title: Antitumor gemcitabine conjugated micelles from amphiphilic comb-like random copolymers.
abstract: Gemcitabine is an important pyrimidine antimetabolite that inhibits cellular DNA synthesis. However, the therapeutic efficacy and clinical benefit of gemcitabine are severely compromised due to its rapid plasma metabolism and low selectivity towards tumor tissues. To overcome these limitations, we prepared novel PEGylated gemcitabine-contained comb-like copolymers poly(monomethoxyl PEG350 methylacrylate -co- 5'-O-vinyladipyl- gemcitabine) (poly(mPEG350MA-co-VAG) and (poly(mPEG1000MA-co-VAG), which could self-assemble into micelles and displayed enhanced antitumor activity. The copolymers and the formed micelles were well characterized for their structure, critical aggregation concentration (CAC), morphology, cellular uptake, cell cytotoxicity, and controlled drug release. Cellular uptake and in vitro cytotoxicity assays against human lung cancerous cells (A549) demonstrated that these micelles could be effectively internalized and induced cell apoptosis. These micelles efficiently inhibited tumor growth when injected intravenously into A549 cell derived xenograft tumor bearing Balb/C nude mice using a dose of 10mg/kg in terms of reduced tumor volume compared to free gemcitabine. In conclusion, PEGylated micelles could protect gemcitabine from rapid plasma metabolism, provided a sustained release and showed enhanced antitumor activity, thus have the potential to be used as novel anticancer drug delivery vehicle.
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hangzhou Pushikang Biotechnology Co., Ltd., Hangzhou, Zhejiang, PR China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Cen
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China.
authors.forename: Xianfu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China. Electronic address: wuqi1000@163.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D000093542:Gemcitabine
keywords: Antitumor activity; Comb-like copolymers; Gemcitabine; Nanomicelles; PEG