Due to their accumulation in diseased over healthy tissue and their fluorescing properties, porphyrinicpigments have emerged as promising, minimally invasive drug candidates in the detection and treatment ofneoplastic and non-neoplastic diseases. In spite of their great potential in malignancy treatment, to dateonly six compounds received regulatory approval, all of them as photosensitizers for photodynamic therapy(PDT). However, due to the severe shortcomings of these drugs, leading scientists at photodynamictherapy conferences in 2003 and 2005 urged the community to design more effective photodrugs. Inresponse to this need, the proposed research is aimed at rational porphyrinic drug design with the long-termgoal to understand how photosensitizers have to be designed to enhance their efficacy andselectivity. In pursuit of this goal, it is the hypothesis that the design of more effective photosensitizersrequires their selective uptake and localization in mitochondria as these organelles are not only thepowerhouse of the cell, but also at the center of cell death. To test this hypothesis, the specific aims are to:I. Synthesize porphyrinic pigments and their metal complexes with recognized mitochondrialtargeting characteristics. We propose to prepare (a) porphyrins, chlorins, and phthalocyanines withcarefully selected properties and (b) related aluminum(lll), gallium(lll), indium(lll), and zinc(ll) complexes.II. Determine the ability of the porphyrinic pigments and their metal complexes to targetmitochondria. To uncover how structural features of the proposed photosensitizers will influencemitochondrial and cellular uptake, we will (a) measure their partition coefficients to predict uptake andphotosensitizing outcomes and (b) determine their uptake in functional vesicles, and when successful, inisolated mitochondria and cancer cell mitochondria to assess their mitochondrial targeting selectivity.III. Determine the photosensitizing efficiency of the porphyrinic pigments and their metal complexes.To better understand how structural characteristics of the proposed drug candidates will define theirphotosensitizing and phototoxic activities, we propose to determine (a) their abilities to cause oxidativedamage to isolated mitochondria and cancer cells, and (b) their photophysical and phototoxic properties.Relevance to Public Health: This project is to determine how photodrugs have to be designed to targetmitochondria, which will have far-reaching consequences for disease-specific therapeutic approaches. Thestudies hold the promise to empower PDT to turn into a clinically viable alternative in the simultaneousdetection, diagnosis, and treatment of diseases and to provide clinicians with a viable alternative in the fightagainst cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Minority Biomedical Research Support - MBRS (S06)
Project #
2S06GM052588-12
Application #
7229130
Study Section
Minority Programs Review Committee (MPRC)
Project Start
2007-01-01
Project End
2010-12-31
Budget Start
2007-01-10
Budget End
2007-12-31
Support Year
12
Fiscal Year
2007
Total Cost
$247,172
Indirect Cost
Name
San Francisco State University
Department
Type
DUNS #
942514985
City
San Francisco
State
CA
Country
United States
Zip Code
94132
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