Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors.
BACKGROUND
The existence of large pores in the blood-tumor barrier (BTB) of malignant solid tumor microvasculature makes the blood-tumor barrier more permeable to macromolecules than the endothelial barrier of most normal tissue microvasculature. The BTB of malignant solid tumors growing outside the brain, in peripheral tissues, is more permeable than that of similar tumors growing inside the brain. This has been previously attributed to the larger anatomic sizes of the pores within the BTB of peripheral tumors. Since in the physiological state in vivo a fibrous glycocalyx layer coats the pores of the BTB, it is possible that the effective physiologic pore size in the BTB of brain tumors and peripheral tumors is similar. If this were the case, then the higher permeability of the BTB of peripheral tumor would be attributable to the presence of a greater number of pores in the BTB of peripheral tumors. In this study, we probed in vivo the upper limit of pore size in the BTB of rodent malignant gliomas grown inside the brain, the orthotopic site, as well as outside the brain in temporalis skeletal muscle, the ectopic site.


METHODS
Generation 5 (G5) through generation 8 (G8) polyamidoamine dendrimers were labeled with gadolinium (Gd)-diethyltriaminepentaacetic acid, an anionic MRI contrast agent. The respective Gd-dendrimer generations were visualized in vitro by scanning transmission electron microscopy. Following intravenous infusion of the respective Gd-dendrimer generations (Gd-G5, N = 6; Gd-G6, N = 6; Gd-G7, N = 5; Gd-G8, N = 5) the blood and tumor tissue pharmacokinetics of the Gd-dendrimer generations were visualized in vivo over 600 to 700 minutes by dynamic contrast-enhanced MRI. One additional animal was imaged in each Gd-dendrimer generation group for 175 minutes under continuous anesthesia for the creation of voxel-by-voxel Gd concentration maps.


RESULTS
The estimated diameters of Gd-G7 dendrimers were 11 +/- 1 nm and those of Gd-G8 dendrimers were 13 +/- 1 nm. The BTB of ectopic RG-2 gliomas was more permeable than the BTB of orthotopic RG-2 gliomas to all Gd-dendrimer generations except for Gd-G8. The BTB of both ectopic RG-2 gliomas and orthotopic RG-2 gliomas was not permeable to Gd-G8 dendrimers.


CONCLUSIONS
The physiologic upper limit of pore size in the BTB of malignant solid tumor microvasculature is approximately 12 nanometers. In the physiologic state in vivo the luminal fibrous glycocalyx of the BTB of malignant brain tumor and peripheral tumors is the primary impediment to the effective transvascular transport of particles across the BTB of malignant solid tumor microvasculature independent of tumor host site. The higher permeability of malignant peripheral tumor microvasculature to macromolecules smaller than approximately 12 nm in diameter is attributable to the presence of a greater number of pores underlying the glycocalyx of the BTB of malignant peripheral tumor microvasculature.
Sarin
Hemant
H
National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA. sarinh@mail.nih.gov
Kanevsky
Ariel S
AS
Wu
Haitao
H
Sousa
Alioscka A
AA
Wilson
Colin M
CM
Aronova
Maria A
MA
Griffiths
Gary L
GL
Leapman
Richard D
RD
Vo
Howard Q
HQ
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology*; D003287:Contrast Media / Q000493:pharmacokinetics; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005119:Extravasation of Diagnostic and Therapeutic Materials; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D005910:Glioma / Q000098:blood supply* / Q000473:pathology*; D006207:Half-Life; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D055806:Microvessels; D008970:Molecular Weight; D053758:Nanoparticles; D010316:Particle Size; D011073:Polyamines / Q000493:pharmacokinetics; D016062:Porosity; D051381:Rats; D011916:Rats, Inbred F344; D013194:Staining and Labeling; D013997:Time Factors
D003287:Contrast Media; D050091:Dendrimers; C104700:PAMAM Starburst; D011073:Polyamines; D019786:Gadolinium DTPA