(190b) 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.