A chemotherapeutic approach targeting the acidic tumor microenvironment: combination of a proton pump inhibitor and paclitaxel for statistically optimized nanotherapeutics

摘要

Paclitaxel (PTX) is a major chemotherapeutic drug that is effective against a wide variety of cancers, particularly breast, ovarian and lung cancer. For a weakly basic chemotherapeutic drug such as PTX, the development of the acidic tumor microenvironment (Warburg effect) has a remarkable impact on therapeutic resistance. The present approach takes advantage of the acidic tumor microenvironment by incorporating lansoprazole (LAN), a proton pump inhibitor (PPI), with PTX as a potent therapeutic combination that is capable of reversing PTX resistance. To deliver optimal amounts of the drugs to neoplastic cells, a nano drug delivery system was selected. To design the nanoformulation process in a limited framework, typical formulation parameters were optimized and validated by the application of response surface methodology (RSM) using Box–Behnken design (BBD). On the basis of critical quality aspects, the experimental design helped to determine the optimal particle size (243.7 nm), zeta potential (?9.14 mV) and encapsulation efficiencies (88.91% and 80.35% for PTX and LAN respectively). The optimized formulation (PTX–LAN–PLGA-NPs) exhibited sustained in vitro release profiles over 384 hours for both the encapsulated drugs. The Korsmeyer–Peppas model was found to be the best fitted model for the release kinetics, where the release mechanism follows Fickian diffusion. In in vitro anti-tumor efficacy experiments using Michigan Cancer Foundation-7 (MCF-7) breast cancer cells, the PTX–LAN–PLGA-NPs exhibited a steep decrease in cell viability compared to the pure drugs. Taken together, the results strongly support that incorporation of PTX and LAN in nanoparticles (NPs) is a promising approach for cancer chemotherapy.