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. Graphic Abstract

Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

“…5A and C). 34 These results suggested that L@S/L has a strong potential for tumor accumulation via the EPR effect.…”

Nano-Codelivery of Temozolomide and siPD-L1 to Reprogram the Drug-Resistant and Immunosuppressive Microenvironment in Orthotopic Glioblastoma

“…This indicated that TMZ/siPD-L1@GLPN/dsb and TMZ/siPD-L1@LPN/dsb escaped from the endosome/lysosome, which reduced the enzymatic degradation of siPD-L1 in endosome/lysosomes. Many cationic polymers such as PEI are used to help siRNA-PEI electrostatic complex escape from endosomes through the proton sponge mechanism . Besides, DOPE, a noncationic helper lipid, is often used to facilitate endosomal escape of lipid-based siRNA delivery systems .…”

“…Many cationic polymers such as PEI are used to help siRNA-PEI electrostatic complex escape from endosomes through the proton sponge mechanism. 45 Besides, DOPE, a noncationic helper lipid, is often used to facilitate endosomal escape of lipid-based siRNA delivery systems. 46 Thus, PEI and DOPE were important components in TMZ/siPD-L1@GLPN/dsb, Table 1.…”

Synergistic photothermal-photodynamic-chemotherapy toward breast cancer based on a liposome-coated core–shell AuNS@NMOFs nanocomposite encapsulated with gambogic acid

“…Among those organic photosensitizers, special attention was paid to the porphyrin derivative TCPP [TCPP = tetrakis (4-carboxyphenyl) porphyrin] due to its merits of fluorescence imaging and PDT effect [11,12]. The appropriate proportion of metal ions and TCPP can result in the reasonable force between the metal ions and carboxylate groups to disrupt the π-π stacking of the free TCPP ligands and form NMOFs with good biological and light stability [13,14].…”