An improved d-α-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance

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 (~ 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.