Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy

作     者：Lu Zhong Lu Xu Yanying Liu Qingsong Li Dongyang Zhao Zhenbao Li Huicong Zhang Haotian Zhang Qiming Kan Yongjun Wang Jin Sun Zhonggui He 

作者机构：Department of Pharmaceutics Wuya College of Innovation Shenyang Pharmaceutical University Department of Pharmacy Shenyang Pharmaceutical University 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第2期

页      面：397-409页

核心收录：

学科分类：100702[医学-药剂学] 1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Basic Research Program of China(No.81573371) the Key Projects of Liaoning Province Department of Education(No.2017LZD03,China) 

主　　题：Hyaluronic acid Benzoic imine linkage Active-targeting Cancer therapy Natural ligand Supramolecular nanoplatform Transformative nanoparticles PEG dilemma 

摘      要：Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES ***, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine *** in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a stealth state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a recognition state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.