A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity.

Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant activity against P-glycoprotein (P-gp) mediated multi drug resistant cancer cells. However, because of the poor aqueous solubility and high toxicity, PPT cannot be used in clinical cancer therapy. In order to enhance the efficiency and reduce side effect of PPT, a polypeptide based PPT conjugate PLG-g-mPEG-PPT was developed and used for the treatment of multi drug resistant breast cancer. The PLG-g-mPEG-PPT was prepared by conjugating PPT to poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) via ester bonds. The PPT conjugates self-assembled into nanoparticles with average sizes about 100 nm in aqueous solution. Western blotting assay showed that the PLG-g-mPEG-PPT could effectively inhibit the expression of P-gp in the multiple drug resistant MCF-7/ADR cells. In vitro cytotoxicity assay indicated that the resistance index (RI) values of PLG-g-mPEG-PPT on different drug-resistant cancer cell lines exhibited 57–270 folds reduction than of traditional microtubule inhibitor chemotherapeutic drug PTX or DTX. Hemolysis assay demonstrated that the conjugation greatly decreased the hemolytic activity of free PPT. Maximum tolerated dose (MTD) of PLG-g-mPEG-PPT increased greatly (13.3 folds) as compared to that of free PPT. In vivo study showed that the PLG-g-mPEG-PPT conjugate remarkably enhanced the antitumor efficacy against MCF-7/ADR xenograft tumors with a tumor suppression rate (TSR) of 82.5%, displayed significantly improved anticancer efficacy as compared to free PPT (TSR = 37.1%) with minimal toxicity when both of the two formulations were used in MTD.