Abstract 4918: Modeling polymersome delivery of anticancer therapeutics

Abstract

Abstract Polymersomes are synthetic nano-spheres that have the potential to specifically deliver anticancer therapeutics to tumor cells. They are an ideal delivery vector because of their nanometer size, structural architecture, stealth characteristics and the ability to attach tumor-specific ligands to their outer surface. The possible benefits of targeted polymersome drug delivery include reduced off-target toxic effects in healthy tissue and increased drug uptake by diseased tissue. In this study, in vitro experimentation is used to validate a mathematical description of polymersome-mediated therapy. Mathematical predictions are given for how the properties of polymersomes (size, membrane properties) and drug load affects rates of polymersome internalisation by tumor cells and therefore treatment efficacy. This allows for an optimisation of treatment design prior to clinical development. A key focus is polymersome-drug delivery via the clathrin-mediated endocytotic pathway. We include in our theoretical description specific details of this process (including specific binding ligands, receptor clustering, ligand tether length) and show how the characteristics of receptor targeting, number of ligands per polymersome, and polymersome concentration alters its uptake by tumor cells. The theoretical model is validated against in vitro studies using polymersome drug delivery to cell monolayers derived from different tumors. Next we describe how to scale-up the model to a tissue representation of the tumor mass. In this description the concentration of solutes (including oxygen and polymersomes) are tracked throughout the tumor using computational models based on realistic tumor vascular network structures with associated blood flow that have been constructed from confocal microscopic observations of a xenograft sub-cutaneously implanted tumor. Our results quantify the dependence of polymersome uptake rate and tumor distribution on polymersome properties and dosage. This multiscale approach identifies the key polymersome properties that influence treatment outcome and enables the treatment regime to be designed specifically in response to these features. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4918. doi:1538-7445.AM2012-4918