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.

Public Health Relevance

The development of a tumor imaging agent or a photosensitizer with optimal activity by itself represents an important step, but a multifunctional agent as proposed in this study illustrates a first example of using a cost effective single molecule for tumor detection by fluorescence tomography/PET imaging and treatment by photodynamic therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055791-17
Application #
8034272
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-01-31
Budget End
2011-01-30
Support Year
17
Fiscal Year
2010
Total Cost
$312,124
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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Baran, Timothy M (2016) Recovery of optical properties using interstitial cylindrical diffusers as source and detector fibers. J Biomed Opt 21:77001
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