Avino, A. | bioRxiv Science

bioRxiv2025

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

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

bioengineering↗

bioRxiv2024

Systematic study of hybrid triplex topology and stability suggests a general triplex-mediated regulatory mechanism

By combining in-silico, biophysical and in-cellulo experiments, we decipher the topology, physical and potential biological properties of hybrid-parallel nucleic acids triplexes; an elusive structure at the basis of life. We found that hybrid triplex topology follows a stability order: r(Py)-d(Pu){middle dot}r(Py)> r(Py)-d(Pu){middle dot}d(Py)> d(Py)-d(Pu){middle dot}d(Py)> d(Py)-d(Pu){middle dot}r(Py). The r(Py)-d(Pu){middle dot}d(Py) triplex is expected to be the preferred in the cell as it avoids the need to open the duplex reducing the torsional stress required for triplex formation in the r(Py)-d(Pu){middle dot}r(Py) topology. Upon a massive collection of melting data, we have created the first predictor for hybrid triplex stability. Leveraging this predictor, we conducted a comprehensive scan to assess the likelihood of the human genome and transcriptome to engage in triplex formation. Our findings unveil a remarkable inclination - of both the human genome and transcriptome - to generate hybrid triplex formation, particularly within untranslated (UTRs) and regulatory regions, thereby corroborating the existence of a triplex-mediated regulatory mechanism. Furthermore, we found a correlation between nucleosome linkers and TFS which agree with a putative role of triplexes in arranging chromatin structure and local/global level.

molecular biology↗