In our initial study, an effective photosensitizer, HPPH (a chlorophyll-a derivative) was conjugated with Gd (lll)-aminophenylDTPA, an imaging agent. In vivo reflectance spectroscopy confirmed that tumor uptake of the HPPH-aminophenylDTPA Gd (III)conjugate was higher than that of HPPH alone in the radiation-induced fibrosarcoma (RIF) tumor of C3H mice. The subcutaneously implanted Ward colon carcinoma in rats showed markedly increased MRI signal at twenty-four hours after intravenous injection of the conjugate. Both in vitro (RIF tum6r cells) and in vivo (mice bearing RIF tumors) the conjugate produced significant efficacy. We have also synthesized a """"""""higher payload"""""""" molecule [two Gd (III)atoms per HPPH molecule] that also remained tumor-avid, PDT-active, and with improved MRI enhancing ability than the related mono-Gd (Ill) analog. Unfortunately, at the MRI dose (10 mmole/kg), these conjugates produced severe skin phototoxicity. However, replacing the hexyl- group of the pyropheophorbide-a with a PEG group, produced remarkable tumor enhancing at 8 hour postinjection, significant tumoricidal activity (80% of mice were tumor free on day 90) with reduced skin phototoxicity than the related hexyl- ether analogs. The poor water-solubility problem of these conjugates was resolved by liposomal formulation. We herein propose to prepare the Gd (III)DTP conjugate of those bacteriochlorin analogs that exhibit long wavelength absorption near 750-800 nm (for treating larger tumors) and are superior in terms of tumoravidity than HPPH. The comparative study of the conjugates wilt include: tumor uptake by in vivo reflectance spectroscopy, in vitro and in vivo PDT efficacy, tumor enhancement (imaging) by in vivo MRI, skin phototoxicity at the MR imaging doses, T1, T2 relaxitivity, intracellular localization, and general toxicology. Finally, we will define the biodistribution of the most effective conjugates by using C-14 labeled analogs of the most effective candidates. The development of a tumor-avid contrast medium for MRI would by jtself represent an important step in the diagnosis of cancer, but a dual function agent presents the potential for a diagnostic body scan followed by targeted photodynamic therapy, combining two modalities into a single cost-effective """"""""see and treat"""""""" approach.
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| Spernyak, Joseph A; White 3rd, William H; Ethirajan, Manivannan et al. (2010) Hexylether derivative of pyropheophorbide-a (HPPH) on conjugating with 3gadolinium(III) aminobenzyldiethylenetriaminepentaacetic acid shows potential for in vivo tumor imaging (MR, Fluorescence) and photodynamic therapy. Bioconjug Chem 21:828-35 |
| Pandey, Ravindra K; James, Nadine S; Chen, Yihui et al. (2010) Bifunctional agents for imaging and therapy. Methods Mol Biol 635:223-59 |
| Goswami, Lalit N; White 3rd, William H; Spernyak, Joseph A et al. (2010) Synthesis of Tumor-avid Photosensitizer-Gd(III)DTPA conjugates: impact of the number of gadolinium units in T1/T2 relaxivity, intracellular localization, and photosensitizing efficacy. Bioconjug Chem 21:816-27 |
