Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based "combo" nanoagent together with PD-L1 blockade in reversing multidrug resistance.

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.

• Authors: Weixi Jiang, Lei Su, Meng Ao, Xun Guo, Chen Cheng, Yuanli Luo, Zhuoyan Xie, Xingyue Wang, Junrui Wang, Shuling Liu, Yang Cao, Pan Li, Zhigang Wang, Haitao Ran, Zhiyi Zhou, Jianli Ren
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 19 Issue 1 Pg. 200 (Jul 05 2021) ISSN: 1477-3155 [Electronic] England
• PMID: 34225744 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• Heterocyclic Compounds
• Immune Checkpoint Inhibitors
• Metalloporphyrins
• Organophosphorus Compounds
• tris(o-phenylenedioxy)cyclotriphosphazene
• 5,10,15,20-tetrakis(4-carboxyphenyl)porphinatocopper(II)
• Copper
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• B7-H1 Antigen (metabolism)
• Cell Line, Tumor
• Copper
• Drug Delivery Systems (methods)
• Drug Liberation
• Drug Resistance, Neoplasm (drug effects)
• Drug Therapy
• Female
• Heterocyclic Compounds
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Lysosomes
• MCF-7 Cells
• Metalloporphyrins
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanomedicine
• Nanoparticles (chemistry, therapeutic use)
• Organophosphorus Compounds
• Paclitaxel (pharmacology)