During the current and prior PO1 funding, Project 1 has made certain important discoveries: (i) on the basis of SAR and QSAR studies, we were able to select the highly effective PS from pyropheophorbide-a (660 nm), purpurinimides (700 nm) and bacteriopurpurinimide (800 nm) series and one of the PS (HPPH) is currently in Phase II human clinical trials, (ii) among the carbohydrate-PS, we discovered that, compared to HPPH (localized in mitochondria), the corresponding galactose conjugate (lysosomal localization) exhibits improved photodynamic activity in certain tumors with minimal skin phototoxicity (iii) in the pyro-series, compared to HPPH, the corresponding Indium analog (In-HPPH), which also localizes in mitochondria showed 8-fold increase in efficacy and (iv) in the pyro- series, an 1-124 labeled PS showed the potential of imaging tumor and tumor metastases, which certainly warrants further investigation. In a separate study, we showed that tumor-avid photosensitizers (e.g. HPPH) can be used as a vehicle to deliver non tumor-specific fluorophores to target sites for fluorescence imaging. In particular, conjugation of a cyanine dye to HPPH resulted in an efficient optical imaging and PDT agent. However, a significant difference between the imaging and PDT dose dose was observed (the therapeutic dose was -10-fold higher than the required imaging dose). Therefore, the conjugation of the highly potent In-HPPH or the metallated analogs of other PS selected on the basis of SAR studies with the cyanine dye could generate optimized compounds for fluorescence tomography and phototherapy. For selecting a compound with optimal imaging and therapeutic potential for Phase I human clinical trials, the aims of the project are as follows:
Aim 1 : To synthesize galactose conjugated long-wavelength absorbing photosensitizers (selected on the basis of SAR studies) and investigate the impact of the galactose moiety in PDT efficacy;
Aim 2 : To synthesize and investigate the effect of certain metallated long wavelength photosensitizers (selected from Aim 1, with or without a carbohydrate moiety) in optimizing their photosensitizing ability;
Aim 3 : To synthesize metallated 1241-photosensitizers (selected from Aim 2) and the corresponding cyanine dye conjugates for developing multifunctional agents for tumor imaging (PET, fluorescence tomography) and PDT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055791-19
Application #
8376638
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
19
Fiscal Year
2012
Total Cost
$302,844
Indirect Cost
$118,967
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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