Multifunctional biodegradable nanoplatform based on oxaliplatin prodrug cross-linked mesoporous polydopamine for enhancing cancer synergetic therapy

ABSTRACT Due to the limitations of conventional chemotherapy including side effects , poor prognosis, and drug resistance, there is an urgent need for the development of a novel multi-functional combined therapy strategy. Dopamine-modified oxaliplatin prodrug (OXA-DA) was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects, and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform. The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline) (PEOz), which occurred charge reversal in the tumor microenvironment , and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1 (siPD-L1). The pH-responsive charge reversal, photothermal, biodegradation, lysosomal escape ability, PD-L1 protein degradation, toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments. The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy, and upregulated CD8 + T cells produced interferon- γ ( IFN- γ ) to further attack the tumor cells. In conclusion, the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.