A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity

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• 作者：Zhijian He^a ; ¹ ; Xiaomeng Wan^a ; ¹ ; Anita Schulz^b ; Herdis Bludau^b ; Marina A. Dobrovolskaia^c ; Stephan T. Stern^c ; Stephanie A. Montgomery^d ; Hong Yuan^e ; Zibo Li^e ; Daria Alakhova^a ; Marina Sokolsky^a ; David B. Darr^f ; Charles M. Perou^f ; Rainer Jordan^b ; Robert Luxenhofer^g ; ^{robert.luxenhofer@uni-wuerzburg.de" class="auth_mail" title="E-mail the corresponding author} ; Alexander V. Kabanov^a ; ^h ; ^{kabanov@email.unc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Polyoxazolines ; Paclitaxel nanoformulation ; In vitro ; In vivo ; Efficacy ; Multi-drug resistant cancer
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：101
• 期：Complete
• 页码：296-309
• 全文大小：4868 K

文摘

The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive “T11” mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials.