Targeted Tumor Microenvironment Delivery of Floxuridine Prodrug via Soluble Silica Nanoparticles in Malignant Melanoma as a Model for Aggressive Cancer Treatment

Abstract

Malignant melanoma presents a significant challenge in oncology due to its aggressive nature and high metastatic potential. Conventional systemic treatments often fail to effectively reach tumor sites, limiting their therapeutic impact. This study introduces a groundbreaking triple-strategy approach for treating malignant melanoma. We developed a novel prodrug, an oligonucleotide, comprising 10 units of Floxuridine (5-fluoro-2-deoxyuridine) (FdU) nucleoside antimetabolites, to enhance half-life and reduce rapid metabolism. Encapsulated in soluble colloidal silica nanoparticles, this compound is protected and directed towards tumor neovasculature precursor endothelial cell receptors, ensuring local delivery. The strategy focuses on releasing the prodrug in the tumor microenvironment, aiming to eradicate both melanoma cells and their supportive structures. Efficacy was demonstrated in cell culture studies and preclinical models of malignant melanoma, showing a remarkable 50% reduction in tumor size after just three intravenous treatments. These findings underscore the transformative potential of targeting endothelial cell membrane proteins for drug delivery. Our study paves the way for innovative targeted therapies, promising significant advancements in treatment strategies and improved outcomes for patients with metastatic cancers. Key PointsO_LITriple-strategy for treating melanoma: FdU10 prodrug, silica nanoparticle and targeted delivery. C_LIO_LIOligonucleotide prodrug (Floxuridine units) enhances half-life and reduces metabolism. C_LIO_LISoluble silica nanoparticles protect therapeutic FdU10 from nucleases and decorated with protein ligands are directed to tumor neovasculature endothelial cells. C_LIO_LISignificant 50% tumor reduction in preclinical melanoma models after systemic administration with targeted therapies. C_LI