Overcoming Transport Barriers in Drug Delivery to Tumors

The natural defenses of the human body create many challenges for chemotherapeutics to reach their intended targets. In order to be effective, chemotherapy agents must travel through the blood vessels, extravasate out of the vessels into the interstitium and diffuse through tumor cells without being phagocytosed in the reticuloendothelial system, binding to proteins in serum or being metabolized by red blood cells. A largely overlooked limitation of traditional chemotherapy delivery is the transport within the tumor microenvironment. The unstructured and limited vasculature in tumors makes them a very heterogeneous microenvironment causing inconsistencies in the delivery and distribution of drugs. Because of these heterogeneities, in traditional chemotherapy administration, drugs are only transported to perfused regions. One approach to overcome these transport barriers is to utilize nanocarriers to selectively target and deliver drugs to malignant tumor cells.

Here, we present a mathematical model that describes in vitro cytotoxicity assay data for parental and multi-drug resistant human hepatocellular carcinoma cell lines using the common anticancer drug, doxorubicin. The mathematical model was solved analytically and fit to data for both free doxorubicin and doxorubicin-loaded protocells to obtain parameters describing cell death rate and delay time. The information from this model and experimental data can be used to predict the fraction of tumor volume that will be killed.