Sialic Acid-Modified Nanoparticles in Combination Therapy with 5-Carboxy-8-hydroxyquinoline: Dual Effects of Intrinsic Blockade of Cellular Escape and Extrinsic Relief of Immunosuppression.

Epigenetic homeostasis is integral to the development of malignant tumors. Combining epigenetic drugs with chemotherapy is a promising strategy to overcome the challenges in treating lung metastasis from melanoma. In this study, we constructed sialic acid-modified ibrutinib-phospholipid complex nanoparticles (SA-IBR-NPs) to actively target and deliver the drug to lung metastasis sites through the mononuclear phagocytic system (MPS) pathway. A highly soluble 5-Carboxy-8-hydroxyquinoline-arginine salt (IOX1-Arg) was also developed to inhibit tumor cells' intrinsic immune escape mechanisms. The combined administration of IOX1-Arg and SA-IBR-NPs significantly reduced the migration and invasion abilities of B16F10 cells and inhibited lung metastasis. The number of tumor nodules in experimental groups (including single-agent treatment groups, non-SA-modified nanoparticle groups, and non-IOX1-Arg combined groups) was 3.67-28.00 times higher than that of the IOX1-Arg + SA-IBR-NPs. The malignant index of tumor metastasis in single therapy or plain nanoparticle groups was 5.38-1062.29 times higher than that of the IOX1-Arg + SA-IBR-NP treatments, as well. This combination therapy also increased the levels of cytotoxic T cells. The antitumor immune response was effectively restructured by blocking the intrinsic escape mechanism of tumor cells and simultaneously inhibiting the immunosuppressive factors in the microenvironment. This strategy presents a novel approach to enhancing targeted therapy for metastatic tumors.