectively overcome drug resistance with stronger antitumor activity and lower toxicity than the corresponding combination therapy.
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Affiliation(s)
- Yuanjiang Wang
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China
- Jiangsu Province Key Laboratory for Biopharmaceuticals and Small Molecule Drugs, Southeast University, Nanjing 211189, P. R. China
| | - Wenqing Xu
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China
| | - Bin Zhang
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China
| | - Xinyi Wang
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China
| | - Shaohua Gou
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China
- Jiangsu Province Key Laboratory for Biopharmaceuticals and Small Molecule Drugs, Southeast University, Nanjing 211189, P. R. China
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Zhao X, Zhang Y, Wang X, Fu Z, Zhong Z, Deng C. Multivalent ionizable lipid-polypeptides for tumor-confined mRNA transfection. Bioact Mater 2025; 46:423-433. [PMID: 39850023 PMCID: PMC11754973 DOI: 10.1016/j.bioactmat.2024.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/25/2024] [Accepted: 12/28/2024] [Indexed: 01/25/2025] Open
Abstract
mRNA therapeutics is revolutionizing the treatment concepts toward many diseases including cancer. The potential of mRNA is, however, frequently limited by modest control over site of transfection. Here, we have explored a library of multivalent ionizable lipid-polypeptides (MILP) to achieve robust mRNA complexation and tumor-confined transfection. Leveraging the multivalent electrostatic, hydrophobic, and H-bond interactions, MILP efficiently packs both mRNA and plasmid DNA into sub-80 nm nanoparticles that are stable against lyophilization and long-term storage. The best MILP@mRNA complexes afford 8-fold more cellular uptake than SM-102 lipid nanoparticle formulation (SM-102 LNP), efficient endosomal disruption, and high transfection in different cells. Interestingly, MILP@mLuc displays exclusive tumor residence and distribution via multivalency-directed strong affinity and transcytosis, and affords specific protein expression in tumor cells and macrophages at tumor sites following intratumoral injection, in sharp contrast to the indiscriminate distribution and transfection in main organs of SM-102 LNP. Notably, MILP@mIL-12 with specific and efficient cytokine expression generates significant remodeling of tumor immunoenvironments and remarkable antitumor response in subcutaneous Lewis lung carcinoma and 4T1 tumor xenografts. MILP provides a unique strategy to site-specific transfection that may greatly broaden the applications of mRNA.
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Affiliation(s)
- Xiaofei Zhao
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymers, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Yueyue Zhang
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymers, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Xin Wang
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymers, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Ziming Fu
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymers, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Zhiyuan Zhong
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymers, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Chao Deng
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymers, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
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Sun G, Wang Z, Li Y, Wang J, Liu F, Yu J, Yuan M, Wang N, Liu Z, Xiang C, Zhang Y, Oumata N, Yu P, Teng Y. Design and synthesis of isatin derivative payloaded peptide-drug conjugate as tubulin inhibitor against colorectal cancer. Eur J Med Chem 2025; 285:117276. [PMID: 39818012 DOI: 10.1016/j.ejmech.2025.117276] [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: 12/25/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
A series of isatin derivatives which could inhibit colorectal cancer (CRC) were synthesized. Among those compounds, 5B exhibited good inhibitory activity of CRC through the inhibition of tubulin expression, inducing apoptosis, and causing G2/M phase cell cycle arrest pathway, which suggested that 5B could be a potential tubulin inhibitor. Based on that, a novel peptide-drug conjugate (PDC), which employed the CRC cells related receptor CD44 ligand peptide A6 coupling to 5B to accomplish A6-5B. The in vitro and in vivo studies showed that A6-5B could significantly inhibit the tumor growth and metastasis in CRC cells. Mechanistic studies revealed that both 5B and A6-5B exert their antitumor effects by inhibiting tubulin, demonstrating that 5B might play a payload role and A6 could act as a targeting moiety for selective drug delivery to tumor cells.
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Affiliation(s)
- Guoyang Sun
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Zhaoyang Wang
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Yanping Li
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Jinjin Wang
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Futao Liu
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Jiajia Yu
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Mengzhen Yuan
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Ning Wang
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Zhen Liu
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Cen Xiang
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Yongmin Zhang
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China; Sorbonne Université, Institut Parisien de Chimie Moléculaire, UMR8232 CNRS, 4 Place Jussieu, 75005, Paris, France
| | - Nassima Oumata
- Université Paris Cité, 4, avenue de l'Observatoire, 75006, Paris, France
| | - Peng Yu
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China.
| | - Yuou Teng
- China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China.
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Morga M, Kosior D, Nattich-Rak M, Leszczyńska I, Batys P, Adamczyk Z, Leshansky AM. Kinetics of Macroion Adsorption on Silica: Complementary Theoretical and Experimental Investigations for Poly-l-arginine. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2025; 41:2248-2258. [PMID: 39834293 PMCID: PMC11803736 DOI: 10.1021/acs.langmuir.4c03766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/30/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
A comprehensive approach enabling a quantitative interpretation of poly-l-arginine (PARG) adsorption kinetics at solid/electrolyte interfaces was developed. The first step involved all-atom molecular dynamics (MD) modeling of physicochemical characteristics yielding PARG molecule conformations, its contour length, and the cross-section area. It was also shown that PARG molecules, even in concentrated electrolyte solutions (100 mM NaCl), assume a largely elongated shape with an aspect ratio of 36. Using the parameters derived from MD, the PARG adsorption kinetics at the silica/electrolyte interface was calculated using the random sequential adsorption approach. These predictions were validated by optical reflectometry measurements. It was confirmed that the molecules irreversibly adsorbed in the side-on orientation and their coverage agreed with the elongated shape of the PARG molecule predicted from the MD modeling. These theoretical and experimental results were used for the interpretation of the quartz crystal microbalance measurements carried out under various pH conditions. A comprehensive analysis unveiled that the results stemming from the hydrodynamic theory postulating a lubrication-like (soft) contact of the macroion molecules with the sensor adequately reflect the adsorption kinetics. The range of validity of the intuitively used Sauerbrey model was also estimated. It was argued that acquired results can be exploited to control macroion adsorption at solid/liquid interfaces. This is essential for the optimum preparation of their supporting layers used for bioparticle immobilization and shell formation at nanocapsules in targeted drug delivery.
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Affiliation(s)
- Maria Morga
- Jerzy
Haber Institute of Catalysis and Surface Chemistry, Polish Academy
of Sciences, Niezapominajek 8, PL30239 Krakow, Poland
| | - Dominik Kosior
- Jerzy
Haber Institute of Catalysis and Surface Chemistry, Polish Academy
of Sciences, Niezapominajek 8, PL30239 Krakow, Poland
| | - Małgorzata Nattich-Rak
- Jerzy
Haber Institute of Catalysis and Surface Chemistry, Polish Academy
of Sciences, Niezapominajek 8, PL30239 Krakow, Poland
| | - Izabella Leszczyńska
- Jerzy
Haber Institute of Catalysis and Surface Chemistry, Polish Academy
of Sciences, Niezapominajek 8, PL30239 Krakow, Poland
| | - Piotr Batys
- Jerzy
Haber Institute of Catalysis and Surface Chemistry, Polish Academy
of Sciences, Niezapominajek 8, PL30239 Krakow, Poland
| | - Zbigniew Adamczyk
- Jerzy
Haber Institute of Catalysis and Surface Chemistry, Polish Academy
of Sciences, Niezapominajek 8, PL30239 Krakow, Poland
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Li Q, Liu Y, Cheng Y, Cao H, Du K, Zhu T, Xu D, Hu H. Reduction-Responsive RGD-Docetaxel Conjugate: Synthesis, In Vitro Drug Release and In Vitro Antitumor Activity. Drug Dev Res 2025; 86:e70043. [PMID: 39722470 DOI: 10.1002/ddr.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/22/2024] [Accepted: 12/15/2024] [Indexed: 12/28/2024]
Abstract
Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug docetaxel (DTX). Peptide-drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. In the present research, DTX is condensed with 3-(pyridin-2-yldisulfanyl) propanoic acid via ester bond to obtain the intermediate Py-SS-DTX. Two conjugates GSS-DTX and RGDC-SS-DTX were obtained by conjugation of Py-SS-DTX with glutathione (GSH) and RGDC peptide through a thiol-disulfide exchange reaction. Afterwards, these two peptide-DTX conjugates were characterized by proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, and high-resolution mass spectrometry. The GSS-DTX and RGDC-SS-DTX were further evaluated in terms of drug release, cell cycle inhibition, cell apoptosis, and cytotoxicity. The results show that both the GSS-DTX and RGDC-SS-DTX exhibit reduction-responsive drug release and RGDC-SS-DTX exhibit higher reduction-responsiveness. The in vitro antitumor activity study shows that RGDC-SS-DTX exhibits enhanced G2/M phase arrest, cell apoptosis rate, and cytotoxicity as compared to GSS-DTX and free DTX. Besides, RGDC-SS-DTX shows reduced cytotoxicity on normal cells as compared to free DTX. The RGDC-SS-DTX synthesized in this study represents a novel DTX conjugate to effectively and selectively inhibit tumor cells.
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Affiliation(s)
- Qingqing Li
- School of Pharmacy, Changzhou University, Changzhou, PR China
| | - Yufeng Liu
- School of Pharmacy, Changzhou University, Changzhou, PR China
| | - Yilin Cheng
- School of Pharmacy, Changzhou University, Changzhou, PR China
| | - Huaibao Cao
- Changzhou Vocational Institute of Textile and Garment, Changzhou, PR China
| | - Kunda Du
- School of Pharmacy, Changzhou University, Changzhou, PR China
| | - Tianyu Zhu
- School of Pharmacy, Changzhou University, Changzhou, PR China
| | - Defeng Xu
- School of Pharmacy, Changzhou University, Changzhou, PR China
| | - Hang Hu
- School of Pharmacy, Changzhou University, Changzhou, PR China
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Song Y, Lei L, Cai X, Wei H, Yu CY. Immunomodulatory Peptides for Tumor Treatment. Adv Healthc Mater 2025; 14:e2400512. [PMID: 38657003 DOI: 10.1002/adhm.202400512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/07/2024] [Indexed: 04/26/2024]
Abstract
Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented.
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Affiliation(s)
- Yang Song
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Longtianyang Lei
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Xingyu Cai
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Hua Wei
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Cui-Yun Yu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
- Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha, 410013, China
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Lu X, Qiu J, Li Y, Cai M, Yang X, Li S, Ye G, Yi W, Huang Y. PEGylation Can Effectively Strike a Balance in siRNA Delivery Performances of Guanidinylated Linear Synthetic Polypeptides with Potential Use for Transcriptional Gene Silencing. ACS Macro Lett 2024; 13:1251-1257. [PMID: 39259674 DOI: 10.1021/acsmacrolett.4c00405] [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: 09/13/2024]
Abstract
The prevailing design philosophy for polymeric vectors delivering siRNA is rooted in the post-transcriptional gene silencing (PTGS) mechanism. Yet, the transcriptional gene silencing (TGS) mechanism offers a potentially more durable silencing effect, which necessitates efficient siRNA delivery into the nucleus. However, it remains a challenge for the polymeric vectors to efficiently deliver siRNA into the nucleus. We have explored guanidinylated cyclic synthetic polypeptides (GCSPs) to enhance the nuclear delivery of siRNA, but an increased cytotoxicity and difficulty in producing the GCSPs on a large scale limit their utility. Herein, we simply prepare PEGylated guanidinylated linear synthetic polypeptides (PGLSPs) exhibiting improved membrane penetration, direct siRNA transport to the nucleus, reduced toxicity, high cellular uptake, and mitigation of protein corona formation. The PEGylation can effectively balance the vector's nuclear delivery capacity with other critical aspects of performances for siRNA delivery. Therefore, the PGLSPs hold promise as TGS-based delivery vectors, offering potential for future therapeutic applications.
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Affiliation(s)
- Xujun Lu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Jiajian Qiu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Yilan Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Ming Cai
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Xiaohan Yang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Suifei Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Guodong Ye
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Wei Yi
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Yugang Huang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
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Guo RX, Zhang H, Chen Y, Li P, Du B. Identification of peptides from Corneum Galli Gigeri Endothelium and inhibiting H2O2-induced gastric mucosa associated with the Rho signaling pathway. FOOD BIOSCI 2024; 61:104418. [DOI: 10.1016/j.fbio.2024.104418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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11
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Sun X, Li A, Li N, Ji G, Song Z. Facile Preparation of Heteropolypeptides from Crude Mixtures of α-Amino Acid N-Carboxyanhydrides. Biomacromolecules 2024; 25:6093-6102. [PMID: 39167691 DOI: 10.1021/acs.biomac.4c00746] [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: 08/23/2024]
Abstract
Heteropolypeptides bearing two or more functional side chains are promising polymeric materials for various biomedical applications. However, conventional preparation of heteropolypeptides relies on the synthesis and purification of each N-carboxyanhydride (NCA) monomer in a separate manner, which substantially increases the time and cost. Herein, we report the facile preparation of heteropolypeptides with up to 86% yield within several hours, which are obtained from a mixture of crude NCA monomers. The combination of n-hexane precipitation and biphasic segregation effectively removed >90% impurities from crude NCA mixtures, allowing for the successful polymerization process. Various heteropolypeptides with monomodal distribution and narrow dispersity were efficiently prepared, whose compositions were predetermined by the feeding ratios of amino acids. We believe that this work significantly simplifies the preparation of various heteropolypeptides, boosting the downstream studies of these promising materials.
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Affiliation(s)
- Xiao Sun
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, China
| | - Aoting Li
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, China
| | - Ning Li
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, China
| | - Guonan Ji
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, China
| | - Ziyuan Song
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, China
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12
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Wang Y, Yang F, Li H. Development of a Novel, Easy-to-Prepare, and Potentially Valuable Peptide Coupling Technology Utilizing Amide Acid as a Linker. Pharmaceuticals (Basel) 2024; 17:981. [PMID: 39204086 PMCID: PMC11356999 DOI: 10.3390/ph17080981] [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: 05/10/2024] [Revised: 06/16/2024] [Accepted: 07/19/2024] [Indexed: 09/03/2024] Open
Abstract
The process of synthesizing radionuclide-coupled drugs, especially shutdown technology that links bipotent chelators with biomolecules, utilizes traditional coupling reactions, including emerging click chemistry; these reactions involve different drawbacks, such as complex and cumbersome reaction steps, long reaction times, and the use of catalysts at various pH values, which can negatively impact the effects of the chelating agent. To address the above problems in this study, This research designed a novel bipotent chelator coupled with peptides. In the present study, dichloromethane was used as a solvent, and the reaction was conducted at room temperature for 12 h. A one-step ring-opening method was employed to introduce the coupling functional group of tridentate amide acid. The coupling materials consisted of the amino active site of the peptide and diethylene glycol anhydride. In this paper, this study explored the reactions between different equivalents of acid anhydride coupled to the peptide (peptide sequence: HLRKLRKR) and determined that the maximum conversion of the peptide feedstock was 87%. To determine the selectivity of the reaction sites in this polypeptide, This study identified the peptide sequence at the reaction site using nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS). For the selected peptide, the first reactive site was on the terminal amino group, followed by the amino group on the tetra- and hepta-lysine side chains. The tridentate amic acid framework functions as a chelating agent, capable of binding a range of lanthanide ions. This significantly reduces and optimizes the time and cost associated with synthesizing radionuclide-coupled drugs.
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Affiliation(s)
- Yaling Wang
- College of Chemistry and Materials Science, Fujian Normal University, Fuzhou 350117, China;
- Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Fan Yang
- Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China
- Xiamen Key-Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen 361021, China
- Key Laboratory of Rare Earths, Chinese Academy of Sciences, China Rare Earth Group Research Institute, Ganzhou 341000, China
- Fujian Province Joint Innovation Key Laboratory of Fuel and Materials in Clean Nuclear Energy System, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
- Key Laboratory of Rare Earths, Ganjiang Innovation Academy, Chinese Academy of Sciences, Ganzhou 341000, China
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
| | - Hongyan Li
- Department of Medical Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
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13
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Ge C, He J, Gan M, Qian Y, Zhu J, Wu F, Song Z, Yin L. Conformation-Switchable Polypeptides as Molecular Gates for Controllable Drug Release. Biomacromolecules 2024; 25:3373-3383. [PMID: 38713187 DOI: 10.1021/acs.biomac.4c00024] [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: 05/08/2024]
Abstract
The control over secondary structure has been widely studied to regulate the properties of polypeptide materials, which is used to change their functions in situ for various biomedical applications. Herein, we designed and constructed enzyme-responsive polypeptides as gating materials for mesoporous silica nanoparticles (MSNs), which underwent a distorted structure-to-helix transition to promote the release of encapsulated drugs. The polypeptide conjugated on the MSN surface adopted a negatively charged, distorted, flexible conformation, covering the pores of MSN to prevent drug leakage. Upon triggering by alkaline phosphatase (ALP) overproduced by tumor cells, the polypeptide transformed into positively charged, α-helical, rigid conformation with potent membrane-penetrating capabilities, which protruded from the MSN surface to uncover the pores. Such a transition thus enabled cancer-selective drug release and cellular internalization to efficiently kill tumor cells. This study highlights the important role of chain flexibility in modulating the biological function of polypeptides and provides a new application paradigm for synthetic polypeptides with secondary-structure transition.
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Affiliation(s)
- Chenglong Ge
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Jianyin He
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Mudan Gan
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yu Qian
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Junliang Zhu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Fan Wu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Ziyuan Song
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Lichen Yin
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
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14
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Liu J, Zhang J, Zhang Y, Wei W, Zhan M, Zhang Z, Liu B, Hu X, He W. A mitochondria-targeting heptamethine cyanine-chlorambucil formulated polymeric nanoparticle to potentiate native tumor chemotherapeutic efficacy. Biomater Sci 2024; 12:2614-2625. [PMID: 38591255 DOI: 10.1039/d4bm00003j] [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: 04/10/2024]
Abstract
Chlorambucil (Cbl) is a DNA alkylating drug in the nitrogen mustard family, but the clinical applications of nitrogen mustard antitumor drugs are frequently limited by their poor aqueous solubility, poor cellular uptake, lack of targeting, and severe side effects. Additionally, mitochondria are the energy factories for cells, and tumor cells are more susceptible to mitochondrial dysfunction than some healthy cells, thus making mitochondria an important target for tumor therapy. As a proof-of-concept, direct delivery of Cbl to tumor cells' mitochondria will probably bring about new opportunities for the nitrogen mustard family. Furthermore, IR775 chloride is a small-molecule lipophilic cationic heptamethine cyanine dye with potential advantages of mitochondria targeting, near-infrared (NIR) fluorescence imaging, and preferential internalization towards tumor cells. Here, an amphiphilic drug conjugate was facilely prepared by covalently coupling chlorambucil with IR775 chloride and further self-assembly to form a carrier-free self-delivery theranostic system, in which the two components are both functional units aimed at theranostic improvement. The theranostic IR775-Cbl potentiated typical "1 + 1 > 2" tumor inhibition through specific accumulation in mitochondria, which triggered a remarkable decrease in mitochondrial membrane potential and ATP generation. In vivo biodistribution and kinetic monitoring were achieved by real-time NIR fluorescence imaging to observe its transport inside a living body. Current facile mitochondria-targeting modification with clinically applied drugs was promising for endowing traditional drugs with targeting, imaging, and improved potency in disease theranostics.
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Affiliation(s)
- Jing Liu
- College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Jie Zhang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, Guangdong, China.
| | - Yongteng Zhang
- Key Laboratory of Precision and Intelligent Chemistry, and CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, and School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026 Anhui, China.
- Suzhou Institute for Advanced Research, University of Science and Technology of China, 215123 Suzhou, China
| | - Wei Wei
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, Guangdong, China.
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, Guangdong, China.
| | - Zhiren Zhang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, Guangdong, China.
| | - Bing Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, Guangdong, China.
| | - Xianglong Hu
- Key Laboratory of Precision and Intelligent Chemistry, and CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, and School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026 Anhui, China.
- Suzhou Institute for Advanced Research, University of Science and Technology of China, 215123 Suzhou, China
| | - Weiling He
- Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China.
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15
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Tang B, Zhang Y, Liu X, Wang Y, He P. A Novel Polyamino Acid Sulfur Dioxide Prodrug Synergistically Elevates ROS with β-Lapachone in Cancer Treatment. J Pharm Sci 2024; 113:1239-1247. [PMID: 38042342 DOI: 10.1016/j.xphs.2023.11.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/22/2023] [Accepted: 11/22/2023] [Indexed: 12/04/2023]
Abstract
Due to the distorted redox balance, cancer cells are considered more vulnerable to excessive reactive oxygen species (ROS). In a variety of oxidative stress-related therapies, gas therapy has emerged as a new therapeutic strategy owing to its efficacy and biosafety. Herein, a newly-discovered gasotransmitter sulfur dioxide (SO2) and a tumor specific ROS generation agent β-lapachone (Lapa) were firstly combined for anticancer therapy. Firstly, amphiphilic glutathione (GSH) responsive polypeptide SO2 prodrug PEG-b-poly(Lys-DNs) was synthesized by ring opening polymerization of SO2-containing N-carboxyanhydride. Then, Lapa was encapsulated into the polymeric micelles with loading content of 8.6 % and loading efficiency of 51.6 %. The obtained drug-loaded nanoparticles (NPs(Lapa)) exhibited a fast release of Lapa and SO2 in the stimuli of 10 mM GSH in PBS. Subsequently, in vitro experiment showed that NPs(Lapa) exhibited obvious cytotoxicity towards 4 T1 cancer cells at a concentration of 2.0 μg/mL, which may be attributed to the depletion of intracellular GSH and upregulation of ROS level both by SO2 release and by the ROS generation from lapachone transformation. In vivo fluorescence imaging showed that the NPs were gradually enriched in tumor tissues in 24 h, probably due to the enhanced permeability and retention effect of NPs. Finally, NPs(Lapa) showed the best anticancer effect in 4 T1 tumor bearing mice with a tumor inhibiting rate (IRT) of 61 %, whereas IRT for free Lapa group was only 23.6 %. This work may be a new attempt to combine SO2 gas therapy with ROS inducer for anticancer therapy through oxidative stress.
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Affiliation(s)
- Bingtong Tang
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, PR China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China
| | - Yu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
| | - Xinming Liu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China
| | - Yanping Wang
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, PR China; Chongqing Research Institute, Changchun University of Science and Technology, No.618 Liangjiang Avenue, Longxing Town, Yubei District, Chongqing City, 401135, PR China
| | - Pan He
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, PR China.
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16
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Zhang Y, Zhang H, Wang Y, Ji Y, Wang F, He P. A Novel Cu(II) Loaded Polypeptide SO 2 Prodrug Nanoformulation Combining Chemodynamic and Gas Anticancer Therapies. Macromol Biosci 2024; 24:e2300429. [PMID: 37985928 DOI: 10.1002/mabi.202300429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/06/2023] [Indexed: 11/22/2023]
Abstract
Sulfur dioxide (SO2)-based gas therapy and chemodynamic therapyare both reactive oxygen species (ROS)-mediated anticancer strategies, but there are few reports of their combined application. To this end, a novel graft-type copolymeric SO2 prodrug, PLG-g-mPEG-DNs, is designed and synthesized in this work. The amphiphilic polypeptides can self-assemble into nanoparticles (NPs) and encapsulated Cu(II) ions by metal-carboxyl coordination. In vitro release results showed that the obtained NPs-Cu can respond to the acidic pH and high glutathione levels typical of a tumor microenvironment to release Cu(II) and SO2 simultaneously. Both a Cu(II)-triggered Fenton-like reaction and the SO2 gas would promote ROS production and upregulate the oxidative stress in tumor cells, leading to an enhanced killing effect towards 4T1 cancer cells compared to either Cu(II) or the NPs alone. Furthermore, the in vitro hemolysis of NPs-Cu is less than 1.0% at a high concentration of 8 mg/mL, indicating good blood compatibility and the potential for in vivo tumor inhibition application.
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Affiliation(s)
- Yu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Hongyu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Yanfang Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Yingying Ji
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, P. R. China
| | - Fang Wang
- Department of Regeneration Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, P. R. China
| | - Pan He
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, P. R. China
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17
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Xu L, He L, Li Y, Cai T, Zhang J, Chu Z, Shen X, Cai R, Shi H, Zhu C. Stimuli-triggered multilayer films in response to temperature and ionic strength changes for controlled favipiravir drug release. Biomed Mater 2024; 19:035004. [PMID: 38364282 DOI: 10.1088/1748-605x/ad2a3b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 02/16/2024] [Indexed: 02/18/2024]
Abstract
The block copolymer micelles and natural biopolymers were utilized to form layer-by-layer (LbL) films via electrostatic interaction, which were able to effectively load and controllably release favipiravir, a potential drug for the treatment of coronavirus epidemic. The LbL films demonstrated reversible swelling/shrinking behavior along with the manipulation of temperature, which could also maintain the integrity in the structure and the morphology. Due to dehydration of environmentally responsive building blocks, the drug release rate from the films was decelerated by elevating environmental temperature and ionic strength. In addition, the pulsed release of favipiravir was observed from the multilayer films under the trigger of temperature, which ensured the precise control in the content of the therapeutic reagents at a desired time point. The nanoparticle-based LbL films could be used for on-demandin vitrorelease of chemotherapeutic reagents.
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Affiliation(s)
- Li Xu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Lang He
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Yinzhao Li
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Tingwei Cai
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Jianhua Zhang
- N.O.D topia (GuangZhou) Biotechnology Co., Ltd, Guangzhou, Guangdong 510599, People's Republic of China
| | - Zihan Chu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Xiaochen Shen
- China Tobacco Jiangsu Industrial Co., Ltd, Nanjing, Jiangsu 210019, People's Republic of China
| | - Raymond Cai
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Haifeng Shi
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Chunyin Zhu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China
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18
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Zhang Y, Lu Y, Li Y, Xu Y, Song W. Poly(Glutamic Acid)-Engineered Nanoplatforms for Enhanced Cancer Phototherapy. Curr Drug Deliv 2024; 21:326-338. [PMID: 36650626 DOI: 10.2174/1567201820666230116164511] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 01/19/2023]
Abstract
Phototherapies, including photothermal therapy and photodynamic therapy, have gained booming development over the past several decades for their attractive non-invasiveness nature, negligible adverse effects, minimal systemic toxicity, and high spatial selectivity. Phototherapy usually requires three components: light irradiation, photosensitizers, and molecular oxygen. Photosensitizers can convert light energy into heat or reactive oxygen species, which can be used in the tumor-killing process. The direct application of photosensitizers in tumor therapy is restricted by their poor water solubility, fast clearance, severe toxicity, and low cellular uptake. The encapsulation of photosensitizers into nanostructures is an attractive strategy to overcome these critical limitations. Poly(glutamic acid) (PGA) is a kind of poly(amino acid)s containing the repeating units of glutamic acid. PGA has superiority for cancer treatment because of its good biocompatibility, low immunogenicity, and modulated pH responsiveness. The hydrophilicity nature of PGA allows the physical entrapment of photosensitizers and anticancer drugs via the construction of amphiphilic polymers. Moreover, the pendent carboxyl groups of PGA enable chemical conjugation with therapeutic agents. In this mini-review, we highlight the stateof- the-art design and fabrication of PGA-based nanoplatforms for phototherapy. We also discuss the potential challenges and future perspectives of phototherapy, and clinical translation of PGA-based nanomedicines.
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Affiliation(s)
- Yu Zhang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai-201318, P. R. China
| | - Yiming Lu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai-201318, P. R. China
| | - Yicong Li
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai-200093, P. R. China
| | - Yixin Xu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai-201318, P. R. China
| | - Wenliang Song
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai-200093, P. R. China
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19
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Li C, Jin K. Chemical Strategies towards the Development of Effective Anticancer Peptides. Curr Med Chem 2024; 31:1839-1873. [PMID: 37170992 DOI: 10.2174/0929867330666230426111157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/28/2023] [Accepted: 02/24/2023] [Indexed: 05/13/2023]
Abstract
Cancer is increasingly recognized as one of the primary causes of death and has become a multifaceted global health issue. Modern medical science has made significant advancements in the diagnosis and therapy of cancer over the past decade. The detrimental side effects, lack of efficacy, and multidrug resistance of conventional cancer therapies have created an urgent need for novel anticancer therapeutics or treatments with low cytotoxicity and drug resistance. The pharmaceutical groups have recognized the crucial role that peptide therapeutic agents can play in addressing unsatisfied healthcare demands and how these become great supplements or even preferable alternatives to biological therapies and small molecules. Anticancer peptides, as a vibrant therapeutic strategy against various cancer cells, have demonstrated incredible anticancer potential due to high specificity and selectivity, low toxicity, and the ability to target the surface of traditional "undruggable" proteins. This review will provide the research progression of anticancer peptides, mainly focusing on the discovery and modifications along with the optimization and application of these peptides in clinical practice.
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Affiliation(s)
- Cuicui Li
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Kang Jin
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
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20
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Đorđević S, Medel M, Hillaert J, Masiá E, Conejos-Sánchez I, Vicent MJ. Critical Design Strategies Supporting Optimized Drug Release from Polymer-Drug Conjugates. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2303157. [PMID: 37752780 DOI: 10.1002/smll.202303157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 08/19/2023] [Indexed: 09/28/2023]
Abstract
The importance of an adequate linking moiety design that allows controlled drug(s) release at the desired site of action is extensively studied for polymer-drug conjugates (PDCs). Redox-responsive self-immolative linkers bearing disulfide moieties (SS-SIL) represent a powerful strategy for intracellular drug delivery; however, the influence of drug structural features and linker-associated spacers on release kinetics remains relatively unexplored. The influence of drug/spacer chemical structure and the chemical group available for conjugation on drug release and the biological effect of resultant PDCs is evaluated. A "design of experiments" tool is implemented to develop a liquid chromatography-mass spectrometry method to perform the comprehensive characterization required for this systematic study. The obtained fit-for-purpose analytical protocol enables the quantification of low drug concentrations in drug release studies and the elucidation of metabolite presence. and provides the first data that clarifies how drug structural features influence the drug release from SS-SIL and demonstrates the non-universal nature of the SS-SIL. The importance of rigorous linker characterization in understanding structure-function correlations between linkers, drug chemical functionalities, and in vitro release kinetics from a rationally-designed polymer-drug nanoconjugate, a critical strategic crafting methodology that should remain under consideration when using a reductive environment as an endogenous drug release trigger.
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Affiliation(s)
- Snežana Đorđević
- Polymer Therapeutics Laboratory, Príncipe Felipe Research Center (CIPF) and CIBERONC, Eduardo Primo Yúfera 3, Valencia, 46012, Spain
| | - María Medel
- Polymer Therapeutics Laboratory, Príncipe Felipe Research Center (CIPF) and CIBERONC, Eduardo Primo Yúfera 3, Valencia, 46012, Spain
| | - Justine Hillaert
- Polymer Therapeutics Laboratory, Príncipe Felipe Research Center (CIPF) and CIBERONC, Eduardo Primo Yúfera 3, Valencia, 46012, Spain
| | - Esther Masiá
- Polymer Therapeutics Laboratory, Príncipe Felipe Research Center (CIPF) and CIBERONC, Eduardo Primo Yúfera 3, Valencia, 46012, Spain
- Screening Platform, Príncipe Felipe Research Center (CIPF), Eduardo Primo Yúfera 3, Valencia, 46012, Spain
| | - Inmaculada Conejos-Sánchez
- Polymer Therapeutics Laboratory, Príncipe Felipe Research Center (CIPF) and CIBERONC, Eduardo Primo Yúfera 3, Valencia, 46012, Spain
| | - María J Vicent
- Polymer Therapeutics Laboratory, Príncipe Felipe Research Center (CIPF) and CIBERONC, Eduardo Primo Yúfera 3, Valencia, 46012, Spain
- Screening Platform, Príncipe Felipe Research Center (CIPF), Eduardo Primo Yúfera 3, Valencia, 46012, Spain
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21
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Liu YD, Chen HR, Zhang Y, Yan G, Yan HJ, Zhu Q, Peng LH. Progress and challenges of plant-derived nucleic acids as therapeutics in macrophage-mediated RNA therapy. Front Immunol 2023; 14:1255668. [PMID: 38155963 PMCID: PMC10753178 DOI: 10.3389/fimmu.2023.1255668] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 11/27/2023] [Indexed: 12/30/2023] Open
Abstract
Plant-derived nucleic acids, especially small RNAs have been proved by increasing evidence in the pharmacological activities and disease treatment values in macrophage meditated anti-tumor performance, immune regulating functions and antiviral activities. But the uptake, application and delivery strategies of RNAs as biodrugs are different from the small molecules and recombinant protein drugs. This article summarizes the reported evidence for cross-kingdom regulation by plant derived functional mRNAs and miRNAs. Based on that, their involvement and potentials in macrophage-mediated anti-tumor/inflammatory therapies are mainly discussed, as well as the load prospect of plant RNAs in viruses and natural exosome vehicles, and their delivery to mammalian cells through macrophage were also summarized. This review is to provide evidence and views for the plant derived RNAs as next generation of drugs with application potential in nucleic acid-based bio-therapy.
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Affiliation(s)
- Yu-Da Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hao-Ran Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yao Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ge Yan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hao-Jie Yan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qi Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Li-Hua Peng
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
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22
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Zhang Y, Liu X, He P, Tang B, Xiao C, Chen X. Thiol-Responsive Polypeptide Sulfur Dioxide Prodrug Nanoparticles for Effective Tumor Inhibition. Biomacromolecules 2023; 24:4316-4327. [PMID: 37611178 DOI: 10.1021/acs.biomac.3c00767] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Sulfur dioxide (SO2) based gas therapy has emerged as a novel anticancer therapeutic strategy because of its high therapeutic efficacy and biosafety. To precisely adjust the SO2 content and control gas release, herein, a thiol-responsive polypeptide SO2 prodrug mPEG-block-poly(2-amino-6-(2,4-dinitrophenylsulfonamido)hexanoic acid) (PEG-b-PLys-DNs) was designed and facilely synthesized by polymerization of a novel N-carboxyanhydride SO2-NCA. The anticancer potential of the self-assembled nanoparticles (SO2-NPs) was investigated in detail. First, PEG-b-PLys-DNs were synthesized by ring-opening polymerization of SO2-NCA, which self-assembled into NPs sized 88.4 nm in aqueous. Subsequently, SO2-NPs were endocytosed into 4T1 cells and quickly released SO2 under a high concentration of glutathione in tumor cells. This process depleted cellular glutathione, generated reactive oxygen species, and dramatically increased oxidative stress, which led to cancer cell apoptosis. Finally, the in vivo anticancer efficacy of SO2-NPs was verified in 4T1-tumor-bearing mice. Our results indicated that this novel SO2 polymeric prodrug has great potential in eradicating tumors.
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Affiliation(s)
- Yu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Xinming Liu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Pan He
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, P. R. China
| | - Bingtong Tang
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, P. R. China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
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23
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Xu X, Ma J, Zheng Y, Wang S, Wang A, Zheng N. Secondary Structure in Overcoming Photosensitizers' Aggregation: α-Helical Polypeptides for Enhanced Photodynamic Therapy. Adv Healthc Mater 2023; 12:e2203386. [PMID: 37016763 DOI: 10.1002/adhm.202203386] [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: 12/29/2022] [Revised: 04/03/2023] [Indexed: 04/06/2023]
Abstract
Aggregation caused quenching (ACQ) effect can severely inhibit the application of hydrophobic photosensitizers (PSs) bearing planar and rigid structures. Most of the reported cases utilized random-coiled polymers for the in vivo delivery of PSs, which would inevitably aggravate ACQ effect due to the flexible chains. In this work, the role of polymers' secondary structures (especially α-helical conformation) in overcoming the PSs' aggregation is systemically investigated based on the design of α-helical polypeptides bearing tetraphenylporphyrin (TPP) side chains. Atomistic molecular dynamics simulation, fluorescence quantum yield, and reactive oxygen species (ROS) generation yield are evaluated to demonstrate that α-helical polypeptide backbones can significantly boost both fluorescence quantum yield and ROS by suppressing the π-π stacking interaction between TPP units. The enhanced in vitro and in vivo phototoxicity for helical polypeptides also reveal functions of secondary structures in inhibiting ACQ and improving the membrane activity. Successful in vivo photodynamic therapy (PDT) results in mice bearing H22 tumors showed great potentials for further clinical applications.
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Affiliation(s)
- Xiang Xu
- School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China
| | - Jinjuan Ma
- Department of Comparative Medicine Laboratory Animal Center, Dalian Medical University Dalian, Dalian, 116000, China
| | - Yubin Zheng
- School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China
- Dalian University of Technology Corporation of Changshu Research Institution, Suzhou, 215500, China
| | - Shaolei Wang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital&Institute, Department of Radiology Intervention, Shenyang, China
| | - Aiguo Wang
- Department of Comparative Medicine Laboratory Animal Center, Dalian Medical University Dalian, Dalian, 116000, China
| | - Nan Zheng
- School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China
- Dalian University of Technology Corporation of Changshu Research Institution, Suzhou, 215500, China
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24
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Wang P, Liu J, Zhu X, Yan Z, Yan J, Jiang J, Fu M, Ge J, Zhu Q, Zheng Y. Modular synthesis of clickable peptides via late-stage maleimidation on C(7)-H tryptophan. Nat Commun 2023; 14:3973. [PMID: 37407547 DOI: 10.1038/s41467-023-39703-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/20/2023] [Indexed: 07/07/2023] Open
Abstract
Cyclic peptides have attracted tremendous attention in the pharmaceutical industry owing to their excellent cell penetrability, stability, thermostability, and drug-like properties. However, the currently available facile methodologies for creating such peptides are rather limited. Herein, we report an efficient and direct peptide cyclization via rhodium(III)-catalyzed C(7)-H maleimidation. Notably, this catalytical system has excellent regioselectivity and high tolerance of functional groups which enable late-stage cyclization of peptides. This architecture of cyclic peptides exhibits higher bioactivity than its parent linear peptides. Moreover, the Trp-substituted maleimide displays excellent reactivity toward Michael addition, indicating its potential as a click functional group for applications in chemical biology and medicinal chemistry. As a proof of principle, RGD-GFLG-DOX, which is a peptide-drug-conjugate, is constructed and it displays a strong binding affinity and high antiproliferative activity toward integrin-αvβ3 overexpressed cancer cell lines. The proposed strategy for rapid preparation of stapled peptides would be a robust tool for creating peptide-drug conjugates.
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Affiliation(s)
- Peng Wang
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jiang Liu
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Xiaomei Zhu
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Zhengqing Yan
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jiahui Yan
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jitong Jiang
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Manlin Fu
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jingyan Ge
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Qing Zhu
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
| | - Yuguo Zheng
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
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25
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Guo T, Zhong H, Li X, Mu J, Liu T, Yu N, Zhao Y, Liang XJ, Guo S. Drug content on anticancer efficacy of self-assembling ketal-linked dextran-paclitaxel conjugates. J Control Release 2023; 359:175-187. [PMID: 37271184 DOI: 10.1016/j.jconrel.2023.05.045] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/06/2023]
Abstract
Although polymer-drug conjugates (PDCs) show great promise as versatile drug delivery systems, no antitumor PDCs based on small-molecule drugs are currently on the market, partly because of the lack of validated design principles for PDCs. High drug content is thought to be essential for devising highly efficacious PDCs based on poorly soluble antitumor drugs, but this has not been well validated. Therefore, revisiting the relationship between drug content and PDC performance is vital. In this study, we synthesized four dextran-paclitaxel (PTX) conjugates (designated as DKPs) with different drug contents by linking dextran and PTX via an acid-responsive ketal, and we used the conjugates to construct self-assembled DKP nanoparticles (NPs) for antitumor therapy. We focused on how PTX content influenced the hydrolysis kinetics, cytotoxicity, cellular uptake and intracellular hydrolysis, pharmacokinetics, biodistribution, and antitumor efficacies of the DKP NPs. We found that DKP NPs with lower PTX content showed accelerated drug release and increased tumor accumulation, and consequently enhanced antitumor efficacy. In 4T1-Luc and Panc02-Luc cancer models, the NPs showed considerably improved therapeutic efficacy than the micellar formulation of PTX that is currently in clinical use. Our results indicate that DKP NPs with lower PTX content possess greater antitumor potential, and our findings offer new insights for the connection of drug content-formulation-bioactivity relationship in the rational design of PDC prodrugs.
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Affiliation(s)
- Tiantian Guo
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Haiping Zhong
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xingwei Li
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Jingqing Mu
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Tao Liu
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Na Yu
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China; Translational Medicine Center, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Yang Zhao
- Department of Radiology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Xing-Jie Liang
- Translational Medicine Center, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China; CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Shutao Guo
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China.
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26
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Hu R, Wang X, Han L, Lu X. The Developments of Surface-Functionalized Selenium Nanoparticles and Their Applications in Brain Diseases Therapy. Biomimetics (Basel) 2023; 8:259. [PMID: 37366854 DOI: 10.3390/biomimetics8020259] [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: 04/03/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
Selenium (Se) and its organic and inorganic compounds in dietary supplements have been found to possess excellent pharmacodynamics and biological responses. However, Se in bulk form generally exhibits low bioavailability and high toxicity. To address these concerns, nanoscale selenium (SeNPs) with different forms, such as nanowires, nanorods, and nanotubes, have been synthesized, which have become increasingly popular in biomedical applications owing to their high bioavailability and bioactivity, and are widely used in oxidative stress-induced cancers, diabetes, and other diseases. However, pure SeNPs still encounter problems when applied in disease therapy because of their poor stability. The surface functionalization strategy has become increasingly popular as it sheds light to overcome these limitations in biomedical applications and further improve the biological activity of SeNPs. This review summarizes synthesis methods and surface functionalization strategies employed for the preparation of SeNPs and highlights their applications in treating brain diseases.
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Affiliation(s)
- Rong Hu
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Xiao Wang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Lu Han
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, China
| | - Xiong Lu
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
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27
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An L, Jia Y, Li J, Xiao C. Reduction-responsive dextran-based Pt(IV) nano-prodrug showed a synergistic effect with doxorubicin for effective melanoma treatment. Int J Biol Macromol 2023; 233:123277. [PMID: 36706874 DOI: 10.1016/j.ijbiomac.2023.123277] [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: 10/08/2022] [Revised: 12/18/2022] [Accepted: 01/11/2023] [Indexed: 01/26/2023]
Abstract
Melanoma, the deadliest skin cancer with high metastasis potential, has posed a great threat to human health. Accordingly, early efficient blocking of melanoma progression is vital in antitumor treatment. Herein, a reduction-responsive dextran-based Pt(IV) nano-prodrug (PDPN) was synthesized and used for doxorubicin (DOX) delivery to combat melanoma synergistically. First, PDPN was prepared by one-pot chemical coupling of carboxylated methoxy poly(ethylene glycol) (mPEG), dextran (Dex), and the crosslinking agent cisPt (IV)-COOH. PDPN had a spherical structure (Rh = 34 ± 11.3 nm). Then, DOX was encapsulated into the PDPN core to form DOX-loaded PDPN (PDPN-DOX). The obtained PDPN-DOX displayed reduction-responsive release of DOX and Pt, thus showing a synergistic anticancer effect in B16F10 cells (combination index, 0.46). Furthermore, in vivo experiments demonstrated that PDPN-DOX was effective for the synergistic treatment of subcutaneous melanoma. Collectively, the as-prepared PDPN could serve as a promising and versatile nano-prodrug carrier for the co-delivery of chemotherapeutics in tumor combination therapy.
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Affiliation(s)
- Lin An
- Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuxi Jia
- Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinran Li
- Department of Dermatology, Second Hospital of Jilin University, Changchun, China.
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China; Jilin Biomedical Polymers Engineering Laboratory, Changchun, China
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28
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Zhang P, Zhu Y, Xiao C, Chen X. Activatable dual-functional molecular agents for imaging-guided cancer therapy. Adv Drug Deliv Rev 2023; 195:114725. [PMID: 36754284 DOI: 10.1016/j.addr.2023.114725] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 01/16/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
Theranostics has attracted great attention due to its ability to combine the real-time diagnosis of cancers with efficient treatment modalities. Activatable dual-functional molecular agents could be synthesized by covalently conjugating imaging agents, therapeutic agents, stimuli-responsive linkers and/or targeting molecules together. They could be selectively activated by overexpressed physiological stimuli or external triggers at the tumor sites to release imaging agents and cytotoxic drugs, thus offering many advantages for tumor imaging and therapy, such as a high signal-to-noise ratio, low systemic toxicity, and improved therapeutic effects. This review summarizes the recent advances of dual-functional molecular agents that respond to various physiological or external stimuli for cancer theranostics. The molecular designs, synthetic strategies, activatable mechanisms, and biomedical applications of these molecular agents are elaborated, followed by a brief discussion of the challenges and opportunities in this field.
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Affiliation(s)
- Peng Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, PR China; State Key Laboratory of Molecular Engineering of Polymers (Fudan University), Shanghai 200433, PR China
| | - Yaowei Zhu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Department of Chemistry, Northeast Normal University, Changchun 130024, PR China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, PR China.
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, PR China.
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29
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Koran K, Çalışkan E, Altay Öztürk D, Çapan İ, Tekin S, Sandal S, Orhan Görgülü A. The first peptide derivatives of dioxybiphenyl-bridged spiro cyclotriphosphazenes: In vitro cytotoxicity activities and DNA damage studies. Bioorg Chem 2023; 132:106338. [PMID: 36603512 DOI: 10.1016/j.bioorg.2022.106338] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/03/2022] [Accepted: 12/23/2022] [Indexed: 12/25/2022]
Abstract
In this study, we aimed to synthesize new peptide-substituted cyclotriphosphazenes from a series of tyrosine-based peptides and dioxyphenyl-substituted spirocyclotriphosphazenes, and to evaluate their in vitro cytotoxicity and genotoxicity activities. Genotoxicity studies were conducted to understand whether the cytotoxic compounds cause cell death through DNA damage. The structures of the novel series of phosphazenes were characterized by FT-IR, elemental analysis, MS, 1D (31P, 1H, and 13C-APT NMR), and 2D (HETCOR) NMR spectroscopic techniques. In vitro cytotoxic activities were carried out against human breast (MCF-7), ovarian (A2780), prostate (PC-3), colon (Caco-2) cancer cell lines and human normal epithelial cell line (MCF-10A) at different concentrations by using an MTT assay. The compounds showed considerable reductions in cell viability against all human cancer cell lines. Especially, the compounds exhibited notable effects in A2780 cell lines (p < 0.05). The IC50 values of the compounds in the A2780 cell line were calculated to be 1.914 µM for TG, 20.21 µM for TV, 20.45 µM for TA, 4.643 µM for TP, 5.615 µM for BTG, 1.047 µM for BTV, 27.02 µM for BTA, 0.7734 µM for BTP, 21.5 µM for DTG, 1.65 µM for DTV, 2.89 µM for DTA and 4.599 µM for DTP. DNA damage studies of the compounds were conducted by the comet assay method using tail length, tail density, olive tail moment, head length, and head density parameters, and the results showed that the cell death occurred through DNA damage mechanism. In a nutshell, these compounds show promising cytotoxic effects and can be considered powerful candidate molecules for pharmaceutical applications.
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Affiliation(s)
- Kenan Koran
- Kenan Koran - Department of Chemistry, Faculty of Science, Fırat University, Elazig 23119, Turkey.
| | - Eray Çalışkan
- Department of Chemistry, Faculty of Science, Bingöl University, Bingöl 12000, Turkey
| | - Dilara Altay Öztürk
- Department of Physiology, Faculty of Medicine, Turgut Ozal University, Malatya 44210, Turkey
| | - İrfan Çapan
- Department of Materials and Material Processing Techn. Polymer Technology Program, Vocational School of Technical Sciences, Gazi University, Ankara 06560, Turkey
| | - Suat Tekin
- Department of Physiology, Faculty of Medicine, Inonu University, Malatya 44280, Turkey
| | - Süleyman Sandal
- Department of Physiology, Faculty of Medicine, Inonu University, Malatya 44280, Turkey
| | - Ahmet Orhan Görgülü
- Department of Chemistry, Faculty of Science, Marmara University, Istanbul, Turkey
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30
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Sun Y, Zhang Y, Guo X, Wang Y, He P, Xiao C. Oxidation Responsive PEGylated Polyamino Acid Bearing Thioether Pendants for Enhanced Anticancer Drug Delivery. Macromol Biosci 2023; 23:e2200498. [PMID: 36610012 DOI: 10.1002/mabi.202200498] [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: 11/17/2022] [Revised: 12/21/2022] [Indexed: 01/09/2023]
Abstract
Reactive oxygen species (ROS) in biological tissues are in a state of dynamic balance. However, many diseases such as cancer and inflammation, are accompanied by a long-term increase in ROS. This situation inspires researchers to use ROS-sensitive nanocarriers for a site-specific release of cargo in pathological areas. Polyamino acid materials with good biodegradability, biocompatibility, and regular secondary structure are widely used in the biomedical field. Herein, a new oxidation responsive PEGylated polyamino acid is synthesised for anticancer drug delivery by ring-opening polymerisation of N-carboxyanhydrides bearing thioether pendants. The obtained block copolymer mPEG-b-PMLG self-assembles into spherical nanoparticles (NPs) in water with diameter ≈68.3 nm. NMR measurement demonstrated that the hydrophobic thioether pendants in the NPs can be selectively oxidised to hydrophilic sulfoxide groups by H2 O2 , which will lead to the disassociation of NPs. In vitro drug release results indicated that the encapsulated Nile red is selectively released in the trigger of 10 mM H2 O2 in PBS. Finally, anticancer drug doxorubicin (DOX) is encapsulated to the NPs, and the obtained NPs/DOX exhibits an improved antitumor efficacy in 4T1 tumour-bearing mice and lower cardiotoxicity than free DOX. These results indicates that the mPEG-b-PMLG NPs are promising for anticancer drug delivery.
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Affiliation(s)
- Yitao Sun
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, P. R. China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Yu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Xin Guo
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, P. R. China
| | - Yanping Wang
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, P. R. China
| | - Pan He
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, P. R. China
- Engineering Research Center of Optoelectronic Functional Materials, Ministry of Education, Changchun, 130022, P. R. China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
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31
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Yang Y, Wang S, Ma P, Jiang Y, Cheng K, Yu Y, Jiang N, Miao H, Tang Q, Liu F, Zha Y, Li N. Drug conjugate-based anticancer therapy - Current status and perspectives. Cancer Lett 2023; 552:215969. [PMID: 36279982 DOI: 10.1016/j.canlet.2022.215969] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/08/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022]
Abstract
Drug conjugates are conjugates comprising a tumor-homing carrier tethered to a cytotoxic agent via a linker that are designed to deliver an ultra-toxic payload directly to the target cancer cells. This strategy has been successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce their toxic side effects. Drug conjugates are being developed worldwide, with the potential to revolutionize current cancer treatment strategies. Antibody-drug conjugates (ADCs) have developed rapidly, and 14 of them have received market approval since the first approval event by the Food and Drug Administration in 2000. However, there are some limitations in the use of antibodies as carriers. Other classes of drug conjugates are emerging, such as targeted drugs conjugated with peptides (peptide-drug conjugates, PDCs) and polymers (polymer-drug conjugates, PolyDCs) with the remaining constructs similar to those of ADCs. These novel drug conjugates are gaining attention because they overcome the limitations of ADCs. This review summarizes the current state and advancements in knowledge regarding the design, constructs, and clinical efficacy of different drug conjugates.
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Affiliation(s)
- Yuqi Yang
- NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Shuhang Wang
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Peiwen Ma
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yale Jiang
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Keman Cheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
| | - Yue Yu
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ning Jiang
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Huilei Miao
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qiyu Tang
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Funan Liu
- First Affiliated Hospital of China Medical University, Shenyang, 110002, China
| | - Yan Zha
- NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
| | - Ning Li
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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32
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Yang T, Zhai J, Hu D, Yang R, Wang G, Li Y, Liang G. "Targeting Design" of Nanoparticles in Tumor Therapy. Pharmaceutics 2022; 14:pharmaceutics14091919. [PMID: 36145668 PMCID: PMC9501451 DOI: 10.3390/pharmaceutics14091919] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/01/2022] [Accepted: 09/06/2022] [Indexed: 11/22/2022] Open
Abstract
Tumor-targeted therapy based on nanoparticles is a popular research direction in the biomedical field. After decades of research and development, both the passive targeting ability of the inherent properties of NPs and the active targeting based on ligand receptor interaction have gained deeper understanding. Unfortunately, most targeted delivery strategies are still in the preclinical trial stage, so it is necessary to further study the biological fate of particles in vivo and the interaction mechanism with tumors. This article reviews different targeted delivery strategies based on NPs, and focuses on the physical and chemical properties of NPs (size, morphology, surface and intrinsic properties), ligands (binding number/force, activity and species) and receptors (endocytosis, distribution and recycling) and other factors that affect particle targeting. The limitations and solutions of these factors are further discussed, and a variety of new targeting schemes are introduced, hoping to provide guidance for future targeting design and achieve the purpose of rapid transformation of targeted particles into clinical application.
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Affiliation(s)
- Tingting Yang
- School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang 471023, China
| | - Jingming Zhai
- Department of General Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science & Technology, Luoyang 471003, China
| | - Dong Hu
- School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang 471023, China
| | - Ruyue Yang
- School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang 471023, China
| | - Guidan Wang
- School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang 471023, China
| | - Yuanpei Li
- School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang 471023, China
- Correspondence: (Y.L.); (G.L.)
| | - Gaofeng Liang
- School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang 471023, China
- Correspondence: (Y.L.); (G.L.)
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Zhang Y, Kim I, Lu Y, Xu Y, Yu DG, Song W. Intelligent poly(l-histidine)-based nanovehicles for controlled drug delivery. J Control Release 2022; 349:963-982. [PMID: 35944751 DOI: 10.1016/j.jconrel.2022.08.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022]
Abstract
Stimuli-responsive drug delivery systems based on polymeric nanovehicles are among the most promising treatment regimens for malignant cancers. Such intelligent systems that release payloads in response to the physiological characteristics of tumor sites have several advantages over conventional drug carriers, offering, in particular, enhanced therapeutic effects and decreased toxicity. The tumor microenvironment (TME) is acidic, suggesting the potential of pH-responsive nanovehicles for enhancing treatment specificity and efficacy. The synthetic polypeptide poly(l-histidine) (PLH) is an appropriate candidate for the preparation of pH-responsive nanovehicles because the pKa of PLH (approximately 6.0) is close to the pH of the acidic TME. In addition, the pendent imidazole rings of PLH yield pH-dependent hydrophobic-to-hydrophilic phase transitions in the acidic TME, triggering the destabilization of nanovehicles and the subsequent release of encapsulated chemotherapeutic agents. Herein, we highlight the state-of-the-art design and construction of pH-responsive nanovehicles based on PLH and discuss the future challenges and perspectives of this fascinating biomaterial for targeted cancer treatment and "benchtop-to-clinic" translation.
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Affiliation(s)
- Yu Zhang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China.
| | - Il Kim
- School of Chemical Engineering, Pusan National University, Busan 46241, Republic of Korea.
| | - Yiming Lu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Yixin Xu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Deng-Guang Yu
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai 200093, PR China.
| | - Wenliang Song
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai 200093, PR China.
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Çalışkan E, Altay Öztürk D, Koran K, Tekin S, Sandal S, Erkan S, Görgülü AO, Çetin A. Synthesis of new cinnamoyl-amino acid conjugates and in vitro cytotoxicity and genotoxicity studies. Chem Biodivers 2022; 19:e202200426. [PMID: 35864058 DOI: 10.1002/cbdv.202200426] [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: 05/04/2022] [Accepted: 07/18/2022] [Indexed: 11/10/2022]
Abstract
Amino acid conjugates are described by the reaction of amino acids with bioactive organic groups such as vitamins, hormones, flavonoids, steroids, and sugars. In this study, 12 new conjugates were synthesized by reaction of cinnamic acid derivatives with various amino acids. Cytotoxic studies against four different human cancer cells (MCF7, PC-3, Caco-2, and A2780) were carried out by MTT assay method at five different concentrations. The structure-activity relationships based on the cell viability rates were evaluated. To compare the anticancer activities of the compounds using computational chemistry methods, they were docked against A2780 human ovarian cancer, Michigan Cancer Foundation-7 (MCF7), human prostate cancer (PC-3) and human colon epidermal adenocarcinoma (Caco-2) cell lines and compared with the standard 5-Fluorouracil. The results indicate that the efficacy of cinnamic acid derivatives increases with the presence of amino acids. Comet assay was conducted to understand whether the cell deaths occur through DNA damage mechanism and the results exhibit that the changes in the specified parameters were statistically significant (P<0.05). Our study demonstrated that the compounds cause cell death through the formation of DNA damage mechanism.
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Affiliation(s)
- Eray Çalışkan
- Bingol University: Bingol Universitesi, Chemsitry Department, Bingöl Üniversitesi Fen Edebiyat Fakültesi D3-33, 12000, Bingol, TURKEY
| | - Dilara Altay Öztürk
- Turgut Ozal University: Turgut Ozal Universitesi, Physiology Department, Malatya, Malatya, TURKEY
| | - Kenan Koran
- Firat University Faculty of Science: Firat Universitesi Fen Fakultesi, Chemistry, Elazığ 23000, Elazığ, TURKEY
| | - Suat Tekin
- Inonu University School of Medicine: Inonu Universitesi Tip fakultesi, Physiology Department, Bulgurlu Mahallesi, Elazığ Yolu 15. Km., 44280 Merkez/Battalgazi/Malatya, Malatya, TURKEY
| | - Süleyman Sandal
- Inonu University School of Medicine: Inonu Universitesi Tip fakultesi, Physiology Department, Bulgurlu Mahallesi, Elazığ Yolu 15. Km., 44280 Merkez/Battalgazi/Malatya, Malatya, TURKEY
| | - Sultan Erkan
- Cumhuriyet University: Sivas Cumhuriyet Universitesi, Chemistry, Sivas, Sivas, TURKEY
| | - Ahmet Orhan Görgülü
- Marmara Universitesi - Goztepe Kampusu: Marmara Universitesi, Chemistry, Marmara Üniveristesi Göztepe kampüsü Fen Edebiyat Fakültesi, 34722, kadıköy, TURKEY
| | - Ahmet Çetin
- Bingol University: Bingol Universitesi, Chemistry, Bingöl Üniversitesi Fen Edebiyat Fakültesi D3-33, 12000, Merkez, TURKEY
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Zhao B, Chen S, Hong Y, Jia L, Zhou Y, He X, Wang Y, Tian Z, Yang Z, Gao D. Research Progress of Conjugated Nanomedicine for Cancer Treatment. Pharmaceutics 2022; 14:1522. [PMID: 35890416 PMCID: PMC9315807 DOI: 10.3390/pharmaceutics14071522] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/14/2022] [Accepted: 07/19/2022] [Indexed: 12/05/2022] Open
Abstract
The conventional cancer therapeutic modalities include surgery, chemotherapy and radiotherapy. Although immunotherapy and targeted therapy are also widely used in cancer treatment, chemotherapy remains the cornerstone of tumor treatment. With the rapid development of nanotechnology, nanomedicine is believed to be an emerging field to further improve the efficacy of chemotherapy. Until now, there are more than 17 kinds of nanomedicine for cancer therapy approved globally. Thereinto, conjugated nanomedicine, as an important type of nanomedicine, can not only possess the targeted delivery of chemotherapeutics with great precision but also achieve controlled drug release to avoid adverse effects. Meanwhile, conjugated nanomedicine provides the platform for combining several different therapeutic approaches (chemotherapy, photothermal therapy, photodynamic therapy, thermodynamic therapy, immunotherapy, etc.) with the purpose of achieving synergistic effects during cancer treatment. Therefore, this review focuses on conjugated nanomedicine and its various applications in synergistic chemotherapy. Additionally, the further perspectives and challenges of the conjugated nanomedicine are also addressed, which clarifies the design direction of a new generation of conjugated nanomedicine and facilitates the translation of them from the bench to the bedside.
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Affiliation(s)
- Bin Zhao
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
- Department of Epidemiology, Shaanxi Provincial Cancer Hospital, Xi’an 710061, China
| | - Sa Chen
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
- Shaanxi Provincial Centre for Disease Control and Prevention, Xi’an 710054, China
| | - Ye Hong
- Center of Digestive Endoscopy, Shaanxi Provincial Cancer Hospital, Xi’an 710061, China;
| | - Liangliang Jia
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
| | - Ying Zhou
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
| | - Xinyu He
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
| | - Ying Wang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
| | - Zhongmin Tian
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
| | - Zhe Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
- Research Institute of Xi’an Jiaotong University, Hangzhou 311200, China
| | - Di Gao
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (B.Z.); (S.C.); (L.J.); (Y.Z.); (X.H.); (Y.W.); (Z.T.)
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Liu P, Zhang W, Deng J, Zheng Y, Weng J, Yu F, Wang D, Zheng M, Kang B, Zeng H. Chain-shattering polymeric sulfur dioxide prodrug micelles for redox-triggered gas therapy of osteosarcoma. J Mater Chem B 2022; 10:5263-5271. [PMID: 35762903 DOI: 10.1039/d2tb00287f] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Sulfur dioxide (SO2) based gas therapy has received great attention recently. Nevertheless, it is still a challenge to fabricate a SO2 delivery system to achieve effective delivery and on-demand stimuli triggered release at tumor sites. Herein, a chain-shattering polymeric SO2 prodrug micelle system was fabricated for effective SO2 based gas therapy. First, an amphiphilic polymer (mPEG-P(HDI-DN)) was prepared by polycondensation of poly(ethylene glycol) methyl ether, hexamethylene diisocyanate and monomer containing SO2. mPEG-P(HDI-DN) can self-assemble into spherical micelles with a diameter of around 50-90 nm. Triggered release of SO2 from micelles can be achieved in the presence of GSH with the degradation of mPEG-P(HDI-DN) into small molecules. The in vitro experiment proved that mPEG-P(HDI-DN) micelles can enter into osteosarcoma cells and inhibit the growth of osteosarcoma cells by increasing the ROS level in cells. The in vivo experiments demonstrate that mPEG-P(HDI-DN) micelles can inhibit the growth of osteosarcoma effectively without obvious tissue toxicity. These results indicate that this chain-shattering polymeric SO2 prodrug micelle system is a promising candidate for effective SO2 based gas therapy.
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Affiliation(s)
- Peng Liu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Weifei Zhang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Jiapeng Deng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Yien Zheng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Jian Weng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Fei Yu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Deli Wang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Ming Zheng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, 100191, P. R. China
| | - Bin Kang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
| | - Hui Zeng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China. .,Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China
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37
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Han Y, Lafleur RPM, Zhou J, Xu W, Lin Z, Richardson JJ, Caruso F. Role of Molecular Interactions in Supramolecular Polypeptide-Polyphenol Networks for Engineering Functional Materials. J Am Chem Soc 2022; 144:12510-12519. [PMID: 35775928 DOI: 10.1021/jacs.2c05052] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Supramolecular assembly affords the development of a wide range of polypeptide-based biomaterials for drug delivery and nanomedicine. However, there remains a need to develop a platform for the rapid synthesis and study of diverse polypeptide-based materials without the need for employing complex chemistries. Herein, we develop a versatile strategy for creating polypeptide-based materials using polyphenols that display multiple synergistic cross-linking interactions with different polypeptide side groups. We evaluated the diverse interactions operating within these polypeptide-polyphenol networks via binding affinity, thermodynamics, and molecular docking studies and found that positively charged polypeptides (Ka of ∼2 × 104 M-1) and polyproline (Ka of ∼2 × 106 M-1) exhibited stronger interactions with polyphenols than other amino acids (Ka of ∼2 × 103 M-1). Free-standing particles (capsules) were obtained from different homopolypeptides using a template-mediated strategy. The properties of the capsules varied with the homopolypeptide used, for example, positively charged polypeptides produced thicker shell walls (120 nm) with reduced permeability and involved multiple interactions (i.e., electrostatic and hydrogen), whereas uncharged polypeptides generated thinner (10 nm) and more permeable shell walls due to the dominant hydrophobic interactions. Polyarginine imparted cell penetration and endosomal escape properties to the polyarginine-tannic acid capsules, enabling enhanced delivery of the drug doxorubicin (2.5 times higher intracellular fluorescence after 24 h) and a corresponding higher cell death in vitro when compared with polyproline-tannic acid capsules. The ability to readily complex polyphenols with different types of polypeptides highlights that a wide range of functional materials can be generated for various applications.
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Affiliation(s)
- Yiyuan Han
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - René P M Lafleur
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Jiajing Zhou
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.,Department of NanoEngineering, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, United States
| | - Wanjun Xu
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Zhixing Lin
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Joseph J Richardson
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Materials Engineering, School of Engineering, University of Tokyo, Tokyo 113-8656, Japan
| | - Frank Caruso
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
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Liang J, Guo R, Xuan M, Sun Q, Wu W. An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer. Int J Nanomedicine 2022; 17:2961-2973. [PMID: 35818401 PMCID: PMC9270908 DOI: 10.2147/ijn.s359642] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 06/26/2022] [Indexed: 11/26/2022] Open
Abstract
Purpose This study aimed to construct a DOX conjugate with liver tumor targeting and acid sensitivity based on a short aromatic peptide FFYEE, which could amplify the tumor inhibition efficacy of DOX and alleviate tissue toxicity. Methods A novel DOX-peptide conjugate, D-gal-FFYEE-hyd-DOX, was constructed by linking DOX to the side chain of FFYEE with acid-sensitive hydrazone bond and by modifying the C-terminal of peptide with α-D-galactosamine (D-gal) as targeting ligand. The structure of D-gal-FFYEE-hyd-DOX was characterized by mass spectrometry, infrared spectroscopy (IR), and UV-Vis spectroscopy (UV-Vis). The assembly characteristics of pentapeptide FFYEE and D-gal-FFYEE-hyd-DOX were observed by transmission electron microscope (TEM). In vitro drug release, cytotoxicity, endocytosis, in vivo antitumor experiment and histopathology analysis were investigated. Results Peptide FFYEE endowed the D-gal-FFYEE-hyd-DOX with self-assembly performance and improved biocompatibility. D-gal-FFYEE-hyd-DOX can self-assemble into nanofibers with a diameter of ~ 40 nm in neutral aqueous solution and significantly reduced the cytotoxicity of free DOX to L02 cells. In vitro drug release results showed that D-gal-FFYEE-hyd-DOX had acid sensitivity and controlled release characteristics. The cytotoxicity and endocytosis investigations confirmed that D-gal-FFYEE-hyd-DOX enhanced the cellular uptake of DOX and inhibition effect on HepG2 cells. In vivo antitumor experiment indicated that D-gal-FFYEE-hyd-DOX could significantly inhibit the growth of liver tumor in mice and reduce the side effects of DOX. Conclusion The conjugate D-gal-FFYEE-hyd-DOX with liver tumor targeting and acid sensitivity has the characteristics of strong tumor inhibition and low toxicity, hinting the great clinical application potential for targeted delivery of DOX in cancer treatment.
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Affiliation(s)
- Ju Liang
- School of Chemical Engineer and Pharmacy, Henan University of Science and Technology, Luoyang, People’s Republic of China
- Correspondence: Ju Liang, School of Chemical Engineer and Pharmacy, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of China, Email
| | - Runfa Guo
- School of Chemical Engineer and Pharmacy, Henan University of Science and Technology, Luoyang, People’s Republic of China
| | - Maosong Xuan
- School of Chemical Engineer and Pharmacy, Henan University of Science and Technology, Luoyang, People’s Republic of China
| | - Qiankun Sun
- School of Chemical Engineer and Pharmacy, Henan University of Science and Technology, Luoyang, People’s Republic of China
| | - Wenlan Wu
- School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, People’s Republic of China
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He M, Du C, Xia J, Zhang ZG, Dong CM. Multivalent Polypeptide and Tannic Acid Cooperatively Iron-Coordinated Nanohybrids for Synergistic Cancer Photothermal Ferroptosis Therapy. Biomacromolecules 2022; 23:2655-2666. [PMID: 35583462 DOI: 10.1021/acs.biomac.2c00409] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Owing to having a unique mechanism to kill cancer cells via the membrane accumulation of lipid peroxide (LPO) and the downregulation of glutathione peroxidase-4 (GPX-4), the ferroptosis therapy (FT) of tumors based on the Fenton reaction of iron nanoparticles has been receiving much attention in the past decade; however, there are some hurdles including the uncontrollable release of iron ions, slower kinetics of the intracellular Fenton reaction, and poor efficacy of FT that need to be overcome. Considering cooperative coordination of a multivalent thiol-pendant polypeptide ligand with iron ions, we put forward a facile strategy for constructing the iron-coordinated nanohybrid of methacryloyloxyethyl phosphorylcholine-grafted polycysteine/iron ions/tannic acid (i.e., PCFT), which could deliver a higher concentration of iron ions into cells. The dynamic and unsaturated coordination in PCFT is favorable for the intracellular stimuli-triggered release and fast Fenton reaction to realize efficient FT, while its intrinsic photothermia would boost the Fenton reaction to induce a synergistic effect between FT and photothermal therapy (PTT). Both immunofluorescence analyses of reactive oxygen species (ROS) and LPO confirmed that the intracellular Fenton reaction resulted in efficient FT, during which process the photothermia greatly boosted ferroptosis, and the Western blot assay corroborated that the expression level of GPX-4 was downregulated by FT and highly degraded by the photothermia to induce synergistic PTT-FT in vitro. Excitingly, by a single intravenous dose of PCFT plus one NIR irradiation, in vivo PTT-FT treatment completely eradicated 4T1 tumors without skin scar and tumor recurrence for 16 days, demonstrating prominent antitumor efficacy, as evidenced by the GPX-4, H&E, and TUNEL assays.
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Affiliation(s)
- Meng He
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory of Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Chang Du
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Jindong Xia
- Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, P. R. China
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Chang-Ming Dong
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory of Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
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40
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Guo W, Liu W, Wan P, Wang H, Xiao C, Chen L, Chen X. Cationic Amphiphilic Dendrons with Anticancer Activity. ACS Biomater Sci Eng 2022; 8:2121-2130. [PMID: 35395157 DOI: 10.1021/acsbiomaterials.2c00181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Cancer has become the leading cause of human death worldwide, and there is an urgent need to design and develop new oncology drugs. In this study, we report series of cationic amphiphilic dendrons with different hydrophobic alkyl chains (Cn) and different generations (Gx) and demonstrate their use for anticancer applications. The results revealed that lower-generation dendrons (G1) with a longer hydrophobic alkyl chain (C12 and C18) have stronger antitumor activity. Among these dendrons, a lead candidate C12-G1 was identified that demonstrated excellent broad-spectrum antitumor activity in 7 cancer cell lines including highly metastatic tumor cells, while simultaneously, hemolysis was negligible. Mechanistic studies showed that C12-G1 could lead to cytoplasmic leakage and induce cancer cell necrosis through membrane disruption. In addition, C12-G1 showed potent inhibition of tumor growth in a B16-F10 melanoma model. In conclusion, these findings demonstrate that the cationic amphiphilic dendron might be a promising agent for anticancer application.
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Affiliation(s)
- Wei Guo
- Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Wenchang Liu
- Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Pengqi Wan
- Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China.,Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Hao Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Li Chen
- Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
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Zhang Y, Song W, Lu Y, Xu Y, Wang C, Yu DG, Kim I. Recent Advances in Poly(α- L-glutamic acid)-Based Nanomaterials for Drug Delivery. Biomolecules 2022; 12:636. [PMID: 35625562 PMCID: PMC9138577 DOI: 10.3390/biom12050636] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/16/2022] [Accepted: 04/23/2022] [Indexed: 02/06/2023] Open
Abstract
Poly(α-L-glutamic acid) (PGA) is a class of synthetic polypeptides composed of the monomeric unit α-L-glutamic acid. Owing to their biocompatibility, biodegradability, and non-immunogenicity, PGA-based nanomaterials have been elaborately designed for drug delivery systems. Relevant studies including the latest research results on PGA-based nanomaterials for drug delivery have been discussed in this work. The following related topics are summarized as: (1) a brief description of the synthetic strategies of PGAs; (2) an elaborated presentation of the evolving applications of PGA in the areas of drug delivery, including the rational design, precise fabrication, and biological evaluation; (3) a profound discussion on the further development of PGA-based nanomaterials in drug delivery. In summary, the unique structures and superior properties enables PGA-based nanomaterials to represent as an enormous potential in biomaterials-related drug delivery areas.
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Affiliation(s)
- Yu Zhang
- School of Pharmacy, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China; (Y.Z.); (Y.L.); (Y.X.)
| | - Wenliang Song
- Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Korea;
- School of Materials Science & Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China;
| | - Yiming Lu
- School of Pharmacy, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China; (Y.Z.); (Y.L.); (Y.X.)
| | - Yixin Xu
- School of Pharmacy, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China; (Y.Z.); (Y.L.); (Y.X.)
| | - Changping Wang
- School of Materials Science & Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China;
| | - Deng-Guang Yu
- School of Materials Science & Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China;
| | - Il Kim
- Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Korea;
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Nanotheranostics for Image-Guided Cancer Treatment. Pharmaceutics 2022; 14:pharmaceutics14050917. [PMID: 35631503 PMCID: PMC9144228 DOI: 10.3390/pharmaceutics14050917] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 12/13/2022] Open
Abstract
Image-guided nanotheranostics have the potential to represent a new paradigm in the treatment of cancer. Recent developments in modern imaging and nanoparticle design offer an answer to many of the issues associated with conventional chemotherapy, including their indiscriminate side effects and susceptibility to drug resistance. Imaging is one of the tools best poised to enable tailoring of cancer therapies. The field of image-guided nanotheranostics has the potential to harness the precision of modern imaging techniques and use this to direct, dictate, and follow site-specific drug delivery, all of which can be used to further tailor cancer therapies on both the individual and population level. The use of image-guided drug delivery has exploded in preclinical and clinical trials although the clinical translation is incipient. This review will focus on traditional mechanisms of targeted drug delivery in cancer, including the use of molecular targeting, as well as the foundations of designing nanotheranostics, with a focus on current clinical applications of nanotheranostics in cancer. A variety of specially engineered and targeted drug carriers, along with strategies of labeling nanoparticles to endow detectability in different imaging modalities will be reviewed. It will also introduce newer concepts of image-guided drug delivery, which may circumvent many of the issues seen with other techniques. Finally, we will review the current barriers to clinical translation of image-guided nanotheranostics and how these may be overcome.
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Shang Q, Su Y, Leslie F, Sun M, Wang F. Advances in peptide drug conjugate-based supramolecular hydrogel systems for local drug delivery. MEDICINE IN DRUG DISCOVERY 2022. [DOI: 10.1016/j.medidd.2022.100125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Khan MI, Hossain MI, Hossain MK, Rubel MHK, Hossain KM, Mahfuz AMUB, Anik MI. Recent Progress in Nanostructured Smart Drug Delivery Systems for Cancer Therapy: A Review. ACS APPLIED BIO MATERIALS 2022; 5:971-1012. [PMID: 35226465 DOI: 10.1021/acsabm.2c00002] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Traditional treatment approaches for cancer involve intravenous chemotherapy or other forms of drug delivery. These therapeutic measures suffer from several limitations such as nonspecific targeting, poor biodistribution, and buildup of drug resistances. However, significant technological advancements have been made in terms of superior modes of drug delivery over the last few decades. Technical capability in analyzing the molecular mechanisms of tumor biology, nanotechnology─particularly the development of biocompatible nanoparticles, surface modification techniques, microelectronics, and material sciences─has increased. As a result, a significant number of nanostructured carriers that can deliver drugs to specific cancerous sites with high efficiency have been developed. This particular maneuver that enables the introduction of a therapeutic nanostructured substance in the body by controlling the rate, time, and place is defined as the nanostructured drug delivery system (NDDS). Because of their versatility and ability to incorporate features such as specific targeting, water solubility, stability, biocompatibility, degradability, and ability to reverse drug resistance, they have attracted the interest of the scientific community, in general, and nanotechnologists as well as biomedical scientists. To keep pace with the rapid advancement of nanotechnology, specific technical aspects of the recent NDDSs and their prospects need to be reported coherently. To address these ongoing issues, this review article provides an overview of different NDDSs such as lipids, polymers, and inorganic nanoparticles. In addition, this review also reports the challenges of current NDDSs and points out the prospective research directions of these nanocarriers. From our focused review, we conclude that still now the most advanced and potent field of application for NDDSs is lipid-based, while other significantly potential fields include polymer-based and inorganic NDDSs. However, despite the promises, challenges remain in practical implementations of such NDDSs in terms of dosage and stability, and caution should be exercised regarding biocompatibility of materials. Considering these aspects objectively, this review on NDDSs will be particularly of interest for small-to-large scale industrial researchers and academicians with expertise in drug delivery, cancer research, and nanotechnology.
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Affiliation(s)
- Md Ishak Khan
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - M Imran Hossain
- Institute for Micromanufacturing, Louisiana Tech University, Ruston, Louisiana 71270, United States
| | - M Khalid Hossain
- Interdisciplinary Graduate School of Engineering Science, Kyushu University, Fukuoka 816-8580, Japan.,Atomic Energy Research Establishment, Bangladesh Atomic Energy Commission, Dhaka 1349, Bangladesh
| | - M H K Rubel
- Department of Materials Science and Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - K M Hossain
- Department of Materials Science and Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - A M U B Mahfuz
- Department of Biotechnology and Genetic Engineering, University of Development Alternative, Dhaka 1209, Bangladesh
| | - Muzahidul I Anik
- Department of Chemical Engineering, University of Rhode Island, South Kingston, Rhode Island 02881, United States
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Dong S, Tang Y, He P, Ma S, Song W, Deng M, Tang Z. Hydrophobic modified poly(
l
‐glutamic acid) graft copolymer micelles with ultrahigh drug loading capacity for anticancer drug delivery. POLYM INT 2021. [DOI: 10.1002/pi.6342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Si Dong
- Department of Chemistry Northeast Normal University Changchun PR China
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun PR China
| | - Yue Tang
- Department of Chemistry Northeast Normal University Changchun PR China
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun PR China
| | - Pan He
- School of Materials Science and Engineering Changchun University of Science and Technology Changchun PR China
| | - Sheng Ma
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun PR China
| | - Wantong Song
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun PR China
| | - Mingxiao Deng
- Department of Chemistry Northeast Normal University Changchun PR China
| | - Zhaohui Tang
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun PR China
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Zhang P, Li M, Xiao C, Chen X. Stimuli-responsive polypeptides for controlled drug delivery. Chem Commun (Camb) 2021; 57:9489-9503. [PMID: 34546261 DOI: 10.1039/d1cc04053g] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Controlled drug delivery systems, which could release loaded therapeutics upon physicochemical changes imposed by physiological triggers in the desired zone and during the required period of time, offer numerous advantages over traditional drug carriers including enhanced therapeutic effects and reduced toxicity. A polypeptide is a biocompatible and biodegradable polymer, which can be conveniently endowed with stimuli-responsiveness by introducing natural amino acid residues with innate stimuli-responsive characteristics or introducing responsive moieties to its side chains using simple conjugating methods, rendering it an ideal biomedical material for controlled drug delivery. This feature article summarizes our recent work and other relevant studies on the development of polypeptide-based drug delivery systems that respond to single or multiple physiological stimuli (e.g., pH, redox potential, glucose, and hypoxia) for controlled drug delivery applications. The material designs, synthetic strategies, loading and controlled-release mechanisms of drugs, and biomedical applications of these stimuli-responsive polypeptides-based drug delivery systems are elaborated. Finally, the challenges and opportunities in this field are briefly discussed.
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Affiliation(s)
- Peng Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. .,Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. .,Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. .,Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
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