Polymeric Nanoassemblies based Gene/drug Co-delivery for Autophagy Modulation and Tumor Multidrug-resistance

Abstract Multidrug resistance (MDR) has been restricting the efficacy of chemotherapy, which mainly include pump resistance and nonpump resistance. In order to fight overall MDR, a novel targeted gene/drug co-deliver nano system is developed, which can suppress the drug efflux pumps and modulate autophagy to overcoming both pump and nonpump resistance. RNA interference (RNAi) is widely applied in combating MDR through knocking down MDR-related gene. Here, small interfere RNA (siRNA) is incorporated into polymer-drug conjugates (PP) which are composed of polyethyleneimine (PEI) and paclitaxel (PTX) via covalent bonds, and hyaluronic acid (HA) is coated on the surface of PP/siRNA to achieve long blood cycle and CD44-targeted delivery. The polymeric nanoassemblies (PP/siRNA/HA) would be shattered and release PTX under the enrich-enzyme intracellular environment. This study identifies PP/siRNA/HA could efficiently facilitate apoptosis of Taxol-resistant lung cancer cells (A549/T) to reverse MDR through down-regulating P-gp and block autophagic flux. Further study indicates that PEI conjugates play a significant role to block the autophagosome–lysosome fusion process by means of alkalizing lysosomes. Both in vitro and in vivo studies confirm that the nanoassemblies can successfully deliver drug into tumor cells and significantly inhibited A549/T tumor growth. In summary, the polymeric nanoassemblies provide a potential strategy for combating both pump and nonpump resistance via the synergism of RNAi and autophagy modulation.