Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment.
Novel anti-neoplastic agents such as gene targeting vectors and encapsulated 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 transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular 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 cutoff size ranging from 200 nm to 1.2 microm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
Hobbs
S K
SK
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St., Cox-7, Boston, MA 02114, USA.
Monsky
W L
WL
Yuan
F
F
Roberts
W G
WG
Griffith
L
L
Torchilin
V P
VP
Jain
R K
RK
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D008081:Liposomes; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000473:pathology* / Q000648:ultrastructure; D008863:Microspheres; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology* / Q000628:therapy / Q000648:ultrastructure; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009919:Orchiectomy
D008081:Liposomes; D016222:Fibroblast Growth Factor 2