REGULATION OF TRANSPORT PATHWAYS IN TUMOR VESSELS - ROLE OF TUMOR TYPE AND MICROENVIRONMENT

Novel anti-neoplastic agents such as gene targeting vectors and encaps ulated carriers are quite large (approximately 100-300 nm in diameter) . An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transpo rt and its modulation by the microenvironment. One human and five muri ne tumors including mammary and colorectal carcinomas, hepatoma, gliom a, and sarcoma were implanted in the dorsal skin-fold chamber or crani al window, and the pore cutoff size, a functional measure of transvasc ular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore c utoff size ranging from 200 nm to 1.2 mu m. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after h ormone withdrawal. Vessels induced in basic fibroblast growth factor c ontaining gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major im plications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) de livery may be reduced during tumor regression induced by hormonal abla tion, and (iii) permeability to a molecule is independent of pore cuto ff size as long as the diameter of the molecule is much less than the pore diameter.