Multidrug Loaded Thermosponge Nanoparticle for Synergistic Anticancer therapy on Colorectal Cancer with Multidrug Resistance

Abstract

Multidrug resistance (MDR) effect in cancer cells is main obstacle for effective cancer chemotherapy. Overexpression of P-glycoprotein (p-gp) on surface of tumor cells is a key point leading to the development of drug resistance. For the efficient treatment of multidrug resistance cancers in clinics, chemotherapeutic drugs such as paclitaxel (PTX) and doxorubicin (DOX) and p-gp inhibitors have been simultaneously used as a cocktail. Among the p-gp inhibitors, tetrandrine (TET) as a plant-derived p-gp inhibitor has been recently utilized because it could effectively reduce the drug efflux from inside cells to outside cells caused by p-gp. However, the treatment of free drugs and p-gp inhibitors have several limitations including short circulation period in blood, low drug accumulation in cancer cells, and low inhibition against drug resistance of cancer cells. Several delivery systems that were suggested to overcome the limitation showed inefficient anticancer effect. To improve anticancer effect using delivery system, in this study, we have developed co-delivery of anticancer drugs and p-gp inhibitor using TNP (DOX/PTX/TET@TNP) to overcome drug resistance in cancer cell with MDR by simple nanoprecipitation without any chemical crosslinking synthesis. The drugs are loaded in TNP successfully via not significant difference of physicochemical property. In addition to, in vitro anticancer effect in p-gp overexpressed HCT 15 was highest effect using free anticancer drugs with p-gp inhibitor loaded TNP (DOX/PTX/TET@TNP) through synergistic effect between anticancer drugs. In vitro p-gp inhibition of inhibitors showed that TNP, composed of Pluronic polymer which has capability of p-gp inhibition, affect p-gp inhibition resulting possibility of synergistic effect to multidrug resistance. in vitro intracellular uptake of drug exhibited that DOX/PTX/TET@TNP are higher drug accumulation in cells due to synergistic effect of inhibitor (TET) and TNP having capability of p-gp inhibition. We suggest that the DOX/PTX/TET@TNP without any complicated fabrication and chemical synthesis could be advantageous in treatment of MDR cancer by synergistic effect.