title: Stimuli-Sensitive Biodegradable and Amphiphilic Block Copolymer-Gemcitabine Conjugates Self-Assemble into a Nanoscale Vehicle for Cancer Therapy.
abstract: The availability and the stability of current anticancer agents, particularly water-insoluble drugs, are still far from satisfactory. A widely used anticancer drug, gemcitabine (GEM), is so poorly stable in circulation that some polymeric drug-delivery systems have been under development for some time to improve its therapeutic index. Herein, we designed, prepared, and characterized a biodegradable amphiphilic block N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-GEM conjugate-based nanoscale and stimuli-sensitive drug-delivery vehicle. An enzyme-sensitive oligopeptide sequence glycylphenylalanylleucylglycine (GFLG) was introduced to the main chain with hydrophilic and hydrophobic blocks via the reversible addition-fragmentation chain transfer (RAFT) polymerization. Likewise, GEM was conjugated to the copolymer via the enzyme-sensitive peptide GFLG, producing a high molecular weight (MW) product (90 kDa) that can be degraded into smaller MW segments (<50 kDa), and ensuring potential rapid site-specific release and stability in vivo. The amphiphilic copolymer-GEM conjugate can self-assemble into compact nanoparticles. NIR fluorescent images demonstrated that the conjugate-based nanoparticles could accumulate and be retained within tumors, resulting in significant increased antitumor efficacy compared to free GEM. The conjugate was not toxic to organs of the mice as measured by body weight reductions and histological analysis. In summary, this biodegradable amphiphilic block HPMA copolymer-gemcitabine conjugate has the potential to be a stimuli-sensitive and nanoscale drug-delivery vehicle.
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Duan
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Sun
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.forename: Bijin
authors.initials: B
authors.lastname: Li
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Gong
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China.
authors.forename: Zhongwei
authors.identifier: http://orcid.org/0000-0003-1547-6880
authors.initials: Z
authors.lastname: Gu
authors.forename: Kui
authors.identifier: http://orcid.org/0000-0002-3536-1485
authors.initials: K
authors.lastname: Luo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry; D004317:Doxorubicin; D004337:Drug Carriers; D016503:Drug Delivery Systems; D051379:Mice; D011108:Polymers; D000093542:Gemcitabine
chemical_list: D004337:Drug Carriers; D011108:Polymers; D003841:Deoxycytidine; D004317:Doxorubicin; D000093542:Gemcitabine
keywords: HPMA; biodegradability; block polymer; drug delivery; nanoscale