In vivo microscopic evaluation of the microvascular behavior of FITC-labeled macromolecular MR contrast agents in the hamster skinfold chamber.
OBJECTIVE
The extravasation properties of two macromolecular MR imaging contrast media (CM) in relation to structural differences of the terminal vascular bed were investigated to determine whether differentiation between normal (physiological) and tumor (pathological) tissue can be achieved by means of extravasation characteristics.


METHODS
Gd-DTPA-polylysine (50 kD, CM1) and Gd-DOTA cascade polymer (Gadomer 17; 20 kD, CM2) were labeled with fluorescein isothiocyanate (FITC) to enable in vivo fluorescence microscopy of the microcirculation. After implantation of a dorsal skinfold chamber and 7 days (range, 6-8) after induction of an amelanotic melanoma (A-Mel-3), 14 male hamsters weighing 85 g (range, 70-95 g) received 200 micromol/kg of CM1 by intravenous injection into the jugular vein. CM2 was similarly investigated after an interval of 24 hours. Fluorescence microscopy was performed in areas of subcutaneous tissue, striated muscle, and tumor tissue. Microscopic images were registered by a charge-coupled-device video camera and transferred to a video system. Distribution intensities of CM were evaluated on a digitally based measurement system. A control investigation was performed with FITC-dextran (150 kD).


RESULTS
Gd-DTPA-polylysine showed no extravasation into physiological tissue for the first 10 minutes after injection. After this period, however, the first signs of leakage became apparent. Gd-DOTA cascade polymer was extravasated after 5 minutes into the tumor-free tissue. In tumor capillaries, Gd-DTPA-polylysine could be detected in the extravasal space as well as in physiological tissue after 15 minutes. After injection of Gd-DOTA cascade polymer, direct leakage from tumor capillaries was observed, with a contrast maximum between tumor and surrounding tissue occurring 3 to 5 minutes after CM injection. Good delineation of tumor vascularization from striated muscle and subcutaneous tissue was achieved.


CONCLUSIONS
The CM studied showed different microvascular permeation properties. Faster leakage of Gd-DOTA cascade polymer was observed in areas with neoplastic tumor vessels, whereas extravasation in physiological tissue was detected after a period of 5 minutes. Gd-DTPA-polylysine demonstrated nonspecific leakage at later time points.
Schneider
G
G
Department of Diagnostic Radiology, University Hospital, Homburg/Saar, Germany. ragsne@med-rz.uni-sb.de
Seidel
R
R
Uder
M
M
Wagner
D
D
Weinmann
H J
HJ
Kramann
B
B
D000818:Animals; D002199:Capillary Permeability; D003287:Contrast Media; D006224:Cricetinae; D005119:Extravasation of Diagnostic and Therapeutic Materials; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005682:Gadolinium; D019786:Gadolinium DTPA; D006571:Heterocyclic Compounds; D008279:Magnetic Resonance Imaging; D008297:Male; D018328:Melanoma, Amelanotic / Q000175:diagnosis*; D008546:Melanoma, Experimental / Q000175:diagnosis*; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009942:Organometallic Compounds; D011897:Random Allocation; D012878:Skin Neoplasms / Q000175:diagnosis*; D013997:Time Factors; D014741:Video Recording
D003287:Contrast Media; D005456:Fluorescent Dyes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D005682:Gadolinium; D016650:Fluorescein-5-isothiocyanate; D019786:Gadolinium DTPA