title: A pH-responsive drug nanovehicle constructed by reversible attachment of cholesterol to PEGylated poly(l-lysine) via catechol-boronic acid ester formation.
abstract: The present work reports the construction of a drug delivery nanovehicle via a pH-sensitive assembly strategy for improved cellular internalization and intracellular drug liberation. Through spontaneous formation of boronate linkage in physiological conditions, phenylboronic acid-modified cholesterol was able to attach onto catechol-pending methoxypoly(ethylene glycol)-block-poly(l-lysine). This comb-type polymer can self-organize into a micellar nanoconstruction that is able to effectively encapsulate poorly water-soluble agents. The blank micelles exhibited negligible in vitro cytotoxicity, yet doxorubicin (DOX)-loaded micelles could effectively induce cell death at a level comparable to free DOX. Owing to the acid-labile feature of the boronate linkage, a reduction in environmental pH from pH 7.4 to 5.0 could trigger the dissociation of the nanoconstruction, which in turn could accelerate the liberation of entrapped drugs. Importantly, the blockage of endosomal acidification in HeLa cells by NH4Cl treatment significantly decreased the nuclear uptake efficiency and cell-killing effect mediated by the DOX-loaded nanoassembly, suggesting that acid-triggered destruction of the nanoconstruction is of significant importance in enhanced drug efficacy. Moreover, confocal fluorescence microscopy and flow cytometry assay revealed the effective internalization of the nanoassemblies, and their cellular uptake exhibited a cholesterol dose-dependent profile, indicating the contribution of introduced cholesterol functionality to the transmembrane process of the nanoassembly.
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Yun-Tao
authors.initials: YT
authors.lastname: Han
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Hui-Zhen
authors.initials: HZ
authors.lastname: Jia
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Wei-Hai
authors.initials: WH
authors.lastname: Chen
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China. Electronic address: fengjun@whu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Xian-Zheng
authors.initials: XZ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Biomedical Polymers (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Ren-Xi
authors.initials: RX
authors.lastname: Zhuo
mesh_terms: D001897:Boronic Acids / Q000737:chemistry; D002396:Catechols / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000138:chemical synthesis; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004952:Esters; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D014677:Pharmaceutical Vehicles / Q000138:chemical synthesis; D011092:Polyethylene Glycols / Q000737:chemistry*; D011107:Polylysine / Q000737:chemistry*
chemical_list: D001897:Boronic Acids; D002396:Catechols; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004952:Esters; D053769:Nanocapsules; D014677:Pharmaceutical Vehicles; D011107:Polylysine; D011092:Polyethylene Glycols; D004317:Doxorubicin; D002784:Cholesterol; C034221:catechol
keywords: Boronate ester; Cellular uptake; Controlled drug release; Self-assembly; pH-responsiveness