Evaluation of Drug-Loaded Gold Nanoparticle Cytotoxicity as a Function of Tumor Vasculature-Induced Tissue Heterogeneity.

The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-mediated drug delivery. This heterogeneity spans from the molecular (genomic, proteomic, metabolomic) to the cellular (cell types, adhesion, migration) and to the tissue (vasculature, extra-cellular matrix) scales. In particular, tumor vasculature forms abnormally, inducing proliferative, hypoxic, and necrotic tumor tissue regions. As the vasculature is the main conduit for nanotherapy transport into tumors, vasculature-induced tissue heterogeneity can cause local inadequate delivery and concentration, leading to subpar response. Further, hypoxic tissue, although viable, would be immune to the effects of cell-cycle specific drugs. In order to enable a more systematic evaluation of such effects, here we employ computational modeling to study the therapeutic response as a function of vasculature-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated interacting with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results quantify the influence that varying levels of tumor vascular density coupled with the drug strength have on nanoparticle uptake and washout, and the associated tissue response. The drug strength affects the proportion of proliferating, hypoxic, and necrotic tissue fractions, which in turn dynamically affect and are affected by the vascular density. Higher drug strengths may be able to achieve stronger tumor regression but only if the intra-tumoral vascular density is above a certain threshold that affords sufficient transport. This study establishes an initial step towards a more systematic methodology to assess the effect of vasculature-induced tumor tissue heterogeneity on the response to nanotherapy.