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Invited researcher Arto Olavi Urtti
Contract number
14.W03.31.0025
Time span of the project
2018-2020

As of 15.02.2021

12
Number of staff members
21
scientific publications
3
Objects of intellectual property
General information

Name of the project: Biohybrid technologies for modern medicine

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Research directions: Chemical technology, pharmacy and pharmacology, biotechnology, cellular engineering

Project objective:

- Creation of a new multidisciplinary laboratory of biohybrid technologies

- Developing and applications of biohybrids for targeted delivery of a broad range of therapeutic compounds including steroids, peptides/proteins, RNA, small organic molecules and organometallic complexes

The practical value of the study

  • The Laboratory has produced new efficient inhibitors of of human carboanhydrase that are able to covalently bind to polymer carriers. Synthesized amide analogs of selective inhibitor of the II isoform of ferment, namely 4-(2-methyl-1,3-oxasol-5-il) benzolsulfonamid possess picomolar activity. On the basis of derivatives of 1,2,4-oxadiazole we have produced a series of bioisosteric analogues of the initial compound, a number of members of this series demonstrates high activity towards target isoforms of carboanhydrase and high cytotoxicity against tumor cell lines PANC-1 and SK-MEL-2 with absence of expressed toxicity against cell line of human retina ARPE-19.
  • Using the method of hydrophylic-hydrophobic modification of chitosan we have produced amphiphilic polymers that show inclination to self-organization under impact of ultrasound with formation of micelle-like structures. Hydrodynamic radius of less than 300 nm in all the cases allow to use them for injection into     vitreous body of eye. Produced nanoparticles show low toxicity to retina pigment cells as well as show ability to encapsulate hydrophobic corticosteroids dexamethasone. Experiments in   dexamethasone release in vitreous body of eyes cattle have shown decelerated release process for 24 hours.
  • Using the method of effective medium inversion we have produced nanoparticles based on static copolymers of amino acids: L-lysine (Lys) and D,L-phenylalanine (Phe). Control of nanoparticle degradation speed is possible by substitution of L-phenylalanine with its D-isomer. Possibility of encapsulation and prolongation of release of dexamethasone has been shown.
  • Our researchers has created systems based on poly(amino acids) that are able to encapsulate plasmid DNA and small interfering RNA. We have proven ability of these systems to penetrate intracellular space and deliver genetic structures.
  • We have produced pseudo-liquid nanoparticles – nanogels that are able to release low molecular drugs and genetic structures under impact of changing external conditions, namely pH, IR radiation in the near infrared range, presence of specific ferments.
  • Our researchers have produced new phosphorescent tags that have longer lifespan of the excited state and quantum output of luminescence. Unique photophysical qualities of synthesized tags allow to not only see positions of nanopartiles (delivery systems) in biological tissues but also to discern their chemical environment (рН-, oxygen content etc).
  • We have developed an approach to creating a therapeutic biohybrid. The approach is based on usage of cells (macrophages) as drug carriers for delivery to the epicenter of infection. The work consisted of several stages: producing polymer micro- and nanoparticles with encapsulated Perchlozone medication, study of kinetics of its release, research of phagocytosis of particles in vitro using cell cultures, conducting an experiment in therapy of mice infected with the multiresistent form of tuberculosis with subsequent study of drug distribution in the organism. The developed approach demonstrated more than 50% increase in survival rate of animals. The developed approach can be used for creating biohybrid systems for ocular therapy.
  • We have proposed computer pharmacological models for creating new systems for delivery of drugs into eyes. These models are useful for choosing dosage of drugs, speed of release of delivered materials. The models have been built accounting for anatomic and physiological parameters of eye as well as pharmacological characteristics of drugs and methods of their administration. The model allows to assess average concentrations of drugs in target compartments of eye (aqueous vein, vitreous body) after applying different methods of drug administration (local, subconjunctival and intravitreal administration).

 Education and career development:

  • The laboratory has developed the «Biomaterials» course for bachelors majoring in «Chemistry, physics and mechanics of materials». This course includes results of research conducted within the project.
  • We have organized internships for our employees, postgraduates and students at the University of Eastern Finland to study methods of biological testing of produced materials and nanostructures.

Collaborations:

  • Faculty of Biopharmacy of the University of Helsinki (Finland), School of Pharmacy of the University of Eastern Finland (Finland): joint research, joint scientific events
  • Institute of Technical Chemistry of the Leibniz University Hannover (Germany), BioCad (Russia): joint research

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M. Krasavin, A. Shetnev, T. Sharonova, S. Baykov, S. Kalinin, A. Nocentini, V. Sharoyko, G. Poli, T. Tuccinardi, S. Presnukhina, T.B. Tennikova, C.T. Supuran
Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase targeting primary arene sulfonamides: discovery of sub-nanomolar inhibitors of membrane-bound hCA IX isoform that selectively kills cancer cells in hypoxic environment. European Journal of Medicinal Chemistry. 2018. V.164.
L. Churilov, V. Korzhikov-Vlakh, E. Sinitsyna, D. Polyakov, O. Darashkevich, M. Poida, G. Platonova, T. Vinogradova, V. Utekhin, N. Zabolotnykh, V. Zinserling, P. Yablonsky, A. Urtti, T. Tennikova
Enhanced delivery of 4-thioureidoiminomethylpyridinium perchlorate in tuberculosis models with IgG functionalized poly(lactic acid) based particles. Pharmaceutics. 2019. V.11.
I. Pilipenko, V. Korzhikov-Vlakh, V. Sharoyko, N. Zhang, M. Schäfer-Korting, E. Rühl, C. Zoschke, T. Tennikova
pH-sensitive chitosan–heparin nanoparticles for effective delivery of genetic drugs into epithelial cells. Pharmaceutics. 2019. V. 11.
M. Krasavin, A. Shetnev, S. Baykov, S. Kalinin, A. Nocentini, V. Sharoyko, G. Poli, T. Tuccinardi, M. Korsakov, T.B. Tennikova, C.T. Supuran
Pyridazinone-substituted benzenesulfonamides display potent inhibition of membrane-bound human carbonic anhydrase IX and promising antiproliferative activity against cancer cell lines. European Journal of Medicinal Chemistry. 2019. V. 168
A. Subrizi, E.M. del Amo, V. Korzhikov-Vlakh, T. Tennikova, M. Ruponen, A. Urtti
Design principles of ocular drug delivery systems: importance of drug payload, release rate, and material properties. Drug Discovery Today. 2019. V. 24.
O. Osipova, V. Sharoyko, N. Zashikhina, N. Zakharova, T. Tennikova, A. Urtti, E. Korzhikova-Vlakh
Amphiphilic Polypeptides for VEGF siRNA Delivery into Retinal Epithelial Cells. Pharmaceutics. 2020. V. 12.
S. Kalinin, A. Valtari, M. Ruponen, E. Toropainen, A. Kovalenko, A. Nocentini, M. Gureev, D. Dar’in, A. Urtti, C.T. Supuran, M. Krasavin
Highly hydrophilic 1,3-Oxazol-5-yl benzene sulfonamide inhibitors of carbonic anhydrase II for reduction of glaucoma-related intraocular pressure. Bioorganic & Medicinal Chemistry. 2020. V. 27.
I.S. Kritchenkov, D.D. Zhukovsky, A. Mohamed, V.A. Korzhikov-Vlakh, T.B. Tennikova, A. Lavrentieva, T. Scheper, V.V. Pavlovskiy, V.V. Porsev, R.A. Evarestov, S.P. Tunik
Functionalized Pt(II) and Ir(III) NIR Emitters and Their Covalent Conjugates with Polymer-Based Nanocarriers. Bioconjugate Chemistry. 2020. V. 31.
I.M. Pilipenko, V.A. Korzhikov-Vlakh, N.V. Zakharova, A. Urtti, T.B. Tennikova
Thermo- and pH-sensitive glycosaminoglycans derivatives obtained by controlled grafting of poly(N-isopropylacrylamide). Carbohydrate Polymers. 2020. V. 248.
N.V. Dubashynskaya, A.S. Golovkin, I.V. Kudryavtsev, S.S. Prikhodko, A.S. Trulioff, A.N. Bokatyi, D.N. Poshina, S.V. Raik, Y.A. Skorik
Mucoadhesive cholesterol-chitosan self-assembled particles for topical ocular delivery of dexamethasone. International Journal of Biological Macromolecules. 2020. V. 158.
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