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Preparations Labeled with Carbon-13

#1490


Creation of Stable Carbon-13 Isotope - Labeled Preparations and Their Application in Practical Medicine

Tech Area / Field

  • MED-RAD/Radiomedicine/Medicine
  • MED-DID/Diagnostics & Devices/Medicine

Status
3 Approved without Funding

Registration date
07.04.1999

Leading Institute
NIIEFA Efremov, Russia, St Petersburg

Supporting institutes

  • TsKBM, Russia, St Petersburg\nMilitary Medical Academy named after S.M.Kirov, Russia, St Petersburg\nInstitute of Highly Pure Biopreparations, Russia, St Petersburg

Collaborators

  • Isonics Corporation, USA, NJ, Edgewater

Project summary

Introduction and overview. Nowadays, production of stable 13C isotope is being established in high developed countries. These works are stimulated by that it is convenient to use it as labels introduced into preparations for medical diagnostics and biological experiments. As compared to radioactive labels, the usage of 13C isotope is harmless and allows to repeat noninvasive diagnostic procedures many times. Currently 13C with high isotopic purity are produced either by the method of low-temperature rectification or combined laser-centrifugal method. In the works performed by NIIEFA under the ISTC Projects 012-94 and 012B-97 “Creation of technological laser complex for separation of average-mass isotopes”) the technological operation for isotope 13C producing has been worked-out.

The diagnostics based on the use of preparations labeled with stable 13C as substrates are actively developing in medicine. In particular, the breath test (BT) with 13C urea is used to reveal the presence of Helicobacter pylori in the stomach and to estimate the efficiency of antiulcer therapy by measuring the 13CO2 and 12CO2 ratio in exhaled breath.

The breath tests, while using 13C-aminopyrine, 13C-phenylalanine, 13C-benzoic, 13C-hippuric acids and detection of 13C in exhaled breath allows to estimate the functional state of the liver at its disease and toxic effects. The use of 13C-glucose followed by detection of 13CH313COOH makes it possible to reveal the presence of bifidum bacteria in the intestines, playing an important role in sustaining of the endoecological homeostasis.

Recently, in order to enhance the accuracy of investigation it has been proposed to measure 13C-bicarbonate in blood rather than 13CO2 in exhaled breath. By a difference in 13CO2 content in aerated and black blood it is possible to estimate the efficiency of the tissue breath system. It is possible to use for medical aims the oxidative reactions of 13C-labeled substrates, for example, the distinction in glucose oxidation metabolism in myocardium in rest and under physical loading allows to reveal the disturbance of energy metabolism in the heart muscle at the early state of disease.

Thus, the subject matter submitted for ISTC consideration is the natural continuation of the cycle of works on development of the technology and creation of the equipment for the laser centrifugal enrichment of 13C isotopes previously completed under ISTC Project 0121-94 and pursued currently under 012B-97. The essence of this work consists in developing of the technology of enrichment of stable 13C isotope, elaboration of the technology of synthesis of a number of biopreparations labeled with 13C isotope, which will be applied in medicinal and biological tests. The development of breath tests modifications and its try-out in diagnostic aims are also among the goals of the project. The tests developed will be applied in St.-Petersburg clinics, and the 13C labeled preparations obtained in the frames of the Project will be used as substrates.

In the project the experience of NIIEFA and CKBM in elaborating of the methods for isotope enrichment and developing of the laser-centrifugal equipment for its realization, NIIOCHB achievements in development of highly pure biopreparations and the experience of physicians from the Naval Medical Academy will be used.

Expected results. The following results will be obtained during the progress of the project:


· the technology for production of 13C isotope by the exclusive laser method will be elaborated and the pilot batch of isotopes will be produced;
· the method for production of fullerenes with various content of 13C isotopes will be developed and pilot batch of fullerenes will be produced;
· the laboratory procedure for synthesis of 13C isotope-labeled glycine and phenylalanine will be developed and the samples of these aminoacids will be obtained;
· samples of two highly purified antibacterial peptides will be synthesized;
· the data on their biological testing will be obtained;
· the laboratory procedure for attachment of activated fullerene molecule to peptide containing charged aminoacid residues will be developed;
· the data on specific biological activity of hybrid molecules produced will be obtained;
· the data on evaluation of the suitability of labeled aminoacids for BTs will be obtained;
· the pilot batch of biopreparations for practical diagnostics will be synthesized;
· diagnostics of liver diseases and alimentary canal disorders associated with Helicobacter Pylori will be improved;
· new methods for evaluation of the efficiency of the treatment of these diseases and some oncopathologies will be developed.

The following goals and objectives of the ISTC will be realized as the result of Project accomplishment:


· opportunity will be provided for employees of NIIEFA, CKBM and NIIOCHB with previous weapons expertise to engage in output of production for peaceful purposes;
· applied investigations will be supported, the final goal of which is to introduce into the Russian practical medicine the up-to-date noninvasive methods of diagnostics using preparations labeled with stable 13C isotope. The latter is of prime importance for treatment of children and inhabitants of ecologically unfavorable regions;
· assistance will be rendered in solving the problems associated with general deterioration of health of Russian population;
· transition to civil market economy will be supported.

Scope of activities. The work comprises three large directions, each of which provides the scientific and engineering basis for the following. They are:


· the works related to production of 13C isotopes, fullerenes with different degree of replacement of carbon atoms with 13C isotopes and improvement of the techniques for measurement of 13C concentration in biological objects;
· the development of synthesis methods and production of biopreparations labeled with 13C isotope;
· medico-biological experiments aiming at try-out of the methods for diagnostics and control of the efficiency of the treatment of liver and alimentary canal diseases, as well as oncopathologies.

The following works will be undertaken to realize the project:


· the technology for production of 13C isotope by the exclusive laser method will be elaborated and the pilot batch of isotopes will be produced;
· the electrodischarge method for production of fullerenes with various content of 13C isotopes will be elaborated and the pilot batch of such fullerenes will be produced;
· the laboratory procedure for synthesis of a number of biopreparations labeled with 13C isotope (glycine, phenylalanine, peptides, hybrid molecules fullerene-peptides) will be worked out;
· pilot batches of these biopreparations will be synthesized;
· suitability of produced 13C-labeled biopreparations for breath tests and specific biological activity of hybrid fullerene-peptide molecules for treatment of oncopathologies will be evaluated;
· pilot batches of 13C labeled biopreparations for practical diagnostics will be synthesized;
· the methods for diagnostics of liver diseases and alimentary canal will be improved;
· new methods for evaluation of the efficiency of treatment of these diseases and some oncopathologies will be developed.

Cooperation with foreign collaborators is perceived to be in the form of:


· exchange of information in the course of the project realization;
· preparation of comments for the technical reports submitted to ISTC;
· cross examinations of the results obtained in the project progress;
· participation in technical inspection of the activities under the Project undertaken by the ISTC employees;
· organization of joint symposia and seminars.

Technical approach and methodology. As the work is persified, different approaches are taken in different directions of the works. Thus, in the first direction the methods characteristic of physical experiments are mainly applied. They are laser-centrifugal enrichment of isotopes and electro-discharge production of fullerenes. The technical basis of these methods have been elaborated with a high level of novelty in ISTC Projects 012-94 and ISTC Project 012B-97. The decision has been taken to issue the patent for the laser-centrifugal method, the main engineering solutions have also been protected. Here, the unique laser complex based on specially developed pulse-repetitive CO2-laser with record parameters is used The unique centrifuge cascade for enrichment of average-mass elements with isotopes has been developed.

In the second direction involving the elaboration of the procedures for synthesis of biopreparations labeled with 13C isotope the various methods and procedures accepted in chemistry and biology are used. The work will be advanced in the following directions:


· elaboration of synthesis methods and production of pilot batches of aminoacids labeled with 13C isotope (e.g. glycine and phenylalanine);
· elaboration of synthesis methods and production of pilot batches of antibacterial highly purified peptides;
· the development of the laboratory procedure for attachment of activated fullerene molecule to the peptide containing charged aminoacid residues and the production of pilot batches of such hybrid molecules.

As a result, a number of novel biopreparations labeled with 13C isotope will be created. Beside necessary labeled substrates will be obtained in order to carry out the medico-biological experiments in the third direction. The work in this direction will be performed by the methods accepted in experimental medicine and biology, from experiments on cell cultures to clinical tests of the preparations selected at previous stages. These preparations will be tested on volunteers with diseases of the liver and alimentary canal and IV degree oncopathologies. The diagnostics techniques, the most prepared for wide application, in particular urea breath test, will be used in St.-Petersburg clinics.

At all stages of activities different measuring methods will be used. They are gas and liquid chromatography, mass-, NMR- and absorption spectroscopy, as well as nuclear in-resonator spectrometry. On the basis of the latter method it is assumed to develop a device for express-measurements of 13C concentrations in exhaled breath during breath tests.

By and large, the work will be of complex character and for its accomplishment various procedures and methods applied in physics, chemistry, biology and medicine will be used.


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