Multifunctional polyamidoamine-modified selenium nanoparticles dual-delivering siRNA and cisplatin to A549/DDP cells for reversal multidrug resistance.

Abstract

Multidrug resistance (MDR) is a major barrier against effective cancer treatment. Dual-delivering a therapeutic small interfering RNA (siRNA) and chemotherapeutic agents has been developed to reverse drug resistance in tumor cells. In this study, amine-terminated generation 5 polyamidoamine (PAMAM) dendrimers (G5.NH2)-modified selenium nanoparticles (G5@Se NP) were synthesized for the systemic dual-delivery of mdr1 siRNA and cisplatin (cis-diamminedichloroplatinum-(II), DDP), which was demonstrated to enhance siRNA loading, releasing efficiency and gene-silencing efficacy. When the mdr1 siRNA was conjugated with G5@Se NP via electrostatic interaction, a significant down-regulation of P-glycoprotein and multidrug resistance-associated protein expression was observed; G5@Se-DDP-siRNA arrested A549/DDP cells at G1 phase and led to enhanced cytotoxicity in A549/DDP cells through induction of apoptosis involving the AKT and ERK signaling pathways. Interestingly, G5@Se-DDP NP were much less reactive than DDP in the reactions with both MT and GSH, indicating that loading of DDP in a nano-delivery system could effectively prevent cell detoxification. Furthermore, animal studies demonstrated that the new delivery system of G5@Se-DDP-siRNA significantly enhanced the anti-tumor effect on tumor-bearing nude mice, with no appreciable abnormality in the major organs. These results suggest that G5@Se NP could be a potential platform to combine chemotherapy and gene therapy technology in the treatment of human disease.