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COMMON PART

Project Number24-62-00018

Project titleAdvanced combined technologies of neutron capture therapy

Project LeadZavestovskaya Irina

AffiliationP.N.Lebedev Physical Institute of the Russian Academy of Sciences,

Research area 02 - PHYSICS AND SPACE SCIENCES, 02-210 - Interaction of X-rays, synchrotron radiation and neutrons with condensed matter

Keywordsoncology, neutron capture therapy of malignant tumors, nanoparticles, boron, toxins, targeted delivery, nuclear reactions

PROJECT CONTENT

Annotation
The goal of the project is to develop combined neutron capture therapy (NCT) technologies using targeted nanoformulations containing elements with a high neutron capture cross-section, functionalized with polymers for biocompatibility and containing tumor-specific ligands, separately and in combination with recombinant targeted toxins. This approach will significantly improve the efficiency of NCT by increasing the gradient between the accumulation of agents in tumor and healthy tissues, enhancing the uniformity of dose distribution in the tumor and using the unique properties of nanomaterials. The urgency of the development of new technologies that improve the effectiveness of the NCT method, including boron-neutron capture therapy (BNCT), consists in increasing interest in the use of BNCT technologies for the treatment of malignant tumors of the head, neck and skin that are difficult to treat with other methods. The boron delivery agents currently used in clinical practice are sodium borocaptate and borphenylalanine, but their accumulation is not selective and strongly depends on the heterogeneity of the tumor, requiring the use of high doses of the drug, often causing severe side effects. In addition, the molecular nature of these agents is not able to provide a long-term retention in a tumor necessary for BNCT for several hours during irradiation, and this significantly affects the effectiveness of the therapy. The problem of developing a new effective and safe agent delivery system in NCT is becoming extremely urgent for introduce NCT into clinical practice, including at the medical accelerator for BNCT being put into clinical practice at the N.N. Blokhin Oncology Research Center. The implementation of the project involves new comprehensive interdisciplinary research in the field of studying the nuclear-physical foundations of combined NCT technologies, the development and optimization of technologies for laser synthesis of nanomaterials, the functionalization of their surface with targeted biomolecules for targeted delivery and retention in the tumor and innovative research in the direction of combined NCT technologies using targeted recombinant toxins. The VITA unique accelerator neutron source (INP SB RAS), which is the only one in the Russian Federation, will be used to generate a flux of thermal neutrons. Interaction with the co-executor of the project – the Institute of Cytology and Genetics SB RAS (Novosibirsk) will allow to conduct biological studies to identify the effectiveness of the proposed combined NCT technologies that have no analogues in the world. The solution of these problems is possible only with the use of an interdisciplinary approach that allows to extract a synergetic effect from the competencies and efforts of specialists in the field of nuclear physics and accelerator technology, biochemistry, radiobiology, laser and nanotechnology. The results obtained during the implementation of the project will make it possible to prepare recommendations to the medical community of the Russian Federation on the use of the developed combined NCT technologies.

Expected results
The synergetic result of the interdisciplinary project is the development of new combined NCT technologies using nanoparticles and targeted nanoformulations of elements with a high neutron capture cross–section separately and/or in combination with targeted toxins, which will significantly enhance the effectiveness of NCT. The development of combined NCT technologies includes the implementation of interdisciplinary work and obtaining the following results: The nuclear physics foundations of modeling in the Geant4 program will be developed and the modes of the proposed combined NCT technologies using nanoparticles will be optimized. Technologies of laser synthesis of colloidal solutions of nanoparticles with a given sizes, morphology and structure based on materials with a high neutron capture cross-section (boron, lithium) will be developed and optimized. Technologies of stabilization of colloidal solutions of nanoparticles using polymers, functionalization of the surface of nanoparticles by biomolecules (including protein scaffolds) for targeted delivery and retention in the tumor will be developed and optimized. Advanced recombinant targeted toxins for combined NCT technologies will be defined, a technology for their separation and purification will be developed. Modes of irradiation of biological objects (cell cultures and laboratory animals) by flux of epithelial neutrons using accumulated targeted nanoformulations and/or targeted toxins to study the effectiveness of combined NCT technologies will be developed and optimized. The effectiveness of combined NCT technologies using targeted nanoformulations and/or targeted toxins in vitro will be investigated. The effectiveness of combined NCT technologies using targeted nanoformulations and/or targeted toxins in vivo on human tumor xenograft models will be investigated. The solution of tasks in this field will be carried out by the co–executor of the project – the Institute of Cytology and Genetics SB RAS (Novosibirsk) by the opportunities of the SPF-Vivarium. Innovativeness of combined NCT technologies, which have no analogues in the world, consists in an innovative approach to solve each of the tasks. The scientific groundwork of the team on the project topic, a high level of competence and a unique resource of the research infrastructure will make it possible to obtain the expected results. The synergetic effect of interdisciplinary research will provide the development and optimization of effective combined NCT technologies and will make it possible to give recommendations to the medical community on the use of technologies in solving the actual problem treatment complex cancers. It is important for the practical application of results of the project that the combined NCT technologies are based on the VITA accelerator neutron source, prototypes of which are being manufactured for medical institutions of the N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of Russia (Moscow) (planned to be introduced into clinical practice in 2027) and for the A.I. Burnazyan SSC FMBC of FMBA of RF (Moscow), which will speed up the approbation of the developed technologies in medical practice.

REPORTS