Silver nanoparticles functionalized Paclitaxel nanocrystals enhance overall anti-cancer effect on human cancer cells

Abstract

Abstract For chemotherapeutic drugs, precise tumor-targeting and high anti-cancer efficiency is equally important in order to enhance chemotherapy and reverse drug resistance. The combination of multifunctional agents to achieve synergy should be a promising strategy. In our study, we have successfully developed novel multifunctionalized drug nanocrystals to realize co-delivery of the organic drug Paclitaxel (PTX), inorganic silver nanoparticles (AgNPs) and a tumor targeting agent. To be specific, PTX nanocrystals were first prepared as a template, then coated with polydopamine (PDA). The PDA layer was utilized as the connection bridge to produce and deposit AgNPs in situ, and provide sites for tumor-targeting peptide NR1 (RGDARF) grafting. As a result, these NR1/AgNP-decorated drug nanocrystals exhibited dramatically improved cellular uptake efficiency, in vitro anti-cancer activity and an anti-migratory effect against a variety of cancer cells, which was attributable to the synergistic, or at least additive, effect of the AgNPs and PTX, enhanced cellular uptake efficiency through NR1-receptor interaction, pH-responsive drug release and the nanoscaled nature. In particular, high anti-cancer activity and low side effects from these NR1/AgNP-decorated PTX nanocrystals were well balanced in terms of good selectivity and biocompatibility. Moreover, these novel drug nanocrystals displayed strong apoptotic-inducing potency, resulting in cell membrane lysis, nuclear damage, mitochondria dysfunction, excessive ROS release and double-stranded DNA breakage. The potential acting mechanism and molecular basis of these novel drug nanocrystals is relevant to the regulation of mitochondria-mediated apoptosis with a greater Bax-to-Bcl-2 ratio and the activation of pro-apoptotic P53 and caspase 3.