Antitumor gemcitabine conjugated micelles from amphiphilic comb-like random copolymers

•Novel comb-like amphiphilic random copolymers with PEG and gemcitabine side chains were prepared.•These random copolymers can efficiently self-assemble into nanomicelles.•PEGylated micelles had prolonged biologic half-life and improved pharmacokinetic behavior.•PEGylated micelles showed significantly higher A549 tumor suppression rate.

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 10 mg/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.

Graphical abstractBRIEF caption:Preparation, characterization and enhanced antitumor activity of PEGylated Gemcitabine-conjugated nanomicelles.Figure optionsDownload full-size imageDownload as PowerPoint slide