Abstract
Multidrug resistance (MDR) has become a very serious problem in cancer therapy. To effectively reverse MDR in tumor treatments, a new pH-sensitive nano drug delivery system (NDDS) composed of mesoporous silica nanoparticles (MSNs) and d-a-tocopheryl poly-ethylene glycol 1000 succinate (TPGS) copolymers was synthesized to deliver doxorubicin (DOX) into drug-resistant breast cancer cell line (MCF-7/ADR). DOX@MSNs-TPGS were characterized to have a single peak size distribution, high DOX loading efficiency and a pH-dependent drug release profile. MSNs-TPGS were internalized via caveolae, clathrin-mediated endocytosis and energy-dependent cellular uptake. The DOX@MSNs-TPGS exhibited 10-fold enhanced cell killing potency compared to free DOX and DOX@MSNs. The enhanced MDR reversal effect was ascribed to the higher amount of cellular uptake of DOX@MSNs-TPGS in MCF-7/ADR cells than that of free DOX and DOX@MSNs, as a result of the inhibition of P-gp mediated drug efflux by TPGS. In vivo studies of NDDS in tumor-bearing mice showed that DOX@MSNs-TPGS displayed better efficacy against MDR tumors in mice and reached the tumor site more effectively than DOX and DOX@MSNs, with minimal toxicity. These results suggest DOX@MSNs-TPGS developed in this study have promising applications to overcome drug resistance in tumor treatments.
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