Abstract 492: Investigating solute carrier SLC46A3 to enhance nanotherapeutic delivery for cancer

Abstract BACKGROUND: Nanoparticle therapeutics have multifaceted potential to improve efficacy and decrease toxicity of cancer treatments. Nanotherapeutics can encapsulate a range of cargos and have tunable surface chemistry that can enhance drug delivery to tumors. Cellular features also play a role in successful drug delivery, and predictive biomarkers may improve patient selection for clinical trials. In previous work, we identified SLC46A3, a poorly characterized lysosomal solute carrier, as a strong negative regulator of lipid-based nanoparticle uptake across many cancer models. We hypothesize that the expression of SLC46A3 will act as a predictive biomarker for therapeutic nanoparticles. METHODS: To test this hypothesis, we used two engineered model systems to probe the relationship between SLC46A3 expression and therapeutic response: lentiviral overexpression in a natively low-expressing melanoma model and genetic deactivation in a natively high-expressing breast cancer model. A library of FDA-approved and experimental therapeutic nanoparticles were screened in both models under a range of conditions. Liposomal formulations of chemotherapeutics were included with high and low surface functionalization of polyethylene glycol to investigate the impact of this ubiquitous ‘stealth’ polymer on our biomarker of interest. Solid lipid nanoparticles with nucleic acid cargo were also included. Orthogonal methods were used to probe these interactions and the therapeutic efficacy of nanotherapeutics, including pulsed dosing viability assays and label-free live-cell imaging. RESULTS: We found that SLC46A3 expression is a class-specific biomarker of lipid-based nanoparticle uptake and is predictive of distinctive patterns of response to therapy-loaded nanoparticles in both formulation and time-dependent manners. Additionally, we present a new technology for long-term, live cell imaging of nanoparticle uptake and trafficking that can discriminate mechanisms of cytotoxicity, accelerating the study of nano-bio interactions. These findings highlight a promising approach for the functional validation of nanoparticle-specific biomarkers using clinically relevant formulations that have the potential for rapid repurposing. Citation Format: Julianna Kenny-Serrano, Elizabeth B. Nelson, Gil Covarrubias, Namita Nabar, Joelle Straehla, Aanchal Gupta, Natalie Boehnke, Paula Hammond. Investigating solute carrier SLC46A3 to enhance nanotherapeutic delivery for cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 492.