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Role of Neovasculature and Vascular Permeability on the Tumor Retention of Photodynamic Agents¹

Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

A variety of photodynamic sensitizers (chloroaluminum sulfonated phthalocyanine, tetraphenyl porphine sulfonate, mono-L-aspartyl chlorin e₆, Photofrin, chlorin e₆, and Uroporphyrin dihydrochloride I) were characterized by their ability to be retained in EMT-6 tumors growing in BALB/c mice. Two properties uniquely associated with tumors, proliferating neovasculature and vascular permeability, were tested for their relative importance in retaining the photosensitizer. A chick embryo model was used to compare photosensitizer uptake/retention in proliferating and nonproliferating neovasculature with retention in proliferating nonvascular tissue. Our results provide evidence that photosensitizers which are preferentially retained by tumors have a selective affinity for proliferating neovasculature. The chloroaluminum sulfonated phthalocyanine and tetraphenyl porphine sulfonate compounds possess the greatest affinity for proliferating neovasculature relative to nonvascular tissue, while the phthalocyanine has the largest tumor/normal differential in vivo of all the photosensitizers tested. Chlorin e₆ and uroporphyrin dihydrochloride I were the only photosensitizers which were not retained in greater amounts by tumor tissues relative to normal tissues. Using a delayed-type hypersensitivity reaction, extended and constant vascular permeability was induced in BALB/c mice. Vascular permeability was quantitated by Evans blue extraction from the delayed-type hypersensitivity sites. Interestingly, leaky vessels alone did not result in photosensitizer retention, as seen with tumors. These data demonstrate that tumorretained photosensitizers possess a selective affinity for proliferating neovasculature and that vascular permeability alone is not sufficient to retain these sensitizers.

¹ This work was supported by ONR Contract N00014-86-K0117, Department of Energy DE-FG02-91-ER61228, and NIH RO1 AR23595. W. G. R. received support from the Ford Foundation postdoctoral fellowship and NIH postdoctoral fellowship (GM13763-02).

² Present address: Howard Hughes Medical Institute, Center for Cellular and Molecular Medicine, Department of Pathology, University of California-San Diego School of Medicine, La Jolla, CA 92093.

³ To whom requests for reprints should be addressed.

Received 7/ 8/91. Accepted 10/29/91.

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