Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size.
Molecular size is one of the key determinants of transvascular transport of therapeutic agents in tumors. However, there are no data in the literature on the molecular size dependence of microvascular permeability in tumors. Therefore, we measured microvascular permeability to various macromolecules in the human colon adenocarcinoma LS174T transplanted in dorsal skin chambers in severe combined immunodeficient mice. These molecules were fluorescently labeled and injected i.v. into mice. The microvascular permeability was calculated from the fluorescence intensity measured by the intravital fluorescence microscopy technique. The value of permeability varied approximately 2-fold in the range of molecular weight from 25,000 to 160,000. These data indicate that tumor vessels are less permselective than normal vessels, presumably due to large pores in the vessel wall. The transport of macromolecules appears to be limited by diffusion through these pores. The cutoff size of the pores was estimated by observations of transvascular transport of sterically stabilized liposomes of 100-600 nm in diameter. We found that tumor vessels in our model were permeable to liposomes of up to 400 nm in diameter, suggesting that the cutoff size of the pores is between 400 and 600 nm in diameter.
Yuan
F
F
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Dellian
M
M
Fukumura
D
D
Leunig
M
M
Berk
D A
DA
Torchilin
V P
VP
Jain
R K
RK
D000818:Animals; D002199:Capillary Permeability; D003208:Concanavalin A / Q000737:chemistry / Q000493:pharmacokinetics; D004058:Diffusion; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D016513:Mice, SCID; D008970:Molecular Weight; D009369:Neoplasms / Q000098:blood supply*; D010047:Ovalbumin / Q000737:chemistry / Q000378:metabolism; D014183:Transplantation, Heterologous
D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008081:Liposomes; D003208:Concanavalin A; D010047:Ovalbumin