title: Folate-decorated hydrophilic three-arm star-block terpolymer as a novel nanovehicle for targeted co-delivery of doxorubicin and Bcl-2 siRNA in breast cancer therapy.
abstract: To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer, [poly(l-glutamic acid γ-hydrazide)-b-poly(N,N-dimethylaminopropyl methacrylamide)]3-g-poly(ethylene glycol) ((PGAH-b-PDMAPMA)3-g-PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition-fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by (1)H-NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ⩾4:1 to form "two-in-one" nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3 nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione: 10mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co-delivery of doxorubicin and therapeutic siRNA in cancer therapy.
authors.affiliation: State Key Laboratory for Mechanical Behaviors of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Qian
authors.affiliation: State Key Laboratory for Mechanical Behaviors of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: ailisuo@mail.xjtu.edu.cn.
authors.forename: Aili
authors.initials: A
authors.lastname: Suo
authors.affiliation: State Key Laboratory for Mechanical Behaviors of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Mechanical Behaviors of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Mechanical Behaviors of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: State Key Laboratory for Mechanical Behaviors of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004587:Electrophoresis, Agar Gel; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D057446:Hydrodynamics; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D017304:Annexin A5; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D004317:Doxorubicin; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate
keywords: Bcl-2 siRNA; Doxorubicin; Nanomicelleplex; Star-block terpolymer; Targeted co-delivery