Two-Dimensional Chemotherapy Simulations Demonstrate Fundamental Transport and Tumor Response Limitations Involving Nanoparticles

摘要

We present multiscale computer simulations of the delivery of chemotherapy and the tumor cells' response to the therapy. Even in a best-case scenario of: constant drug release from the nanoparticles; one cell type, which is drug-sensitive and does not develop resistance; targeted nanoparticle delivery; and for model parameters calibrated to ensure sufficient drug or nanoparticle blood concentration to rapidly kill all cells in vitro; our analysis shows that convective and diffusive transport limitations in vivo 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. The in vivo rate of tumor shrinkage is several orders of magnitude less than in vitro, and after some shrinkage the tumor may achieve a new mass equilibrium far above detectable levels. Adjuvant anti-angiogenic therapy "normalizing" the vasculature may ameliorate transport limitations, although leading to unwanted tumor fragmentation.