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CXCR4 Blocker-Enriched Paclitaxel-Loaded Multifunctional Nanoparticles for the Targeted Reversal of the Immunosuppressive Microenvironment in Ovarian Cancer Therapy

Jiyang Xue,Hai Zhang

Immunotherapy has become a potential treatment technique for ovarian cancer. However, its improvement is impeded by obstacles such as immunosuppression and minimal tumor penetration. Inhibiting the chemokine receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis to enhance tumor infiltration and alleviate the immunosuppressive microenvironment holds promise for enhancing tumor immunotherapy. We developed a targeted drug delivery system by encapsulating the chemotherapeutic drug paclitaxel (PTX) in PEGylated albumin nanoparticles (NPs) modified with the tumor-specific CXCR4 inhibitor plerixafor (AMD3100) (AMD-NP-PTX). The effects of AMD-NPs on cell uptake and migration were investigated using ID8 cells. Subsequently, an ovarian cancer-bearing mouse model was developed to assess the targeting ability of AMD-NP-PTX and its repressive result on ovarian cancer. Lastly, the prospective healing system was investigated. The CXCR4 blocker-enriched NPs showed increased tumor cell uptake in vitro and significant inhibition of CXCL12-mediated immune cell migration. Moreover, this system not only properly targets tumors using AMD3100 but also hinders tumor growth by modulating the CXCR4/CXCL12 axis, hence boosting MAPK expression and lowering PI3K expression. Immune analysis showed that the medicine shipment system upregulates CD8+ T cells as well as natural killer cells in both growth tissues and the spleen, while all at once downregulating myeloid-derived suppressor cells and regulatory T cells. This study underscores the synergistic inflection of the immunosuppressive microenvironment within the tumor, triggering a durable and appropriate antitumor immune response. These findings underscore the potential of a tailored medication delivery system to enhance immunotherapy for ovarian cancer.