PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma

JOURNAL OF CONTROLLED RELEASE

卷:155

Article; Proceedings Paper

Xiao, Kai^2,3  Luo, Juntao^1,2  Li, Yuanpei²  Lee, Joyce S.^2,5  Fung, Gabriel²  Lam, Kit S.^2,4 

[1] SUNY Upstate Med Univ, SUNY Upstate Canc Res Inst, Dept Pharmacol, Syracuse, NY 13210 USA

[2] Univ Calif Davis, UC Davis Canc Ctr, Dept Biochem & Mol Med, Sacramento, CA 95817 USA

[3] Sichuan Univ, W China Hosp, Natl Chengdu Ctr Safety Evaluat Drugs, Chengdu 610041, Peoples R China

[4] Univ Calif Davis, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA

[5] Univ Calif, Davis Med Ctr, Dept Pharm, Sacramento, CA 95817 USA

关键词: Doxorubicin;    Nanotherapeutics;    Polymeric micelles;    Drug delivery;    Biodistribution;    Cardiotoxicity;    Cancer therapy;   

DOI  :  10.1016/j.jconrel.2011.07.018

来源: Elsevier

【 摘 要 】

Doxorubicin (DOX) is one of most common anti-cancer chemotherapeutic drugs, but its clinical use is associated with dose-limiting cardiotoxicity. We have recently developed a series of PEG-oligocholic acid based telodendrimers, which can efficiently encapsulate hydrophobic drugs and self-assemble to form stable micelles in aqueous condition. In the present study, two representative telodendrimers (PEG(5k)-CA(8) and PEG(2k)-CA(4)) have been applied to prepare DOX micellar formulations for the targeted delivery of DOX to lymphoma. PEG(2k)-CA(4) micelles, compared to PEG(5k)-CA(8) micelles, were found to have higher DOX loading capacity (14.8% vs. 8.2%, w/w), superior stability in physiological condition, and more sustained release profile. Both of these DOX-loaded micelles can be efficiently internalized and release the drug in Raji lymphoma cells. DOX-loaded micelles were found to exhibit similar in vitro cytotoxic activities against both T- and B-lymphoma cells as the free DOX. The maximum tolerated dose (MTD) of DOX-loaded PEG(2k)-CA(4) micelles in mice was approximately 15 mg/kg, which was 1.5-fold higher of the MTD of free DOX. Pharmacokinetics and biodistribution studies demonstrated that both DOX-loaded micelles were able to prolong the blood retention time, preferentially accumulate and penetrate in B-cell lymphomas via the enhanced permeability and retention (EPR) effect. Finally, DOX-PEG(2k)-CA(4) micelles achieved enhanced anti-cancer efficacy and prolonged survival in Raji lymphoma bearing mice, compared to free DOX and PEGylated liposomal DOX (Doxil (R)) at the equivalent dose. In addition, the analysis of creatine kinase (CK) and lactate dehydrogenase (LDH) serum enzymes level indicated that DOX micellar formulations significantly reduced the cardiotoxicity associated with free DOX. (C) 2011 Elsevier B.V. All rights reserved.

【 授权许可】

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