The targeted co-delivery of DNA and doxorubicin to tumor cells via multifunctional PEI-PEG based nanoparticles

Abstract

Co-delivery of nucleic acids and chemotherapeutics has a potential to efficaciously treat human diseases via their synergetic effects. Activable therapeutic tools at the nanoscale are suitable platforms for combination therapy. In this study, we have developed a multifunctional nanoscaled delivery system simultaneously integrated with passive and active tumor targeting, cell membrane translocation, pH-triggered drug release and co-delivery strategies. Poly (ethyleneimine) (PEI)-polyethylene glycol (PEG) copolymer was synthesized with coupling TAT to the distal end of PEG for membrane activity. The functional amino group of PEI was used to chemically conjugate doxorubicin (DOX) via a pH-sensitive hydrazone linkage. Meanwhile, the cationic PEI backbone could complex DNA to DOX loaded-TAT modified polyion complex micelles (NPIC). To achieve double targeting effect to tumor vascular endothelial cells and tumor cells either by active or passive targeting, a virus mimetic shell functioned with NGR was conferred by electrostatic adsorption of sulfamerazine (SA)-PEG-NGR on the surface of NPIC to obtain DOX loaded targeted PIC micelles (TPIC). The multifunctional nanoscaled delivery system was established to comprehensively improve the efficacy of cancer therapy through the synergistic effect of gene therapy with chemotherapy. Consequently, the system was shown to be a promising carrier for the co-delivery of DNA and DOX, leading to the efficiency of gene transfection and anti-tumor activity in vitro.