Abstract
BackgroundRecent 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.ResultsIn 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.ConclusionThis 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.Graphic
Highlights
Cancer has been one of the greatest contributors to the high mortality worldwide, considerable attention has been given to developing effective anticancer methods, such as photothermal therapy [1], magnetothermal therapy [2], photodynamic therapy and chemotherapy [3, 4]
The zeta potentials of the NPs modified with tLyP-1-PEI or only PEI were increased to a positive value attributable to the positive charge from either the tLyP-1 peptide or PEI compared with the pristine NPs, according to DLS measurements (Fig. 1C)
Digital photographs validated the successful encapsulation of CuTCPP due to the appearance of the aqueous solution changing from white to pink after CuTCPP loading (Additional file 1: Figure S7)
Summary
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 trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. 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. We verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can activate immunological responses and inhibit P-gp expression to obliterate primary and metastatic tumors
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