An improved D-alpha-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance

作者：Lu Jianqin; Zhao Wenchen; Liu Hao; Marquez Rebecca; Huang Yixian; Zhang Yifei; Li Jiang; Xie Wen; Venkataramanan Raman; Xu Liang; Li Song^*

来源：Journal of Controlled Release, 2014, 196: 272-286.

DOI：10.1016/j.jconrel.2014.10.016

• Fluorenylmethyloxycarbonyl
• Drug-interactive motif
• Nanomedicine
• Reversal of multidrug resistance
• Chemotherapeutics

Nanocarriers have recently emerged as an attractive platform for the delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG(5K)-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG(5K)-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG(5K)-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG(5K)-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG(5K)-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG(5K)-VE2/DOX in PC-3 and 4T1.2 cells. A cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG(5K)-Fmoc-VE2 may have the potential to reverse multidrug resistance, which was supported by its inhibition of P-gp ATPase. Pharmacokinetic (PK) and biodistribution studies showed an increased half-life in blood circulation and more effective tumor accuulation for DOX formulated in PEG(5K)-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG(5K)-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (similar to 30 mg DOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated by PEG(5K)-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG(5K)-VE2/DOX.

• 出版日期2014-12-28