Development of New Effective Low Toxic Polymeric Radioprotectors and Radioactive Metal Binding Agents on the Basis of Biocompatible Copolymers of N-Vinyl-2-Pyrrolidone and Vinyl Alcohol
Tech Area / Field
- CHE-POL/Polymer Chemistry/Chemistry
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Yerevan Institute "Plastpolymer", Armenia, Yerevan
- The Scientific Centre of Radiation Medicine and Burns, Armenia, Yerevan
- Gwangju Institute of Science and Technology, Korea, Gwangju-si\nDSM Food Specialities, The Netherlands, Delft\nUniversity of Minnesota, USA, MN, St Paul
Project summaryThe Project aim. The purpose of the proposed Project is the development of new group effective and low toxic polymeric radioprotectors of the short-term and prolonged action, as well as therapeutical radioactive metal binding agents on the basis of biocompatible copolymers of N-vinyl-2-pyrrolidone (VP) and vinyl alcohol (VA) for potential use in medicine.
Discovery of low toxic medical agents that protect inpidual from radiation injury on the earth and long-term influence of ionizing radiation in space, as well as in radiotherapy remains a very actual problem. Effective radioprotective agents (radioprotectors) are necessary for preventive protection of the personnel of atomic power stations, when working with radioactive sources in the industry and scientific researches, at beam therapy in oncological practice, at piloted space flights, and also in extreme situations, such as accidents or possible terrorist attacks with using “dirty bomb”. Thiolamines are efficient radioprotectors against sparsely ionizing radiations, such as x- or γ-rays. Amifostine is perhaps the most effective of these radioprotectors. One of the promising strategies to suppress the toxicity and to increase the time efficiency of thiolamines involves their incorporation into biocompatible polymers.
The project’s influence on progress in this area. The proposed Project is devoted to the development of new polymeric medicinal agents for human protection from both external and internal irradiation. The strategy for the synthesis of polymeric radioprotective substances involves two approaches. The first is the preparation of target polymeric compounds via modification of anhydride units of VP - maleic anhydride (VP-МА) and VP - 2,3-dimethylmaleic anhydride (VP-DMMA) copolymers with known radioprotectors amifostine, N - (2-mercaptopropionyl) glycine and some of bioactive low-molecular substances. The second way is the immobilization of drugs amifostine, N - (2-mercaptoethyl) 1,3-diaminopropane (WR-1065) and cysteamine on copolymers of VP - maleic acid (VP-MAc) through ionic bonds. Our aim is to develop new water-soluble macromolecular prodrugs of known low-molecular radioprotectors and other bioactive compounds for enhancing the therapeutic efficacy. Controlled gradual release of native drugs from polymeric conjugates by hydrolysis will provide prolonged radioprotective action and low toxicity of these compounds due to prolonged circulation in the blood. Internal irradiation occurs as a result of inhalation or skin penetration of radioactive particles. Some of the derivatives of VP and VA copolymers will be studied as radioactive metal ion (90Sr2+, 60Co2+, 137Cs+) binding agents. Thus, proposed Project will promote the development of polymeric drug delivery systems, polymer - radioprotective drug conjugates and radioactive metal binding therapeutic agents areas.
Novelty of proposed research consists in synthesis and characterization of new macromolecular prodrugs on the basis of biocompatible copolymers of VP - MAc and VA which will be studied both in vivo and in vitro for their possible applications in medicine as external and internal radioprotective agents.
The participants’ expertise. The participants of the Project from the Yerevan Institute “Plastpolymer” have considerable experience in the synthesis and characterization of water-soluble copolymers of vinylacetate, VP, MA, MAc and VA. They have participated in previous ISTC Projects A-183, A-1243, A-1243.2. Studying of radioprotective properties of polymeric compounds will be performed at the Scientific Centre of Radiation Medicine and Burns, personnel of which has extended experience in investigation of radioprotectors action mechanism.
Expected results and their application. The work proposed in the given Project, concerns a category "applied researches" and will allow to receive following main results:
- The development of new highly effective and low toxic polymeric radioprotectors of the short-term and prolonged anti-radiation action on the base of derivatives of VP -MAc copolymers for protection against radiation injury and for potential use in cancer radiotherapy
- The design of new polymeric biocompatible radioprotective drug –delivery carriers
- Working out of new polymeric therapeutic agents on binding and removal radioactive compounds of 137Cs, 60Co and 90Sr from the human body for potential use in medicine
Expected results will promote the development of area of polymeric drug delivery systems and will bring the certain contribution to the sphere of biocompatible polymers and polymeric medicinal agents.
Meeting the ISTC goals and objectives.
Funding of this Project will provide partial or a full employment of the highly qualified scientists and experts from the Yerevan Institute “Plastpolymer” and SCRMB formerly connected with the weapon and will direct their potential and experience to realization of peace problems in the field of medicine, radiology, pharmacology and human protection against an ionizing radiation. It will promote also to an exchange of experience between scientists from the different countries and integration of Project participants into the International Scientific Community. Weapons scientists make up 48% of the total number of Project participants.
Scope of activities. According to the aims of the Project the following tasks will be performed:
- Chemical synthesis of VP - МА and VP - DMMA copolymers with definite composition and average MW (5000-30000 Da) by radical polymerization of comonomers in anhydrous organic solvent in the presence of initiator
- Synthesis and characterization of new water-soluble derivatives of VP and MAc copolymers, containing the residues of drugs amifostine, WR-1065, cysteamine and N - (2-mercaptopropionyl) glycine
- Studying the kinetics of regeneration of amifostine from the polymeric conjugates in a 0.05 M phosphate buffer solution (pH 4.0, 5.0, 6.0, 7.4 and 9.0) at 37 ˚C with a concentration of 4.0 – 20.0 mg/ml of conjugate
- Studying radioprotective and radiorecovery efficiency of new derivatives of VP - MAc copolymers by measuring survival, mean life-times and bone marrow suppression over a 30 days period of post-irradiation of white mice exposed to LD 100/30 or LD 50/30 doses of X-irradiation and treated with polymeric compounds
- Evaluation of radioprotective capability of new VP - MAc copolymers derivatives by using an in vivo micronucleus test (bone marrow cells of irradiated and treated mice) and an in vitro metaphase analysis (reduction of the frequency of chromosomal aberrations in human blood lymphocytes)
- Determine the effective doses, application times and pharmaceutical formulations of polymeric medical agents at the minimum toxicity, depending on polymer MW characteristics, drug immobilization degree and route of drug administration
- Evaluation of acute toxicity of polymeric radioprotective agents in vivo after a single intraperitoneal administration in mice starting at 500 mg/kg and increasing in arithmetic progression up to 4000 mg/kg
- Preparation of carboxyl- and carboxylate groups containing copolymers of VP and VA and studying their properties on binding and removal of non-radioactive and radioactive compounds of cesium, cobalt and strontium
Role of Foreign Collaborators/Partners. Professor Kurt E. Geckeler (Gwangju Institute of Science and Technology (GIST) and Senior Scientist Igor Galaev (DSM Food Specialties B.V.) expressed their wish to become Collaborators of this Project. The role of foreign Collaborators consists in:
- Carrying out of joint working seminars and assistance in polymeric sample characterization with using modern analytical instrumentation of collaborator’s organization
- Information interchanges during realization of the project, discussion of results and review of technical reports
Technical approach and methodology. The synthesis of VP-MA, VP-DMMA and VAc-MA copolymers will be carried out by radical polymerization of comonomers by using radical initiators. Targeting polymer compounds will be obtained by modification of anhydride groups of above mentioned copolymers with known drugs amifostine and N - (2-mercaptopropionyl) glycin. Studying radioprotective efficiency of new derivatives of VP - MAc copolymers will be performed by measuring survival, mean life-times and bone marrow suppression over a 30 days period of post-irradiation of white mice exposed to LD 100/30 or LD 50/30 doses of X-irradiation and treated with polymeric compounds.
The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.
ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.