INFORMATION ABOUT PROJECT,
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COMMON PART

Project Number20-74-20012

Project titleA comprehensive study of multifunctional supramolecular systems that controllably affect eukaryotic cells for the development of effective theranostic agents.

Project LeadShipunova Victoria

AffiliationShemyakin - Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences,

Research area 04 - BIOLOGY AND LIFE SCIENCES, 04-209 - Biotechnology (including biological nanotechnology)

KeywordsNanoparticle modification, bioconjugation, HER2/neu-targeted recombinant proteins, magnetotactic bacteria, biomineralisation, biosensorics, magnetic cytometry, nanoparticle circulation, nanoparticle biodistribution.

PROJECT CONTENT

Annotation
This project is a logical continuation of a comprehensive interdisciplinary study that began within the framework of the RSF project No. 17-74-20146 (hereinafter referred to as the Project 2017), aimed at the development of supramolecular structures based on nanoparticles and multifunctional molecules, as well as methods for their effective use in vivo in order to create effective tools for high-precision diagnostics and effective treatment of cancer. As a result of the successful implementation of the Project, over the previous three years, the declared indicators were exceeded, in particular, 12 publications in the Web of Science were published and accepted in print out of the 8 publications, including 5 papers in Q1 quartile journals (including Advanced Functional Materials and Nature Biomedical Engineering), the total impact factor of all published articles was 51.48, as well as a number of abstracts from Russian and international conferences were published. The results obtained during the implementation of the Project 2017 are an essential step towards the creation of effective methods of therapy and diagnosis of cancer that based on nanostructures of different nature. So, in particular, a number of unique methods for nanostructures modification with targeting molecules have been created, which allow targeted delivery of compounds only to target cells with a specific molecular profile, for example, cancer cells. We also synthesized biocompatible nanostructures capable of selectively visualizing and damaging cancer cells with overexpression of the clinically relevant HER2 tumor marker. Such structures are promising agents for theranostics (therapy and diagnostics) of HER2-positive human cancer. However, there is an extremely serious problem of nanobiotechnology - a considerable number of particles that have demonstrated their effectiveness in vitro turn out to be extremely ineffective in vivo. One of the key challenges that nanoagents in a living organism encounter on the way to a therapeutic goal is their active recognition and absorption by the cells of the mononuclear phagocyte system, mainly macrophages of the liver and spleen. As a result, the efficiency of nanoparticle delivery to the tumor averages 0.7% of the total administered dose of the nanoagent. In this regard, during the implementation of Project 2017 by inhibiting the ability of macrophages to phagocytosis, a number of methods were developed aimed at slowing down the process of removing nanoparticles from the bloodstream by means of the temporary blockade of the system of mononuclear phagocytes, which significantly increased the circulation time of nanoagents in the bloodstream. During the implementation of this Project, it is planned to apply the developed methods for prolongation of the circulation of nanoparticles in the bloodstream for targeted oncotherapy and diagnostics using previously synthesized targeted nanoagents. It is expected that it will be possible to significantly increase the biomedical potential of the synthesized nanoagents. Also, in order to increase the therapeutic index of the developed compounds, it is planned to investigate methods of combined action on the tumor with targeted compounds. In particular, it is planned to use the combined action of previously developed polymer nanoparticles loaded with a chemotherapeutic compound in combination with a targeted immunotoxin. Preliminary in vitro results showed that such a combination could lower the concentration of the active substance by 1000 times to achieve the same cytotoxic effect. This suggests that such combination therapy in vivo will significantly affect the growth dynamics of HER2-positive tumors and stop the spread of metastases in xenograft models in immunodeficient mice. It is also planned to study how the combined effect of immunotoxins of different specificity to different molecular targets (for example, HER2 and EpCAM), affects the dynamics of growth of tumor cells in vitro. It is expected that it will be possible to establish patterns that allow synergy to be achieved when compounds act with a similar mechanism of action, but with different specificity from the point of view of target recognition on the cell surface. The data obtained during the implementation of the Project can significantly increase the effectiveness of cancer therapy. The results obtained can bring therapy and diagnosis of socially significant diseases to a new level.

Expected results
The data obtained during the implementation of the Project can significantly increase the effectiveness of cancer therapy. The results obtained can bring therapy and diagnosis of socially significant diseases to a new level. During the project implementation, the following scientific results are expected to be achieved: 1) Combination therapy methods will be developed using chemotherapeutic nanoformulations in combination with immunotherapeutic drugs, namely, targeted immunotoxins, which will significantly increase the effectiveness of the targeted therapy of HER2-positive tumors and prevent the metastasis of these tumors. 2) Fundamental knowledge will be ibtained on how the combined action of targeted immunotoxins directed toward molecular targets such as HER2 and EpCAM affects cell viability. We expect that with various combinations of expression of HER2 and EpCAM receptors on the cell surface and with various combinations of exposure to HER2 and EpCAM-specific immunotoxins, the information will be obtained that will allow us to develop new approaches to oncotherapy. 3) The developed methods for nanoparticle circulation in the bloodstream prolongation for targeted oncotherapy and oncodiagnostics using previously synthesized targeted nanoagents will be used. It is expected that it will be possible to significantly increase the biomedical potential of the synthesized nanoagents for the treatment and diagnostics of tumors. 4) Nanoagents will be synthesized, which will significantly enhance the diagnostic potential of the developed methods and approaches. In particular, bismuth oxochlorate plates will be obtained, which are a much more promising contrast CT agent compared to barium-based agents that are now used in the clinic (according to the results of a number of our in vivo pilot experiments). 5) Based on the results of the work, at least 8 publications will be published (indexed in Web of Science Сore Сollection or Scopus). Thus, the result of this Project will be the development of the fundamental knowledge for the production of new theranostic nanoagents that effectively affect cells in vivo. Such nanoagents will be multifunctional structures assembled on-demand from existing components with different specificity and selectivity. Despite the fact that the tasks formulated in the Project are quite clearly defined, speaking about their scale, the following points should be noted. Despite the fact that the effectiveness of nanoparticles as a promising tool for the treatment and diagnosis of diseases has been demonstrated in vitro on cell cultures for more than a dozen years, a lot of problems have yet to be solved in vivo to prevent the rapid elimination of nanoparticles from the body and the loss of their functional activity by non-selective accumulation in non-target organs and tissues and so on. In particular, the targeted delivery model chosen for the implementation of the Project - namely, the HER2 receptor, is an already tested target of targeted therapy, for example, by means of monoclonal antibodies Herceptin®, Perjeta®, Kadcyla® in the treatment of breast cancer and annual sales volumes of these drugs are valued at tens of billions of US dollars, which indicates the widespread and social significance of these studies. However, the effectiveness of monoclonal antibodies is not always sufficient for effective monotherapy, and even patients who respond well to such therapy develop resistance to drug exposure over time. In this regard, there is a need to create personalized approaches to treatment and the application of the combined therapy by means of agents of various nature with various functions for more effective treatment. Authors believe that the results of the Project will significantly broaden the capabilities of nanobiotechnologies for solving socially significant biomedical problems. Similar studies have not been conducted previously, and we believe that such an integrated approach to the study of the immunological and molecular genetic characteristics of the tumor will achieve significant success in oncotheranostics, as well as we will publish at least eight articles in leading Russian (with impact factor 0.3-2) and foreign (with impact factor 3-10) scientific journals indexed in Web of Science and Scopus.

REPORTS