Physical modeling of drug delivery in solid tumors

Abstract

Effective delivery of drugs is a major concern in cancer treatment. For a good treatment response, systemically administrated drugs must reach cancer cells in su - cient amounts, and not induce intolerable toxicity in healthy tissues. Toxic side-effects are the major dose-limiting factors in cancer treatment, and they often lead to the suspension of the treatment. Anti-cancer drugs that are effective in the laboratory models may lose potency when systemically administrated in humans. The reason is that, drug particles have to overcome several barriers during their journey to reach cancer cells. Impaired and heterogeneous blood supply, elevated interstitial pressure, and di usional barriers in tumors, all limit the amount of drug that reaches the cancer cells. A good understanding of drug transport in tumors is necessary to improve the effiency of drugs and design tumor-targeted delivery strategies. In this thesis, we study this problem through biophysically-founded mathematical models of drug delivery. We focus on blood ow and interstitial fluid ow in tumors, and study how they in uence the delivery of drug particles. Interestingly, the hyper-permeability of tumor vessels, inhibits the delivery of drug particles. We study this seemingly paradoxical phenomenon, and also evaluate the potential benefits of the vascular normalization treatment, which aims to improve drug delivery by normalizing the tumor vessels. We also study how blood flow patterns are impaired in tumors, and how this in fluences the distribution of drug particles. In our simulations, instead of the conventional cytotoxic drugs, we focus on the delivery of nanoparticles as they form the basis of intelligent treatments in cancer.