Controllable release of self-assembled reduction-sensitive paclitaxel dimer prodrug and tetrandrine nanoparticles promotes synergistic therapy against multidrug-resistant cancer.

Background: Multidrug resistance (MDR) is the main reason for chemotherapy failure. Nanocarriers combined delivery of anti-cancer drugs and MDR inhibitors is an effective strategy to avoid MDR and improve the anti-cancer activity of drugs.

Methods: Two paclitaxel (PTX) molecules are linked by disulfide bonds into PTX. Then, the PTX and tetrandrine (TET) are coated together by mPEG-PLGA self-assembled NPs for combinational treatment. Microstructure, physiological stability, and cytotoxicity are characterized for the co-loaded NPs.

Results: The NPs exhibit excellent suitability and blood safety for intravenous injection, specifically responsive to pH 6-7, and promptly initiate chemical degradation. Ex vivo fluorescence microscopy image studies indicate that co-loaded NPs increase drug penetration into cancer cells compared with free drugs. MTT assay demonstrates that co-loaded NPs have higher cytotoxicity against HeLa and the flow cytometric analysis shows that co-loaded NPs trigger more apoptosis than the free drugs. Reactive oxygen species (ROS) assay indicates that the drug-loaded NPs generated higher levels of ROS to accelerate apoptosis in HeLa cells.

Conclusions: TET can get desirable effects of inhibiting the MDR in advance by binding with the active site on P-gp, then the disulfide bond of PTX is broken by glutathione (GSH) in cancer cells and decomposed into PTX to inhibit cancer cell proliferation.

General Significance: Our studies indicate that the co-loaded NPs can potentially overcome the MDR of conventional chemotherapeutic agents.