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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA109914-02
Application #
6926112
Study Section
Special Emphasis Panel (ZCA1-SRRB-9 (M1))
Program Officer
Liu, Guoying
Project Start
2004-07-21
Project End
2006-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$208,416
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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