Disulphide cross linked pullulan based cationic polymer for improved gene delivery and efflux pump inhibition

Multidrug resistance is a hurdle to successful cancer chemotherapy. Over expression of P-glycoprotein (P-gp) is a prime contributing factor for drug resistance. In this study, a disulphide cross-linked pullulan-based cationic polymer (PPSS) was synthesized to act simultaneously as gene delivery vehicle and efflux pump inhibitor. The PPSS nanoplexes were of size <200nm with the zeta potential of +15 to +20mV. The cytotoxicity studies using C6 and L929 cells showed that PPSS polymers are non-toxic even at high polymer concentrations. The PPSS/pDNA nanoplex showed superior uptake in confocal microscopy with 97% uptake by flow cytometry. The efficacy of efflux pump inhibition by the PPSS nanoplex was established by the enhanced intracellular retention of DOX. The enhanced cell death by p53/PPSS/DOX nanoplexes was attributed to the synergistic effect of P-gp inhibition and p53 transfection efficiency. Therefore, this multifunctional polymeric system may have significant promise for therapeutic application against cancer drug resistance.