1. Design and synthesis of TH19P01-Camptothecin based hybrid peptides inducing effective anticancer responses on sortilin positive cancer cells.
- Author
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Li YJ, Fang CB, Wang SS, Chen XQ, Li Y, Liu Q, Qi YK, and Du SS
- Subjects
- Humans, Peptides chemistry, Peptides pharmacology, Peptides chemical synthesis, Structure-Activity Relationship, Molecular Structure, Cell Line, Tumor, Dose-Response Relationship, Drug, Cell Movement drug effects, Camptothecin pharmacology, Camptothecin chemistry, Camptothecin chemical synthesis, Adaptor Proteins, Vesicular Transport metabolism, Drug Design, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Proliferation drug effects, Drug Screening Assays, Antitumor
- Abstract
Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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