Our previous studies in experimental brain tumors and in patients with brain tumors have shown variability in the rate of blood-to-tissue transport of water-soluble compounds. In addition to these physiological studies, our ultrastructural studies of brain tumor vessels have demonstrated many qualitative differences from normal brain capillaries. At the present time there is no satisfactory explanation to indicate which of the ultrastructural changes are responsible for the changes in permeability. The overall aim of this project is to integrate and unify the physiological and morphological observations.
Our Specific Aims i nclude: 1) To quantify those parameters in brain tumor capillary structure that correlate with blood-to-tissue transport. This will be done with quantitative morphometric studies at both the light (LM) and electron microscopic (EM) levels. 2) We plan to use quantitative autoradiographic measurements of blood-to-tissue transfer, and EM measurements of capillary morphometry in individual ASV-induced rat brain tumors to test our hypotheses about which structural features are responsible for increased rates of capillary transport in brain tumors. 3) Variation in endothelial cell surface charge can influence the rate of transcapillary transport of large or highly charged compounds. We will use EM techniques to determine the role of surface charges on endothelial cell surface microdomains on the rate of transcapillary transport. 4) Marked differences between the rates of blood flow and permeability exist when the same experimental brain tumor is transplanted into brain or systemic tissues. We plan to study the influence of host tissue on brain tumor vascularization. We anticipate that these studies will provide a unified theory about the capillary mechanisms that influence drug delivery to brain tumors, and in addition, by defining which capillary abnormalities are responsible for the changes in blood-to-tissue transport, we hope to identify capillary structural features upon which we can concentrate attempts to manipulate and increase drug delivery to brain tumors.
