LONG CIRCULATING HALF-LIFE AND HIGH TUMOR SELECTIVITY OF THE PHOTOSENSITIZER META-TETRAHYDROXYPHENYLCHLORIN CONJUGATED TO POLYETHYLENE-GLYCOL IN NUDE-MICE GRAFTED WITH A HUMAN COLON-CARCINOMA

In a model of nude mice bearing a human colon carcinoma xenograft, the biodistribution and tumor localization of meta-tetrahydroxyphenylchlo rin (m-THPC) coupled to polyethylene glycol (PEG) were compared with t hose of the free form of this photosensitizer used in photodynamic the rapy (PDT). At different times after i.v. injection of both forms of I -125-labeled photosensitizer, m-THPC-PEG gave on average a 2-fold high er tumor uptake than free m-THPC. In addition, at early times after in jection, m-THPC-PEG showed a 2-fold longer blood circulating half-life and a 4-fold lower liver uptake than free m-THPC. The tumor to normal tissue ratios of radioactivity concentrations were always higher for m-THPC-PEG than for free m-THPC at: any time point studied from 2 to 9 6 hr post-injection. Significant coefficients of correlation between d irect fluorescence measurements and radioactivity counting were obtain ed within each organ tested. Fluorescence microscopy studies showed th at m-THPC-PEG was preferentially localized near the tumor vessels, whe reas m-THPC was more diffusely distributed inside the tumor tissue. To verify whether m-THPC-PEG conjugate remained phototoxic in vivo PDT e xperiments were performed 72 hr after injection and showed that m-THPC -PEG was as potent as free m-THPC in the induction of tumor regression provided that the irradiation dose for m-THPC-PEG conjugate was adapt ed to a well-tolerated 2-fold higher level. The overall results demons trate first the possibility of improving the in vivo tumor localizatio n of a hydrophobic dye used for PDT by coupling it to PEG and second t hat a photosensitizer conjugated to a macromolecule can remain phototo xic in vivo. (C) 1998 Wiley-Liss, Inc.