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Chemical Design of Bionanomaterials

Invited researcher Alexander Viktorovich Kabanov
Contract number
11.G34.31.0004
Time span of the project
2010-2014

As of 30.01.2020

37
Number of staff members
114
scientific publications
15
Objects of intellectual property
General information

Name of the project: Chemical design of bionanomaterials for medical applications

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Project objective: Creating a new generation of bionanosystems for medical applications based on ferments polymer surfaces and magnetic nanoparticles

Research directions: Research in nanomedicine, designing and creating and drugs for targeted impact to treat a wide range of significant diseases (brain diseases, including Parkinson's Alzheimer's, ischemic stroke and other neurodegenerative diseases; dangerous eye diseases leading to blindness; oncological diseases, bacterial infections, spinal brain injuries, neurotoxic damage and others)


The practical value of the study

  • We have developed a series of nanoformulations (nanozymes) based on antioxidant ferments as a part of polyion complexes and conjugates possessing expressed neuroprotective and anti-inflammation capabilities, for treating inflammation conditions of eyes and traumatic spinal brain injuries.
  • As a part of the «Pharma» Federal Target Program we have successfully completed pre-clinical tests of efficiency and safety of the created pharmaceutical medication based on superoxide dismutase for treating uveitis – acute inflammation of eyes leading to blindness. We have created a draft of technological regulations to produce medications, a project of the pharmacopeial article and a project of the investigator's brochure.
  • We have created theoretical and experimental basics of the technology of remote control of biobolymer functions and other nanomolecules immobilized on magnetic nanoparticles using ultra low frequency magnetic field with frequency of 50 Hz. We have produced theoretical models of behavior of functionalized magnetic nanoparticles in alternating magnetic fields dependent on characteristics of nanoparticles and parameters of the field. We have found ranges of frequencies and amplitudes of alternating magnetic fields ensuring the most efficient translation of the field's energy to mechanical deformation of macromolecules. We have assessed threshold parameters of alternating magnetic fields necessary for changing activity of molecules attached nanoparticles, decondensation of lipid biomembranes and controlled release of medications from liposomal nanocontainers as well as for activating various responses and changing functionality of cells.
  • We have conducted a series of experiments using unique equipment generating magnetic fields and allowing to conduct biomedical research of impact of magnetic fields in vitro to prove the data from molecular modeling. We have found impact of variable magnetic field on catalytic activity of chymotrypsin ferments, β-galactosidase, yeast alcohol dehydrogenase, superoxide dismutase (SOD1) immobilized on magnetic nanoparticles.
  • Our research have shown possibility of controlled release of medication molecules from carriers based on magnetic nanoparticles using homogeneous low frequency (non-hearing) alternating magnetic field. The possibility has been shown on the example of the SOD1 ferment that is non-covalently included into nanoparticles of the magnetic stabilized by cationic block copolymer polylysine polyethylene glycol.
  • We have created devices to research biological test objects in the presence of magnetic field impact. The developed technology allows not only to perform controlled release of medications from carriers but also ensures selectivity and locality of the controlling impact at cellular and molecular levels. It also increases security of existing methods of therapy of dangerous diseases.
  • We have created a highly efficient nanodimensional ferment catalyst for detoxification of organophosphorus compounds in vivo that has no analogues in the world. Usage of a genetically modified of recombinant ferment organophosphate hydrolase with high catalytic activity and the NanoZYME technology allowed to synthesize ferment catalyst (hydrolytic nanozymmes) for medical and biological applications. Such nanoformulations are stable and circulate in blood stream for a long time, are not immunotoxc, are suitable for use as both a defensive measure and as an antidote, can be injected intramuscularly, intravenously, abdominally,   transbuccally.
  • Intravenous injection of hydrolytic nanozymes as a defensive measure ensures 100% survival rate of animals even after intoxication with a double lethal dose of organophosphorus compounds (2×LD100). In case of usage of nanozymes as an antidote within 10–15 minutes after intoxication with a lethal dose of organophosphorus compounds it is enough to inject them one time intravenously to ensure 100% survival rate of animals.
  • The Laboratory has conducted research of pathogen lysis and possibility of synthesizing    medicinal form of bacteriophage ferments efficient in destroying gram-positive and gram-negative bacteria to create stable and efficient medications against bacterial infections. For instance, for antistreptococcal ferment PlyC we have synthesized composites from non-ionogenic surfactants and polyelectrolite for PlyC inclusion. Thus, we have eliminated the problem of low stability that was the main obstacle for usage of this ferment as a therapeutic agent. We have achieved 100% activity over the course of several months and shown high efficiency of synthesized nanozymes of PlyC ferments for living cells of hemolytic streptococcus.
  • Strategy of creating a process of efficient lysis of gram-negative microflora limited by presence of an outer membrane of gram-negative bacteria consist of synthesizing active target ferment specific to salmonella and E. сoli and selecting agents increasing permeability of outer membrane. Synthesis of recombinant endolysin of bacteriophage S-394 with high protein output is an important result of our research.
  • We have proposed introduction of additional short cationic peptides supplementing work of antibacterial ferment. We have shown that lysis of of live E. coli bacterial cells under influence of endolysin of phage S-394 becomes possible in the presence of poly-Arg and PGLa.

Implemented results of research:

  • Pre-clinical tests of efficiency and safety of a pharmaceutical medication in the form of eye drops has been conducted. The medication helps to treat inflammatory conditions leading to blindness. Introduction of the medication is planned after passing clinical tests.

Education and career development:

  • 10 undergraduates and 6 postgraduates work at the Laboratory.
  • 3 candidate dissertations and 11 masters dissertations have been defended.
  • We have developed special courses and case studies for undergraduates and postgraduates of the Faculty of Chemistry and other faculties of the Moscow State University: «Contemporary problems of nanomedicine and medication delivery» (2013, 2014, 2016, 2017, 2018); «Selected chapters of enzymology and medical biotechnology» (2018), «Contemporary problems of enzymology and medical biotechnologies» (2018); «Selected chapters of biochemistry and biotechnologies» (2018), «Current problems of biotechnologies» (2017); «Nanobiomaterials and physics of nanostructures» (2016, 2017, 2018, 2019); «Introduction to physics of nanostructures» (2013, 2016, 2018); «Contemporary problems of medicine and medical enzymology» (2016, 2018); «Biotechnologies and nanobiotechnologies» (2015, 2018); «Fundamental and applied enzymology» (2014, 2018); «Fundamental chemistry of ferments and biotechnology» (2013, 2017).
  • We have developed and are constantly updating original courses: «Contemporary problems of enzymology and medical biotechnologies» (2017, 2018); «Selected chapters of enzymology and medical biotechnologies» (2017, 2018); «Selected chapters pf biochemistry and biotechnologies in English» (2017, 2019); «Contemporary problems of biochemistry and biotechnologies in English for postgraduates» (2015, 2019); «Modern problems of nanomedicine and medication delivery» (2014, 2018).
Collaborations:

  • Center for Nanotechnology in Drug Delivery – Eshelman School of Pharmacy – University of North Carolina at Chapel Hill (USA), University of Nebraska Medical Center (USA): joint research of possibilities of targeted delivery of drug nanomedications into central nervous system and joint scientific publications
  • Helmholtz Moscow Research Institute of Eye Diseases (Russia): joint in vivo research of efficiency of therapeutic impact of developed nanoformulations for treatment of eye diseases including conducting pre-clinical tests of pharmaceuticals for treating inflammatory eye diseases based on recombinant superoxide dismutase as a part of polymer nanoparticles; we have prepared a pre-clinical testing report within the «PHARMA» Federal Target Program
  • Serbsky State Scientific Center for Social and Forensic Psychiatry (Russia), Pirogov Russian National Research Medical University (Russia): joint research to create substances based on superoxide dismutase as a pert of polymer nanoparticles for treating spinal brain injuries, research of new possibilities of early diagnostics of brain tumors including magnetic resonance imaging, several patents have been registered
  • «Medical nanotechnologies» LLC (Russia): pre-clinical tests of developed medications, project of technological regulations for producing the pharmaceutical form of a mediation to treat inflammatory eye diseases based on recombinant superoxide dismutase as a part of polymer nanoparticles, project of the investigator's brochure, project of the pharmacopeial article
  • National University of Science and Technology «MISIS« (Russia): creating scientific approaches, synthesis and development of nanoformulations based on magnetic nanoparticles for targeted delivered for diagnostics and treatment of tumors, joint publications

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Efremova M.V., Veselov M.M., Barulin A.V., Gribanovsky S.L., Le-Deygen I.M., Uporov I.V., Kudryashova E.V., Sokolsky-Papkov M., Majouga A.G., Golovin Y.I., Kabanov A.V., Klyachko N. L.
In situ observation of chymotrypsin catalytic activity change actuated by nonheating low-frequency magnetic field. ACS Nano. Vol. 12. № 4: 3190–3199 (2018).
Nukolova N.V., Aleksashkin A.D., Abakumova T.O., Morozova A.Y., Gubskiy I.L., Kirzhanova Е.А., Abakumov M.A., Chekhonin V.P., Klyachko N.L., Kabanov A.V.
Multilayer polyion complex nanoformulations of superoxide dismutase 1 for acute spinal cord injury. Journal of Controlled Release. Vol. 270: 226–236 (2018).
Efremenko E.N., Lyagin I.V., Klyachko N.L., Bronich T., Zavyalova N.V., Jiang Y., Kabanov A.V.
A simple and highly effective catalytic nanozyme scavenger for organophosphorus neurotoxins. Journal of Controlled Release. Vol. 247: 175–181 (2017).
Klyachko N.L., Manickam D.S., Brynskikh A.M., Uglanova S.V., Li S., Higginbotham S.M., Bronich T.K., Batrakova E.V., Kabanov A.V.
Cross-linked antioxidant nanozymes for improved delivery to cns. Nanomedicine: Nanotechnology, Biology, and Medicine. Vol. 8. № 1: 119–129 (2012).
Klyachko N.L., Sokolsky-Papkov M., Pothayee N., Efremova M.V., Gulin D.A., Kuznetsov A.A., Majouga A.G., Riffle J.S., Golovin Y.I., Kabanov A.V.
Changing the enzyme reaction rate in magnetic nanosuspensions by a non-heating magnetic field. Angew. Chem. Int. Ed., Vol. 51: 12016–12019 (2012).
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