Intracellular and extracellular enzymatic responsive micelle for intelligent therapy of cancer
作者机构：School of Chemical Engineering and TechnologyTiangong UniversityTianjin 300387China School of ChemistryTiangong UniversityTianjin 300387China CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing 100190China
出 版 物：《Nano Research》 (纳米研究（英文版）)
年 卷 期：2023年第16卷第2期
页 面：2851-2858页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 0703[理学-化学] 10[医学]
基 金：supported by the National Natural Science Foundation of China(Nos.22078246,22178270,and 82102204) support by the Postdoctoral Research Foundation of China(No.2020M680478).
主 题：cancer micelle peptide enzyme-responsive folate
摘 要：Recently,the incidence of cancer keeps increasing,seriously endangers human health,and has evolved into the main culprit of human death.Conventional chemotherapeutic drugs,such as paclitaxel and doxorubicin(DOX),have some disadvantages,including low therapeutic effect,poor water solubility,high toxic side effects,short blood circulation time in the body,and so on.To improve the anti-tumor effect of the drug in vivo and reduce its side effects on the body,researchers have designed and developed a variety of responsive nanocarriers.In this work,we synthesized D-α-tocopherol polyethylene glycol 3350 succinate(TPGS3350)-Gly-Pro-Leu-Gly-Val-Arg(GPLGVR)-DOX(TPD)prodrugs in response to extracellular enzymes of matrix metalloproteinase(MMP-9)in the tumor microenvironment and FA-Asp-Glu-Val-Asp(DEVD)-DOX(FPD)prodrugs responsive to intracellular enzymes of caspase-3.Then,intracellular and extracellular enzyme-responsive TPD&FPD micelles with DOX(TPD&FPD&D)were successfully prepared through dialysis method.The outer layer of TPGS3350 can prolong the blood circulation time of micelles in vivo,followed by accumulation of micelles at tumor tissue through enhanced permeability and retention(EPR)effect.The peptide of GPLGVR can be cleaved by MMP-9 enzymes to remove the outer layer of TPGS3350,exposing the targeting molecule of folate,and then the micelles are engulfed by tumor cells through folate receptor-mediated endocytosis.After entering the tumor cells,the free DOX loaded in the micelles is released,which induces tumor cell apoptosis to activate caspase-3 in the cells,cutting the peptide DEVD to accelerate the intracellular release of the DOX,which further enhances cytotoxicity to improve antitumor effect.
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