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Photodynamic Therapy of Atherosclerosis

#2579


Development of Technology for Photodynamic Therapy of Atherosclerosis

Tech Area / Field

  • MED-OTH/Other/Medicine

Status
8 Project completed

Registration date
05.08.2002

Completion date
03.08.2009

Senior Project Manager
Gremyakova T A

Leading Institute
State Enterprise Krasnaya Zvezda, Russia, Moscow

Supporting institutes

  • Russian Cardiology Research Center, Russia, Moscow\nNIOPIK (Organic Intermediate Products and Dyes), Russia, Moscow

Collaborators

  • US Department of Health & Human Services / National Institute of Health / National Heart, Lung and Blood Institute, USA, MD, Bethesda\nLilly Corporate Center, USA, IN, Indianapolis

Project summary

Cardiovascular diseases associated with atherosclerosis is the main cause of mortality in Russia and other industrial countries. Morphologically, the atherosclerotic changes in the human arteries are responsible for the cardiovascular diseases such as ischemic heart disease, myocardial infarction, and stroke. Considerable advances have been currently made in creating the drugs for the treatment of cardiovascular diseases. However, this treatment is still symptomatic and involves no cellular mechanisms of atherosclerotic vascular diseases. Creation of a drug, which directly affects the vascular wall, thus preventing or regressing the atherosclerotic changes, has been the subject of much investigation. However, the search for or creation of drugs directly affecting the vascular cells or matrix calls for further investigation. Based on such an approach, the photodynamic treatment (PDT) is among the most promising methods. The PDT is a bi-component method of treatment, the first component of which is the photosensitizer (PS), i.e., a medicine (dye) increasing the photosensitivity of the biological tissues, and another component is the low-energy laser radiation. The interaction of the PS with light of a certain wavelength triggers a photochemical reaction resulting in the intensive release of singlet oxygen. This is the cause of the phototoxic effect resulting in destruction of cells accumulating the PS. The presence of dead cells and their fragments induces the tissue reparation, which consists in elimination of the destroyed cells. In this case, the natural biological mechanism is involved, which represents the consecutive phases of inflammatory reaction (infiltration and reparation (proliferation)) causing the formation of connective-tissue scar. The initiation of the similar changes atherosclerotic lesions may create the prerequisites for preventing further atherosclerotic changes in the vascular wall. The analysis of the published data on the PDT used in animals allows us to make the following conclusions:
  • During angioplasty, the PDT inhibits the development of fibrocellular hyperplasia of vascular endothelium, thus, preventing the development of restenosis.
  • The PDT may be of considerable importance for the prevention and treatment of restenosis after coronary artery bypass grafting and other reparative vascular operations as well as after endarterectomy and heart transplantation.
  • The preliminary data suggest that the PDT may be used for prevention and treatment of the atherosclerotic changes in the vascular walls.
  • The application of the PDT in experimental animals creates the prerequisites for successful application of the PDT in human vascular diseases. However, it is necessary to consider the specific features of the human vascular walls significantly different from those in animals.

The introduction of the PDT into clinical practice for preventing and treating atherosclerosis is currently limited by the following factors:
  • Firstly, there are no data on the interaction of the PS with heterogeneous cellular populations such as vascular cell population and on the selectivity of PS accumulation in different types of target cells (endothelium, smooth muscle, and inflammatory cells, pericytes, fibroblasts, etc.).
  • Secondly, there are no compounds resistant to oxidation, with intensive absorption in the red and near infrared spectrum area, and with high affinity to the atherosclerotic substrate cells.
  • Thirdly, there is no multi-parameter laser unit for external and internal radiation of vessels.
  • Fourthly, there is no mathematical model describing the interaction of chemical, physical, and biological processes under the project. The solving of the above-mentioned problems is the subject of the present project.

The objective of the project is to create the technique of the photodynamic treatment of atherosclerosis.

For this purpose, it is necessary to:

  1. Synthesize the compounds resistant to oxidation and with intensive absorption in the red and near infrared spectrum area and to test their affinity to the atherosclerotic cells;
  2. Study the interaction of the existing and newly synthesized PS with the vascular wall cells;
  3. Design the multi-parameter laser unit meeting the objectives of the project;
  4. Identify the target cells for the photodynamic treatment of atherosclerotic lesions and to develop the method of selective cell exposure to PDT using the synthesized PS and newly developed laser unit;
  5. Create the mathematical model describing the interaction between chemical, physical, and biological processes occurred after exposure of vessels to the PDT.

The members of the project have certain reserves to solve the above-mentioned tasks.
  1. Together with several leading physical and medical centers, the State Research Center NIOPIK has developed and applied the PDT method using the original domestic PS for treating oncological diseases. As for the development of the PS for prevention and treatment of atherosclerosis by the PDT method, the existing PS will be tested and the synthetic research will be started into the new types of the dyes (xanthene, phenoxazine, and phenothiazine) and into the new lines of synthetic research in phthalocyanine and porphyrine classes. It is suggested that the medical experience in oncology be used in order to create the new PDT room complex for the prevention and treatment of the cardiovascular diseases, which complex is based on the newly developed and improved PS, new application techniques, and specially developed domestic laser equipment.
  2. To successfully apply the PDT in the vascular treatment, it is necessary to develop multi-parameter laser unit providing the necessary wavelength of laser radiation for each synthesized PS; the resonance pulse-periodic regime of modulated radiation; and intrapulse modulation of laser radiation power. For the intravascular application of the PDT, the above regimes make it possible to significantly decrease the radiation power so that to eliminate the damage of the formed elements. The laser units with the above-mentioned radiation regimes may be developed, for the first time in the world, in the laboratories of “the Krasnaya Zvezda” state unitary enterprise. The laboratories’ personnel have the unique equipment for and experience in developing the technology of the cosmic-based small-size nuclear power facilities and special-purpose industrial high-power lasers. Therefore, they can develop and produce semiconductor lasers for the PDT, which are compact, light, and convenient in operation.
  3. The specific features of the vascular cell biology determine the main tasks to be solved when using the PDT in vascular pathology. The Russian Cardiology Research-and-Production Center (CARDIOCENTER) shall be involved in solving the task, according to which the target cells for the PDT must be identified in the vascular wall. The CARDIOCENTER has all the necessary techniques and approaches making it possible to solve the problems at the level of a single cell to the whole vessel.
    • The analysis of the interaction between the PS and different types of vascular wall cells. The unique model for cultivating vascular wall cells has been developed in the CARDIOCENTER. To obtain the cells, the human autopsy vascular material obtained during urgent postmortem examination within 1-5 hours is used. No use of such material is possible anywhere in the world. In the primary culture, such cells preserve the main properties they have in the vascular wall. The availability of the urgent autopsy material makes it possible to visualize the interaction of the PS with the vascular wall in ex vivo system, which is similar to that in the vessel in situ. In 1990-1997, a series of mutual investigations was carried out together with Dr. Mark D. Rekhter (collaborator of this project) on a cellular model developed in the CARDIOCENTER, and these investigations shall be continued under this project.
    • 3.2. CARDIOCENTER has a modern Animal House. The animal models of experimental atherosclerosis make it possible to analyze the interaction between the PS and the target cells at the level of the whole body. It is in this part of research that we plan to closely collaborate with Prof. Howard S. Kruth as one of the recognized authority in the field of experimental atherosclerosis. The CARDIOCENTER’s unique methods for modeling cellular populations are of great advantage for the proposed project. It is the use of in vitro and ex vivo models that makes it possible to simplify and reduce the costs of the laser equipment development, because the results may be visualized directly during the experiment.
  4. The statistical processing of the experimental findings makes it possible to develop the mathematical model describing the interaction between all the components, including biological tissue, the PS, and laser radiation, in order to develop the optimum protocol of clinical trials of the PDT for different types of atherosclerotic vascular disease. Moreover, the development staff involved in this project has the necessary knowledge and equipment for solving the particular tasks so that to successfully perform the task of the project, i.e., to develop the technique of the photodynamic treatment of atherosclerosis.


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