1. Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based "combo" nanoagent together with PD-L1 blockade in reversing multidrug resistance.
- Author
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Jiang W, Su L, Ao M, Guo X, Cheng C, Luo Y, Xie Z, Wang X, Wang J, Liu S, Cao Y, Li P, Wang Z, Ran H, Zhou Z, and Ren J
- Subjects
- Animals, B7-H1 Antigen metabolism, Cell Line, Tumor, Copper, Drug Delivery Systems methods, Drug Liberation, Drug Therapy, Female, Heterocyclic Compounds, Humans, Lysosomes, MCF-7 Cells, Metalloporphyrins, Mice, Mice, Inbred BALB C, Mice, Nude, Nanomedicine, Nanoparticles chemistry, Organophosphorus Compounds, Paclitaxel pharmacology, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Immune Checkpoint Inhibitors pharmacology, Nanoparticles therapeutic use
- Abstract
Background: Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy 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 equipping 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, which 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 reduce 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 these 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 tumors., Conclusion: This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel.
- Published
- 2021
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