Mixed PEG-PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: improved drug solubilization and enhanced in vitro cytotoxicity

Abstract

Two poorly soluble, potent anti-cancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug-containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-22 nm and the immuno-modification of micelles did not significantly change it. The solubilization of both drugs by the mixed micelles was more efficient than by micelles made of PEG-PE alone. Solubilization of camptothecin in micelles prevented also the hydrolysis of active lactone form of the drug to inactive carboxylate form. Drug-loaded mixed micelles and mAb 2C5-immunomicelles demonstrated significantly higher in vitro cytotoxicity than free drug against various cancer cell lines.

Figure 1

Chemical structure of CPT.

Figure 2

HPLC chromatograms illustrating the conversion of CPT carboxylate to CPT lactone form in immunomicelles upon the incubation in the reaction buffer at pH 8.5 for 3h (A) and at pH 5.0 after 24h (B).

Figure 3

Immunoreactivity of 2C5-PEG-PE/Vitamin E mixed micelles by ELISA.

Figure 4

CMC determination of PEG-PE/Vitamin E mixed micelles.

Figure 5

Stability of free CPT (lactone form) and CPT (lactone form) loaded “plain” micelles in PBS pH 7.4 and 50% FBS.

Figure 6

In vitro cytotoxicity of various formulations of CPT and PCT against different cancer cell lines.