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Radioprotective and Radiorecovery Agents

#A-1321


Radioprotective and Radiorecovery Cu and Mn Nicotinyl-L-Amino Acid Schiff Base Chelates

Tech Area / Field

  • BIO-RAD/Radiobiology/Biotechnology

Status
8 Project completed

Registration date
25.07.2005

Completion date
25.02.2010

Senior Project Manager
Mitina L M

Leading Institute
The Scientific Centre of Radiation Medicine and Burns, Armenia, Yerevan

Collaborators

  • University of Arkansas for Medical Sciences, USA, AR, Little Rock\nMcMaster University, Canada, ON, Hamilton

Project summary

importance and profound concern for present-day society. Worldwide medical uses of radiation and poor or absent control of nearly spent industrial radiation sources are still the most likely causes of potential accidental or terrorist mediated exposures to ionizing radiation affecting workers and the public. Coupled with these circumstances there is also an increased probability that terrorists might use these nearly spent radioactive materials as “dirty bomb materials” and further increase these risks.

Currently available radioprotectors are classified as thiolamines with antioxidant reactivity. However, they are highly toxic at effective doses. Further, they are very polar compounds with seriously limited potential to penetrate cell membranes or the blood-brain-barrier, which prevents them from reaching intracellular sites required for their pharmacological efficacy. Their general use is further compromised by the requirement that they must be used in radioprotective therapy before irradiation and they have absolutely no radiorecovery activity when used to treat radiation injury after irradiation injury has occurred.

In a search for non-toxic and highly effective agents with both radioprotective and radiorecovery activities, when treatment is given either before or after irradiation respectively, studies of lipophilic essential metalloelement chelates, capable of passively crossing cell membranes and the blood-brain-barrier as radioprotectants and radiation recovery agents seems worthwhile and offers a promising approach to preventing and overcoming the pathological effects of ionizing radiation using metalloelements required by all human cells. In this respect development of possible highly effective non-toxic radioprotectant and radiorecovery agents convenient for wide therapeutic usage would re-establish health in cases of radiation exposure and provide security, which are currently key issue of strategic significance for every country.

Consistent with recently published literature and scientific principals as well as results of our previously funded ISTC A-361 Project devoted to the synthesis and study of antioxidant and radiation protective activities of N-substituted amino acid ethyl ester Schiff base essential metalloelement chelates, we have set new goals for the synthesis of less toxic and more effective chelates with both radioprotectant and radiorecovery activities as outlined below:

  • Synthesis of nicotinyl-L-tyrosine and nicotinyl-L-tryptophan;
  • Synthesis of Cu(II) and Mn(II) nicotinyl-L-amino acid chelates;
  • Determine the concentration related radioprotective and radiorecovery activities of Schiff bases, to determine whether or not they possess these activities and distinguish these ligands form their chelates using different cellular and animal models of ionizing irradiation injury to measure relative efficacies and toxicities as they may occur;
  • Determine biophysical, biochemical, hematological, immunological, and cytogenetic mechanisms of action of these compounds;
  • Compare relative activities obtained with a suitable pharmaceutical formulation of these compounds prepared with a pharmaceutically acceptable suspending agent, 4 % propylene glycol-1.4 % polyvinyl alcohol-saline for use in administering effective amounts of these compounds, for tissue and cellular repair of radiation injuries. Proper formulations will also be developed for effective oral and subcutaneous application of these compounds.

In compliance with the aims of the Project the following tasks will be performed using synthesized metallochelates and their parent ligands:
  • Chemical synthesis of nicotinyl-L-tyrosine and nicotinyl-L-tryptophan, using nicotinylaldehyde and amino acid condensation reactions, as well as their Cu(II) and Mn(II) metallochelates using coordination reactions with the corresponding acetates.
  • Defining structural characteristics of the synthesized compounds with regard to their melting or decomposition point, elemental analyses, including atomic absorption, ESR, IR, UV-Vis spectra.
  • Determine the influence of storage time, humidity, temperature, and light on stability of these compounds.
  • Determine spectrophotometrically the concentration related anti-radical and anti-oxidant reactivities of these compounds with 1,1-diphenyl-2-picrylhydrazil radical (DPPH) in methanol. Determine free radical scavenging activity of the compounds synthesized based on an antioxidant-sensitive inhibition of a photo-induced chemiluminescence accompanying the oxidation of luminol in compare with the standard substances.
  • Determine the antibacterial activities of these compounds using cultures of Escherichia coli and Enterococcus hirae. Bacterial growth and survival under anaerobic and aerobic conditions as well as at alkaline and acidic pH values; bacterial membrane ion-transporting properties, membrane surface effects, membrane associated enzyme activities (ATPase, formate dehydrogenase, hydrogenase), and energy-transduction proton-motive force will concomitantly be analyzed.
  • Determine radioprotective and radiorecovery properties of these compounds by measuring survival and mean life-times over a 30 day period post-irradiation of white inbred rats exposed to LD50/30 or LD100/30 doses of X-irradiation and treated with 0 (vehicle), 20, 40, or 80 mg of compound per kg of body mass administered subcutaneously or orally before or after irradiation respectively.
  • Radioprotective and radiorecovery effects of these pharmacological interventions will also be analyzed based upon hematological, biochemical, immunological, biophysical, and cytogenetic analyses in irradiated and treated rats throughout the post irradiation period.
    • Hematological indices will include determinations of hematocrit; hemoglobin; erythrocyte, leukocyte, and platelet counts as well as indices of blood clotting.
    • Indices of lipid peroxidation in blood plasma and erythrocyte membranes, the content of middle-molecular mass peptides, and total protein in animal blood plasma will also be determined;
    • The activation state of the immune system: the concentration of circulating immune complexes; specifics of complement activation by total classical complement mediated sheep red blood cell hemolytic activity (THAC) and alternative complement mediated hemolytic activity (AHAC) as well as measurements of the concentration of cytokines;
    • The determination of antioxidant capacity of both lipid-soluble and water-soluble non-enzymatic antioxidants will be performed throughout the post irradiation period in animal blood plasma as key components of the endogenous antioxidant defenses.
    • The level of chromosome re-arrangements and the proliferative activity of bone marrow cells will be determined as the primary cytogenetic indices in characterizing the radioprotectant and radiorecovery activities of the test compounds.
  • The metalochelates may also be suspended with biodegradable and biocompatible low-molecular-mass polymers: Polyglucinum, a solution of partially hydrolyzed middle molecular mass fraction of dextran in saline and Haemodesum, a saline solution containing 6% low molecular mass polyvinyl pyrrolidone and Na, K, and CL. The presence of these low-molecular-mass polymers in pharmaceutical formulations will serve as depot forms for compounds studied and will facilitate an increase in duration of the anti-radiation action of compounds used in enteral and parenteral treatment due to gradual release of the active component from these formulations.

These proposed studies are suggested to provide new impetus for development of amino acid and peptide Schiff bases, which have not been examined for radiation protection and recovery activities using our systems or other biosystems. After completion of medical and biological tests, effective radioprotective and radiorecovery formulations will be selected for further study in humans. Results thus acquired will become the basis for suggested effective chemical agents for probable application in medical practice in different pharmaceutical formulations, which would ensure a decrease and recovery from the damaging effects of ionizing radiation. It is anticipated that these formulations will be less toxic in comparison with the well-known existing anti-radiation drugs and offer potential of favorable biochemical and pharmacological effects for use in radiation protection and radiation recovery. These ready-for-use radioprotective and radiorecovery formulations are expected to be inexpensive to manufacture and stable.

A self sufficient scientific research team of highly qualified scientists formerly engaged in programs of USSR Ministry of Defense and young specialists is in place at the Sector of Radiation Medicine and Burns of the CTOBR; Ministry of Health, Armenia.

Project fulfillment will allow researchers to use knowledge and experience gained in closed laboratories of defense for solutions of peaceful medical and biological tasks. The Project will also provide these researchers with an opportunity to reorient their research activities away form weapons development and toward fulfillment of works for peaceful purposes. Weapons scientists make up 57.6% of the total number of Project participants. The proposed study will also facilitate the integration of Armenian, Canadian, and U.S. scientists into the broader International Scientific Community.

Research performed in the framework of this Project will support the transition to market-based economy responsive to civilian needs. Research outcomes of the Project proposed for the development of new highly effective and less toxic radioprotective and radiorecovery agents will make an essential contribution to the solution of national and global problems associated with international security and healthcare.

These scientific results leading to the elaboration of new anti-radiation injury medicines, available as ready-for-use pharmaceutical formulations will be of interest to researchers engaged in radiobiological investigations at Centers affiliated with the Armed Forces, Department of Defense, Department of Energy, the Drug Industry as well as the Ministry of Health, National Health Care System, and Scientific Centers engaged in research in the sphere of radiation medicine, inorganic and organic chemistry, and biotechnology.


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