Immobilized Porphyrins for the Photodynamic Therapy of Cancer
Development of the Systems on the Base of Porphyrins Immobilized on Polymer Carriers Providing Controlled Generation of Singlet Oxygen to Carry out the Photodynamic Therapy of Cancer
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
- CHE-POL/Polymer Chemistry/Chemistry
- CHE-RAD/Photo and Radiation Chemistry/Chemistry
8 Project completed
Senior Project Manager
Novozhilov V V
Russian Academy of Sciences / Semenov Institute of Chemical Physics, Russia, Moscow
- Medical Radiological Scientific Center, Russia, Kaluga reg., Obninsk\nKarpov Institute of Physical Chemistry, Russia, Moscow\nNIIIT (Pulse Techniques), Russia, Moscow
- Boston University/Center for Polymer Studies, USA, MA, Boston\nDepartment of the Navy / Naval Undersea Warfare Center Division, USA, RI, Newport
Project summaryPhotodynamic therapy (PDT) is one of the most organs sparing and efficient methods in oncological diseases treatment. The positive effect of the method is possible for 70-90% of patients. Corresponding to estimations of national and foreign specialists, PDT promises to become one of the main methods of cancer treatment. The method is based on the selective action of laser irradiation onto tumor cells preliminarily covered by a photosensitizer (PS) – tumorotropic dye. Porphyrin photosensitizers (PPS) are currently used in the medical practice which are tetrapyrrole compounds known as the most active and biologically compatible with human organism. Nowadays, the PDT development directions are both searching new types of porphyrins and investigation of new possibilities of porphyrin PSs use. In particular, in the surface tumors treatment PSs have been recently used in the immobilized form, i.e. bound to polymeric films, gels, foams. Application of immobilized PSs allows resolution of a number of problems of photodynamic therapy simultaneously. First, it is no need to inject a PS (intravenously, intramuscularly or subcutaneously) into a patient organism; besides, PS light-toxic action to an organism is excluded and its contamination by the dye photodestruction products is prevented. However, the depth of the effect of PSs immobilized on existing polymeric supports stays rather low: PSs penetrate into the body of a tumor from a support due to gradient diffusion only. Naturally, this fact narrows the group of porphyrins used to water-soluble compounds only. Besides, polymeric supports do not pass through sufficient amount of molecular oxygen, essentially retarding the PDT rate.
The presented project is aimed at the creation of a new generation of PPS immobilized on polymeric membranes (PM). Application of PMs makes it possible to combine the above advantages of common polymeric supports with a number of specific membrane properties. In particular, the usage of PMs as supports for PPS allows combination of PDT seances with thermotherapy of tumors. Thermodestruction of tumors is an independent, intensively developed method of oncological deseases treatment by heating of damaged tissues within a narrow temperature range. It has been shown by the preliminary experiments that the temperature rise in the same range results in an significant increase in the efficiency of singlet oxygen generation in the presence of porphyrins immobilized on polymeric supports. However, thermotherapy and PDT combination is not effective when using porphyrins immobilized on common polymeric supports. Such polymeric films do not pass oxygen through and the oxygen content on the tumor surface decreases with the film temperature rise. The problem is completely solved by use of gas-permeable membranes as supports. They selectively pass oxygen through and provide its continuous feed to a tumor. Usage of gas-permeable membranes will allow development of a new method of tumor treatment, which include both photodynamic therapy and thermotherapy. In doing so, of particular scientific and practical importance for the world community is design of a special unit providing conducting seances of experimental photodynamic therapy combined with thermotherapy, using immobilized PPS (IPPS). The project incorporates development of a laboratory sample of this unit. One of variations of IPPS application may be use of supports based on biodegradable polymeric films. Such films allow more effective release of PPSs localized inside the film and their “delivery” into the tumor body in the process. Another idea is to use films based on natural polysaccharides (chitin, chitosan) which are biocompatible and have their own antitumor activity.
It is very important that supports for PSs based on membranes containing ionogenic groups convert porphyrins into the form of stable dications, as the preliminary experiments have shown. Porphyrin dications have an intense absorption band in the range of 680-750 nm, i.e. in the transmission band of biological tissues that increases the method efficiency.
The presented work is to result in the development of the new preparations for PDT which are polymeric membranes containing PPSs. They are expected to be stable during storage and use and fit the requirements of therapy of both surface malignant tumors and a number of internal tumors. Besides, a laser unit is to be designed for conducting the combined thermo- and PDT using the obtained preparations.
The project is meant for 3 years.
It is expected to obtain to the end of the first year:
– kinetic parameters of singlet oxygen generation in the model conditions (gas and liquid phase) at various excitation wavelengths;
– synthesized samples of the most promising PPSs of different structure;
– samples of ion-exchange films containing PPSs;
– results of tests of ion-exchange films containing PPSs, in the model conditions and on cells cultures (tests on activity, stability, strength of porphyrins binding);
– a mock-up of the unit for conducting PDT seances in the case of surface tumor localization.
It is expected to obtain to the end of the second year:
– samples of gas-permeable membrane materials containing PPS;
– results of tests of the most active samples of gas-permeable and ion-exchange membranes containing porphyrins, temperature dependence of photoactivity, rate of porphyrins diffusion from the polymeric supports into a tumor;
– results of tests of the prepared samples on laboratory animals in the case of surface tumor localization, conducting the combined thermo- and photodynamic therapy;
– set of documentations for making a pilot unit of laser photolize for carry out of photodynamic therapy.
It is expected to obtain to the end of the third year finishing the project:
– samples of biodegradable polymers containing the most effective PPSs;
– results of tests of biodegradable porphyrin-containing polymers on efficiency of singlet oxygen generation, rate of polymeric matrix degradation and rate of PPS diffusion into a tumor (on laboratory animals),
– a pilot unit for conducting seances of combined thermo- and photodynamic therapy using porphyrin-containing cationite and gas-permeable membranes (PCGM);
– results of approbation of the unit and of the prepared samples of porphyrins immobilized on all the types of membrane materials, in the cases of surface and internal localization of a tumor (on laboratory animals).
In the process of the project execution its participants plan information exchange with the foreign collaborators, organization of joint discussion of the obtained results at different stages of execution of the project and comparison of the project results with the data obtained by the collaborators and by the world science. The project accomplishment will give an opportunity to scientists and specialists from the Russian Federation, who took part in the tests of nuclear weapons and in the development of rocket materials and techniques, for re-orientation of their potential toward the peaceful activities. It will also encourage the scientists from the RF to integrate to the international scientific community, support fundamental and applied investigations for peaceful purposes and will contribute to the solution of national and international biotechnological problems. All this corresponds to the aims and directions of the ISTC activities.