Circumvent PEGylation dilemma by implementing matrix metalloproteinase-responsive chemistry for promoted tumor gene therapy  

作　　者：Jingyun Wang Hao Wang Hongyan Cui Peng Sun Xi Yang Qixian Chen 

机构地区：[1]State Key Laboratory of Fine Chemicals,Dalian University of Technology,Dalian 116024,China [2]School of Bioengineering,Dalian University of Technology,Dalian 116024,China [3]Department of Neurosurgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China

出　　处：《Chinese Chemical Letters》2020年第12期3143-3148,共6页中国化学快报（英文版）

基　　金：the National Natural Science Foundation of China(No.21878041);the funding support from Talent Project of Revitalizing Liaoning(No.XLYC1807184);Dalian Science&Technology Innovation Fund(Nos.2020JJ26SN050,2020JJ26GX025)。

摘　　要：Surface modification by poly(ethylene glycol)(PEGylation)has been acknowledged as a powerful strategy in minimizing non-specific reactions for biomedical devices.Once applied into manufacture of drug/gene delivery systems,PEGylation has demonstrated to significantly improve their biocompatibility and stealthiness in physiological environment.Nonetheless,reluctant cell membrane affinities thus cellular uptake efficiencies owing to PEGylation brought up further issues that are imperative to be resolved.Pertain to this PEGylation dilemma,we attempted to introduce peptide(GPLGVRG)linkage between block copolymer of PEG-poly{N’-[N-(2-aminoethyl)-2-aminoethyl]aspartamide}PAsp(DET),wherein the cationic PAsp(DET)could self-assemble with pDNA into nanoscaled complex core.Noteworthy was the peptide linkage whose amino acids sequence could be specifically recognized and degraded by matrix metalloproteinases(MMPs)(overexpressed in extracellular milieu of tumors).Therefore,our subsequent studies validated facile detachment of PEGylation from the aforementioned polyplex micelles upon treatment of MMPs,which elicited improved cytomembrane affinities and cellular uptake efficiencies.In addition,promoted escape from endosome entrapment was also confirmed through direct endosome membrane destabilization by PAsp(DET),which was further elucidated to be attributable to dePEGylation as well as elevated charged density of PAsp(DET)in acidic endosomes.These benefits from dePEGylation eventually contributed to promoted gene expression at the affected cells and potent tumor growth suppression based on anti-angiogenic approach.Therefore,our developed strategy has provided a facile approach in overcoming the dilemma of PEGylation,which could be informative in design of drug/gene delivery systems.

关 键 词：PEGYLATION Tumor Polyplex micelle Gene delivery system Matrix metalloproteinase 

分 类 号：R730.5[医药卫生—肿瘤]