SYNTHESES AND CELLULAR STUDIES OF NEW PHOTOSENSITIZERS FOR MEDICAL APPLICATIONS

Summary

Principal Investigator: Kevin M Smith
Abstract: DESCRIPTION (provided by applicant): This proposal focuses on the design, synthesis, development and optimization of promising tetrapyrrole photodynamic therapy (PDT) photosensitizers for use in diagnosis and treatment of cancer and age-related macular degeneration, for use against atherosclerotic lesions, in virus eradication from blood, bone marrow purging, and for inhibition of transmissible spongiform encephalopathies [bovine (BSE), sheep (scrapie) and human forms (Creutzfeld-Jacob disease)]. PDT is a binary therapy involving light-activation of a photosensitizer that has been targeted to specific cells. This results in the generation of singlet oxygen and other cytotoxic species that cause disease cell destruction while sparing healthy tissues. There are only two FDA-approved tetrapyrrole photosensitizers - Photofrin and Visudyne;both of these drugs are mixtures of compounds with limited selectivity for tumor tissue. It is proposed to develop new efficient organic synthesis methods to three types of tetrapyrrole photosensitizer: amino acid, peptide, and polyethylene glycol (PEG) conjugates of (1) chlorin e6, (2) isoporphyrins, and (3) benzoporphyrins and porphycenes. For the most part, the aim is to prepare cell- and specific organelle-targeted photosensitizers for the PDT treatment of diseased cells and plaque. The tetrapyrrole photosensitizers that are synthesized will be directed to specific organelles (preferably the mitochondria) by conjugation with one or more amino acid, short peptide, or PEG of defined length. Sufficient examples within any series of synthetic sensitizers will permit the investigation of mechanisms of cellular uptake, intracellular localization and cytotoxicity. Modes of cell death for the most promising sensitizers will also be determined. This research will result in structure/activity relationships that are crucial in the design and development of better and more effective PDT photosensitizers for use in cancer, cardiovascular, blood transfusion, bone marrow purging, and spongiform encephalopathy areas of medicine. Extensive preliminary studies have been completed and show viability of all aspects of the proposed research. The new drugs will also be investigated in house for cellular uptake, intracellular localization and dark/light toxicity, and with a consultant for modes of cell death (promoting apoptosis over necrosis);rapid modifications of approach will be possible based on feedback from the biological work. It will be possible to balance biochemical and physicochemical characteristics of drugs with their PDT efficacy, and to use mechanistic knowledge to develop more effective PDT sensitizers. It is intended to understand the mechanisms of cellular targeting, uptake and subcellular localization of new tetrapyrrole sensitizers and to develop new highly effective drugs for medical use. PUBLIC HEALTH RELEVANCE: The proposed program is of major relevance to public health because cancer remains the second most common cause of death in the USA, and macular degeneration, atherosclerosis, viral blood and bone marrow contaminants, and spongiform encephalopathies are major world problems. Photodynamic therapy (PDT) is a treatment modality already approved by the FDA that continues to gain clinical acceptance. The full potential can be realized only when new drugs with higher cellular selectivity and specificity are discovered, their mechanisms of biological action investigated, and their efficacy evaluated relative to existing modalities.
Funding Period: 2009-01-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc 6-Azahemiporphycene: a new member of the porphyrinoid family
    Federica Mandoj
    Department of Chemical Science and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
    Inorg Chem 48:10346-57. 2009
  2. pmc Syntheses and cellular investigations of 17(3)-, 15(2)-, and 13(1)-amino acid derivatives of chlorin e(6)
    R G Waruna Jinadasa
    Louisiana State University, Department of Chemistry, Baton Rouge, LA, USA
    J Med Chem 54:7464-76. 2011
  3. pmc β-Nitro derivatives of iron corrolates
    Sara Nardis
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
    Inorg Chem 51:3910-20. 2012
  4. pmc β-Nitro-5,10,15-tritolylcorroles
    Manuela Stefanelli
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, 00133 Roma, Italy
    Inorg Chem 51:6928-42. 2012
  5. pmc Role of propionates in substrate binding to heme oxygenase from Neisseria meningitidis: a nuclear magnetic resonance study
    Dungeng Peng
    Department of Chemistry, University of California, Davis, CA 95616, USA
    Biochemistry 51:7054-63. 2012
  6. pmc Synthesis and transformations of 5-chloro-2,2'-dipyrrins and their boron complexes, 8-chloro-BODIPYs
    Haijun Wang
    Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803 USA, Fax 1 225 578 3458
    Chemistry 20:5064-74. 2014
  7. pmc Influence of substrate modification and C-terminal truncation on the active site structure of substrate-bound heme oxygenase from Neisseriae meningitidis. A 1H NMR study
    Dungeng Peng
    Department of Chemistry, University of California, Davis, Davis, California 95616, USA
    Biochemistry 50:8823-33. 2011
  8. pmc Synthesis and characterization of free-base, copper, and nickel isocorroles
    Giuseppe Pomarico
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
    Inorg Chem 49:5766-74. 2010
  9. pmc Effect of overall charge and charge distribution on cellular uptake, distribution and phototoxicity of cationic porphyrins in HEp2 cells
    Timothy J Jensen
    Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
    J Photochem Photobiol B 100:100-11. 2010
  10. pmc Functionalization of the corrole ring: the role of isocorrole intermediates
    Luca Tortora
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
    Chem Commun (Camb) 47:4243-5. 2011

Detail Information

Publications22

  1. pmc 6-Azahemiporphycene: a new member of the porphyrinoid family
    Federica Mandoj
    Department of Chemical Science and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
    Inorg Chem 48:10346-57. 2009
    ....
  2. pmc Syntheses and cellular investigations of 17(3)-, 15(2)-, and 13(1)-amino acid derivatives of chlorin e(6)
    R G Waruna Jinadasa
    Louisiana State University, Department of Chemistry, Baton Rouge, LA, USA
    J Med Chem 54:7464-76. 2011
    ..It is hypothesized that the 13(1)-aspartylchlorin e(6) conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 15(2) derivative...
  3. pmc β-Nitro derivatives of iron corrolates
    Sara Nardis
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
    Inorg Chem 51:3910-20. 2012
    ....
  4. pmc β-Nitro-5,10,15-tritolylcorroles
    Manuela Stefanelli
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, 00133 Roma, Italy
    Inorg Chem 51:6928-42. 2012
    ..This effect is more pronounced when the nitro group is introduced at the 2-position, because in this case the conjugation is, for steric reasons, more efficient than in the 3-nitro isomer...
  5. pmc Role of propionates in substrate binding to heme oxygenase from Neisseria meningitidis: a nuclear magnetic resonance study
    Dungeng Peng
    Department of Chemistry, University of California, Davis, CA 95616, USA
    Biochemistry 51:7054-63. 2012
    ..The functional implications of the C-terminus in product release are discussed...
  6. pmc Synthesis and transformations of 5-chloro-2,2'-dipyrrins and their boron complexes, 8-chloro-BODIPYs
    Haijun Wang
    Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803 USA, Fax 1 225 578 3458
    Chemistry 20:5064-74. 2014
    ..The X-ray structures of eleven BODIPYs and two pyrroles are presented, and the spectroscopic properties of the synthesized BODIPYs are discussed. ..
  7. pmc Influence of substrate modification and C-terminal truncation on the active site structure of substrate-bound heme oxygenase from Neisseriae meningitidis. A 1H NMR study
    Dungeng Peng
    Department of Chemistry, University of California, Davis, Davis, California 95616, USA
    Biochemistry 50:8823-33. 2011
    ..7 kcal/mol, which is consistent with optimizing the His207-Asp27 H-bond. Implications of the active site "stress" for product release are discussed...
  8. pmc Synthesis and characterization of free-base, copper, and nickel isocorroles
    Giuseppe Pomarico
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
    Inorg Chem 49:5766-74. 2010
    ..This series of reactions effectively illustrates an isocorrole to corrole conversion upon reduction and reoxidation and was monitored by both electrochemistry and thin-layer spectroelectrochemistry...
  9. pmc Effect of overall charge and charge distribution on cellular uptake, distribution and phototoxicity of cationic porphyrins in HEp2 cells
    Timothy J Jensen
    Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
    J Photochem Photobiol B 100:100-11. 2010
    ..Our results suggest that MAP is the most promising PDT photosensitizer, and that both DADP-o and TRAP might find application as transport vehicles for therapeutics into cells...
  10. pmc Functionalization of the corrole ring: the role of isocorrole intermediates
    Luca Tortora
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
    Chem Commun (Camb) 47:4243-5. 2011
    ..Bromination of 3-nitro-5,10,15-triarylcorrole selectively provides two regioisomers, depending on the reaction pathway. An isocorrole species is the key intermediate to drive the reaction towards the 2-Br-17-nitro regioisomer...
  11. pmc Nitration of iron corrolates: further evidence for non-innocence of the corrole ligand
    Manuela Stefanelli
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
    Chem Commun (Camb) 47:4255-7. 2011
    ..This result is unprecedented for iron corrolates and further evidences the non-innocent character of the corrole ligand...
  12. pmc Amination reaction on copper and germanium β-nitrocorrolates
    Manuela Stefanelli
    Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
    Inorg Chem 50:8281-92. 2011
    ..Finally, the amination reaction was carried out on a Ge(IV) nitrocorrolate, giving in good yield the 2-amino-3-nitroderivative, which was structurally characterized by single crystal X-ray crystallography...
  13. pmc Phenyl derivative of iron 5,10,15-tritolylcorrole
    Sara Nardis
    Department of Chemical Science and Technologies, Universita di Roma Tor Vergata, 00133 Roma, Italy
    Inorg Chem 53:4215-27. 2014
    ....