Pharmacokinetic/Pharmacodynamics Modeling of Drug-Loaded PLGA Nanoparticles Targeting Heterogeneously Vascularized Tumor Tissue

Purpose Nanoparticle-mediated drug delivery and efficacy for cancer applications depends on systemic as well as local microenvironment characteristics. Here, a novel coupling of a nanoparticle (NP) kinetic model with a drug pharmacokinetic/pharmacodynamics model evaluates efficacy of cisplatin-loaded poly lactic-co-glycolic acid (PLGA) NPs in heterogeneously vascularized tumor tissue. Methods Tumor lesions are modeled with various levels of vascular heterogeneity, as would be encountered with different types of tumors. The magnitude of the extracellular to cytosolic NP transport is varied to assess tumor-dependent cellular uptake. NP aggregation is simulated to evaluate its effects on drug distribution and tumor response. Results Cisplatin-loaded PLGA NPs are most effective in decreasing tumor size in the case of high vascular-induced heterogeneity, a high NP cytosolic transfer coefficient, and no NP aggregation. Depending on the level of tissue heterogeneity, NP cytosolic transfer and drug half-life, NP aggregation yielding only extracellular drug release could be more effective than unaggregated NPs uptaken by cells and releasing drug both extra- and intra-cellularly. Conclusions Model-based customization of PLGA NP and drug design parameters, including cellular uptake and aggregation, tailored to patient tumor tissue characteristics such as proportion of viable tissue and vascular heterogeneity, could help optimize the NP-mediated tumor drug response.