"Two-Dimensional Chemotherapy Simulations Demonstrate Fundamental
Transport and Tumor Response Limitations Involving Nanoparticles"
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Abstract: We developed (Zheng et al., Bull Math Biol 2005) a multiscale, two-dimensional tumor simulator with the capability of describing tumoral lesion progression through the stages of diffusion-limited dormancy, neo-vascularization (angiogenesis) and consequent rapid growth and tissue invasion. Here (Sinek et al., Biomed Microdev 2004) we use this simulator to describe delivery of chemotherapeutic drugs to a highly perfused tumoral lesion and the tumor cells' response to the therapy. We perform 2-D simulations based on a rigorous parameter estimation that demonstrate fundamental convective and diffusive transport limitations in delivering anticancer drug into tumors, whether this delivery is via free drug administration (e.g., intravenous drip), or via 100 nm nanoparticles injected into the bloodstream, extravasating and releasing the drug that then diffuses into the tumoral tissue, or via smaller 1-10 nm nanoparticles that are capable of diffusing directly and targeting the individual tumor cell. Even in a best-case scenario involving: constant ("smart") drug release from the nanoparticles; a omogenous tumor of one cell type, which is drug-sensitive and does not develop resistance; targeted nanoparticle delivery, with resulting low host tissue toxicity; and for model parameters calibrated to ensure sufficient drug or nanoparticle blood concentration to rapidly kill all cells in vitro; our analysis shows that fundamental transport limitations are severe and that drug levels inside the tumor are far less than in vitro, leaving large parts of the tumor with inadequate drug concentration.