Amplified Antitumor Efficacy By A Targeted Drugs Retention and Chemosensitization Strategies-Based “Combo” Nanoagent Together With PD-L1 Blockade In Reversing Multidrug Resistance

Abstract Background: Recent studies have demonstrated that multidrug resistance (MDR) plays a critical role in the low efficiency of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. Results: In this study, we fabricated a “combo” nanoagent equipped with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape that enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to relieve the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that the versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumor. Conclusion: This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors compared to an equivalent dose of free paclitaxel by using multiple MDR reversing strategies.