HGF/c-Met Axis-Targeted Nanotherapy via GSH-Responsive Polymer Platforms Suppresses Uveal Melanoma Metastasis.

Abstract

Uveal melanoma (UM), a malignant tumor originating within the ocular, characterizes high metastasis and lethality among patients. Cancer stem cells (CSCs) distinguished by the c-Met protein are believed to mediate tumor metastasis in UM. However, the low bioavailability of c-Met inhibitors like Crizotilib (Criz) limits their clinical application. Herein, a GSH-responsive nanoparticle named NP^@Oxa/Criz to precisely deliver Criz and Oxaliplatin (Oxa) is synthesized in this study. The dual-action mechanism of NP^@Oxa/Criz inhibits the HGF/c-Met axis to prevent the nuclear translocation of β-Catenin, thereby reducing the transcription of metastasis-associated genes and undermining the stemness and metastasis of UM cells. Simultaneously, NP^@Oxa/Criz induces immunogenic cell death to boost anti-tumor immunity. In vivo studies demonstrate that NP^@Oxa/Criz can accumulate in tumor sites, significantly eradicating the primary UM in the ocular and suppressing the metastasis UM in the liver and peritoneal. The outcomes from this work illuminate the therapeutic mechanisms of NP^@Oxa/Criz and provide a precise and potent nanotherapeutic strategy for clinical treatment and research in highly metastatic UM.