Biology subjects

Fanarraga, M. L.

Publications and source records attributed to Fanarraga, M. L..

3 recordsLinked to original sources

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

Engineering an Anthrax Toxin inspired protein-ligand for Nanoparticle-Mediated Treatment of Malignant Melanoma

BackgroundMalignant melanoma is a highly aggressive cancer that presents significant treatment challenges, especially in metastatic stages where conventional therapies often fail due to resistance. Targeting the tumors supportive environment rather than the cancer cells themselves offers a promising strategy. The tumor endothelial marker 8 (TEM8), also known as anthrax toxin receptor 1, is overexpressed in tumor neovasculature endothelial cells and their precursors, making it an attractive therapeutic target. This study introduces PA17, a protein ligand derived from the anthrax toxin binding domain and specifically engineered to target TEM8, aiming to enhance the precision and effectiveness of nanomedicine. ResultsRecombinant and purified PA17 ligand protein exhibited high affinity for TEM8 both in vitro and in vivo in preclinical melanoma models, demonstrating significant intrinsic antitumor activity and no detectable off-target effects. When PA17 was used to functionali ze doxorubicin-loaded mesoporous silica nanoparticles, it resulted in a 65% reduction in tumor mass with a single local administration and a 55% reduction after three systemic administrations. This treatment was significantly more effective than free doxorubicin or non-targeted doxorubicin-loaded nanoparticles and was associated with a marked decrease in tumor vascularization. ConclusionsThis study highlights the potential of toxin-derived ligands as novel targeti ng agents for tumor neovasculature in aggressive cancers such as malignant melanoma. PA17, with its intrinsic antitumor properties and exceptional targeting efficacy, enhances the efficacy of nanomedicine and addresses common challenges such as drug resistance. The use of natural ligands represents a transformative approach to nanomedicine delivery and offers a promising strategy to advance cancer nanotherapy. Graphical abstract image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/626996v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@ae5f6dorg.highwire.dtl.DTLVardef@1fb115borg.highwire.dtl.DTLVardef@309f9eorg.highwire.dtl.DTLVardef@3f53b5_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Biodegradable silica nanoparticles for efficient linear DNA gene delivery

Targeting, safety, scalability, and storage stability of vectors are still challenges in the field of nucleic acid delivery for gene therapy. Silica-based nanoparticles have been widely studied as gene carriers, exhibiting key features such as biocompatibility, simplistic synthesis and enabling easy surface modifications for targeting. However, the ability of the formulation to incorporate DNA is limited, which restricts the number of DNA molecules that can be incorporated into the particle, thereby reducing gene expression. Here we use polymerase chain reaction (PCR)-generated linear DNA molecules to augment the coding sequences of gene-carrying nanoparticles, thereby maximizing nucleic acid loading and minimizing the size of these nanocarriers. This approach results in a remarkable 16-fold increase in protein expression six days post-transfection in cells transfected with particles carrying the linear DNA compared with particles bearing circular plasmid DNA. The study also showed that the use of linear DNA entrapped in DNA@SiO2 resulted in a much more efficient level of gene expression compared to standard transfection reagents. The system developed in this study features simplicity, scalability, and increased transfection efficiency and gene expression over existing approaches, enabled by improved embedment capabilities for linear DNA, compared to conventional methods such as lipids or polymers, which generally show greater transfection efficiency with plasmid DNA. Therefore, this novel methodology can find applications not only in gene therapy but also in research settings for high throughput gene expression screenings.

bioengineering↗