Drug Release of paclitaxel from Ace-DEX Particles: An Experimental and Mathematical Model

Microparticles (MPs) can be used to enhance local drug delivery and control release while protecting the drug from degradation and reducing off-target toxicity. Utilizing acetalated dextran (Ace-DEX) as a MP drug delivery platform allows for triggered release in acidic environments, such as the endosome of phagocytic cells, tumor microenvironments, and sites of inflammation. Ace-DEX is a biodegradable, acid-sensitive polymer that is formed when water-soluble dextran is chemically modified with acetal groups. Reaction time during polymer synthesis determines the ratio of cyclic to acyclic acetal groups, where a longer reaction time yields a higher cyclic acetal coverage (CAC). Since cyclic acetal groups are more stable and have increased resistance to hydrolysis over noncyclic groups, higher CAC Ace-DEX degrades more slowly than lower CAC polymer. In this work, the effect of CAC on the release of paclitaxel (PTX), a hydrophobic small molecule chemotherapeutic, was evaluated in a pH 7.4 environment to mimic physiological pH. A mathematical model to predict drug release from Ace-DEX MPs in vitro was developed based on a combination of relationships modelling simple diffusion and particle degradation via surface erosion. This model was evaluated against our lab’s previously published data for resiquimod release from Ace-DEX particles in pH 5 and pH 7.4 environments before adjusting parameter values to predict PTX release. Our initial results indicate that our mathematical model can accurately predict drug release from Ace-DEX particles, even while varying polymer CAC. To further evaluate our model, we have planned in vivo experiments with our particles.