title: Self-assembled pH-responsive hyaluronic acid-g-poly((L)-histidine) copolymer micelles for targeted intracellular delivery of doxorubicin.
abstract: Hyaluronic acid (HA) was conjugated with hydrophobic poly(l-histidine) (PHis) to prepare a pH-responsive and tumor-targeted copolymer, hyaluronic acid-g-poly(l-histidine) (HA-PHis), for use as a carrier for anti-cancer drugs. The effect of the degree of substitution (DS) on the pH-responsive behaviour of HA-PHis copolymer micelles was confirmed by studies of particles of different sizes. In vitro drug release studies demonstrated that doxorubicin (DOX) was released from HA-PHis micelles in a pH-dependent manner. In vitro cytotoxicity assays showed that all the blank micelles were nontoxic. However, MTT assay against Michigan Cancer Foundation-7 (MCF-7) cells (overexpressed CD44 receptors) showed that DOX-loaded micelles with a low PHis DS were highly cytotoxic. Cellular uptake experiments revealed that these pH-responsive HA-PHis micelles taken up in great amounts by receptor-mediated endocytosis and DOX were efficiently delivered into cytosol. Moreover, micelles with the lowest DS exhibited the highest degree of cellular uptake, which indicated that the micelles were internalized into cells via CD44 receptor-mediated endocytosis and the carboxylic groups of HA are the active binding sites for CD44 receptors. Endocytosis inhibition experiments and confocal images demonstrated that HA-PHis micelles were internalized into cells mainly via clathrin-mediated endocytosis and delivered to lysosomes, triggering release of DOX into the cytoplasm. These results confirm that the biocompatible pH-responsive HA-PHis micelles are a promising nanosystem for the intracellular targeted delivery of DOX.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Qiu
authors.affiliation: School of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Qiao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Long
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Science, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Chenmin
authors.initials: C
authors.lastname: Tian
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; College of Pharmaceutical Science, Soochow University, Suzhou 215123, People's Republic of China. Electronic address: chendawei@syphu.edu.cn.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006639:Histidine / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006820:Hyaluronic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D010316:Particle Size; D011817:Rabbits
chemical_list: D008823:Micelles; C033223:polyhistidine; D006639:Histidine; D004317:Doxorubicin; D006820:Hyaluronic Acid
keywords: Doxorubicin; Hyaluronic acid–g-poly(l-histidine); Self-assembled micelles; Targeted intracellular delivery; pH-responsive