Transport Physics of Nanoparticle Migration in PC3 Tumors Influenced by Local or Whole Body Hyperthermia

Abstract

Advancements in nanotechnology have revolutionized cancer treatment for targeted delivery of therapeutic agents. It is well known that heating itself may damage tumor cells, and change the structures of capillary and interstitial space inside tumors. Mild heating with only several degrees of Celsius of temperature elevations has been used to facilitate drug/nanoparticle delivery to targeted tumors. On the other hand, high intensity heating induces permanent thermal damage in tumors also may alter the porous structure inside the tumor, thus, affecting nanoparticle distribution during the heating. This PhD dissertations research focuses on development of a mathematical simulation platform to understand how local or whole body hyperthermia changes transport properties in tumors, thus, inducing nanoparticle migration via convection and diffusion. Three projects are included in this research. The first project is focused on development of a heat transfer model to investigate how temperature elevation and heating protocol design are significantly affected by nanoparticle distribution and thermal damage models. In the second project, a coupled theoretical framework consisting of nanoparticle migration in a porous medium model and temperature elevation in a heat transfer model was developed to evaluate possible nanoparticle migration/redistribution during local heating. Results have shown nanoparticles diffuse from high concentration region to low concentration region during heating, resulting in a larger nanoparticle distribution volume than that before the heating. The objective of the third research project is to investigate the effect of hyperthermia-induced improvement of hydraulic conductivity and lymphatic function on both tumoral IFP reduction and nanoparticle delivery to PC3 tumors. We developed a theoretical model for nanoparticle transport in a tumor incorporating Starling's law, Darcy's law, transient convection and diffusion of chemical species in porous media, and nanoparticle accumulation in tumors. Results have shown that both mechanisms were effective to decrease the IFP at the tumor center. Due to the IFP reductions at the tumor center and/or local blood perfusion increases induced by whole body hyperthermia, the final amount of accumulated nanoparticles in the tumor increased by more than 35%-95% when compared to the control without heating.