Enhanced antitumor efficacy of arginine modified amphiphilic nanoparticles co-delivering doxorubicin and iSur-pDNA via the multiple synergistic effect

Arginine and α-tocopherol succinate (α-TOS) double grafted N-trimethyl chitosan chloride (TMC) nanoparticles (TAS NPs) were designed and developed for effective co-delivery of doxorubicin (DOX) and Survivin shRNA-expressing pDNA (iSur-pDNA). With DOX loading into the hydrophobic core and iSur-pDNA combining to the hydrophilic shell, TAS/DOX/pDNA NPs demonstrated favorable structural stability and sustained release properties in vitro. With the special non-clathrin-dependent endocytosis, TAS/DOX/pDNA NPs presented higher cellular uptake and mainly distributed in ER and Golgi rather than lysosomes following internalization. The in vitro nuclear localization, gene silencing efficiency, cell apoptosis, and growth inhibition of tumor cells were significantly promoted by arginine modification. In the tumor-bearing mice model, TAS/DOX/pDNA NPs possessed the maximum antitumor efficiency as compared with single delivery of DOX or iSur-pDNA. Particularly, blank TAS NPs were selectively be toxic to tumor cells as evidenced by their capabilities to inhibit proliferation and induce apoptosis of tumor cells. The promising tumor treatment of TAS/DOX/pDNA NPs via a multiple synergistic manner arising from DOX and pDNA as well as the vectors would provide a potential strategy for a dual-delivery system to improve their therapeutic efficacies.