After earning a Ph.D. thesis in Biochemistry (1985) related to the synthesis and application of photoactivatable lipid probes — a new trend of research at that time — she became a staff member of the Lab. In 2007, she presented a Dr. Chemistry thesis devoted to the developing of new photoaffinity lipid probes for the research in structural biology. From 2008 Dr. Vodovozova has headed the Lab of lipid chemistry.

Education

Period	Coyntry, city	University	Additional info
2007	Russia, Moscow	M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry RAS	DSc in chemistry
1985	Russia, Moscow	M.M. Shemyakin and Institute of Bioorganic Chemistry AS USSR	PhD in biochemistry
1976–1981	Russia, Moscow	M.V. Lomonosov Moscow State University (chemical faculty)	Ms in chemistry (Cum laude)

Teaching

Period	Coyntry, city	Course	Additional info

IBCh positions

2008–to date

Head of Laboratory

Laboratory of lipid chemistry

IBCh memberships

Scientific council

Titles

2007	Doctor of Science (Chemistry)
1985	Doctor of Philosophy (Chemistry)

Scientific interests

Dr. Vodovozova has specialized in the design of targeted drug delivery systems (nanocarriers) on the basis of liposomes, lipid derivatives of anticancers (lipophilic prodrugs) and lipophilic glycoconjugates (vectors) from the middle of 1990 years. Another field of the research, which she has developed, relates to the synthesis of photoaffinity probes bearing new high-performance photophore — diazocyclopentadien-2-ylcarbonyl group.

Scientific results

In collaboration with Russian and foreign colleagues, new data on membrane topography of cytochrome P-450 were received. Also, some aspects of knowledge on the mechanism of interleukin-2 receptor assembly in activated T-cells have been clarified, as well as fragments of interleukin-4 molecule involved in the interaction with ganglioside GM1 have been determined.

Work on development of the approach to liposomal therapeutics based on incorporation of lipophilic prodrugs in the lipid bilayer is ongoing in the Laboratory of lipid chemistry (Institute of Bioorganic Chemistry, RAS). Delivery of drugs to tumor cells as lipophilic conjugates within liposomal membrane offers a number of advantages compared to encapsulation of the intact drug in the inner aqueous volume of the carrier: drug leakage in the course of circulation and upon interaction with cells decreases; the mechanisms of cell penetration of a drug and its intracellular traffic is modified, which increases the potential to overcome multiple drug resistance of tumor cells; the technology to produce nanosized liposomes with efficient concentration of drug is simplified. When inside a target cell, prodrug is cleaved by endogenous enzymes releasing the active agent. Earlier we have synthesized diglyceride ester conjuagtes of chemotherapeutic agents widely used in clinic, namely an alkylating agent melphalan and a folic acid antimetabolite methotrexate (Mlph-DG and MTX-DG); based on these lipophilic prodrugs and natural phospholipids, stable 100-nm liposomes were obtained [1–3].Over the past 5 years, efficiency of liposomal formulations of the prodrugs has been demonstrated in the following murine models in vivo: acute T lympholeucosis [4], WNT-1 breast cancer [5]. In alliance with the Drugs Technology company (Khimki, Moscow district), a method to produce liposomes for long-term storage using lyophilization in the presence of a cryoprotector has been developed. Synthesis of lipophilic melphalan prodrug has been scaled up. In preclinical studies, liposomal Mlph-DG showed two-fold decreased toxicity and improved tolerability compared to Alkeran (Glaxo, Italy) upon intravenous administration in rats; liposomal Mlph-DG was recommended for approval for clinical studies [5].In order to increase selectivity of the effect (targeting therapy), liposomes carrying a targeting ligand, the SiaLeX tetrasaccharide, for delivery to angiogenic endothelium have been obtained. Antivascular effect of SiaLeX liposomes loaded with Mlph-DG leading to enhanced tumor growth inhibition in a model of Lewis lung carcinoma compared to ligand-free liposomes has been demosntrated earlier, and binding of SiaLeX liposomes with tumor microvessels and accumulation of targeting ligand-free liposomes in tumor tissue by means of extravasation was visualized. Selective effect of SiaLeX liposomes on endothelial cells activated by an anti-inflammatory cytokine has been established; not activated cells bind insignificant amounts of liposomes independently of the presence of the SiaLeX ligand [6]. Therefore, the potential for targeted effect of SiaLeX liposomes at tumor and inflammation sites is realized.Earlier, we demonstrated that liposomes with Mlph-DG and MTX-DG, including those with SiaLeX targeting ligand, do not affect key constituents of human blood, i.e. red blood cells and platelets [7]. However, in contrast to inert Mlph-DG formulations, MTX-containing liposomes caused impaired coagulation and induced complement (C) activation, which resulted in production of the C3a anaphylatoxin. These undesired effects were minimized upon lower loading percent of MTX-DG in the bilayer [7]. Later, data on differential binding of plasma proteins by liposomes loaded with Mlph-DG and MTX-DG were obtained [8,9]: only formulations with high content of MTX-DG, which caused C activation in vitro [7] bound fragments of the C3 component and factor H. Our recent results have shown that MTX-DG liposomes activate complement system both via classical and alternative way [9]. Recently, we showed ex vivo that inclusion of MTX-DG in liposomes promotes their phagocytosis by monocytes independently upon the presence of stabilizing components in liposomes, obviously, due to the presence of voluminous methotrexate moiety on the membrane surface [10].The effect of a number of amphiphilic molecules incorporated in the bilayer on Mlph-liposomes integrity in human serum has been studied. Phosphatidylinositol has been shown to prevent degradation of fluid lipid bilayer consisting of 80% egg phosphatidylcholine for at least 4 h, while the GM1 ganglioside and a lipid conjugate of an acidic oligopeptide, for up to 24 h. At the same time, PEG2000-lipid conjugate promoted destruction of liposomes with fluid- or gel-phase bilayer; it stabilized lipid bilayer in liquid-ordered phase, that is containing enough cholesterol [11].

Dr. Vodovozova is the author of more then 100 research articles in Russian and international journals, as well as more than 120 abstracts at conferences, a book, a chapter in monograph, and 4 patents.

References

1. Vodovozova E.L., Kuznetsova N.R., Kadykov V.A., Khutsyan S.S., Gaenko G.P., Molotkovsky Yu.G. Liposomes as nanocarriers of lipid-conjugated antitumor drugs melphalan and methotrexate. Nanotechnologies in Russia 2008, 3 (3–4), 228–239.

2. Kuznetsova N., Kandyba A., Vostrov I., Kadykov V., Gaenko G., Molotkovsky J., Vodovozova E. Liposomes loaded with lipophilic prodrugs of methotrexate and melphalan as convenient drug delivery vehicles. J. Drug Deliv. Sci. Technol. 2009, 19 (1), 51-59.

3. Krasnov V.P., Korolyova M.A., Vodovozova E.L. Nano-sized melphalan and sarcolysine drug delivery systems: synthesis and prospects of application. Russian Chemical Reviews 2013, 82 (8), 783-814.

4. Alekseeva A.S., Moiseeva E.V., Onishchenko N.R., Boldyrev I.A., Singin A.S., Budko A.P., Shprakh Z.S., Molotkovsky J.G., Vodovozova E.L. Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma. Int. J. Nanomedicine 2017, 12, 3735–3749.

5. Tretiakova D., Svirshchevskaya E., Onishchenko N., Alekseeva A., Boldyrev I., Kamyshinsky R., Natykan A., Lokhmotov A., Arantseva D., Shobolov D., Vodovozova E. Liposomal formulation of a melphalan lip ophilic prodrug: Studies of acute toxicity, tolerability, and antitumor efficacy, Curr. Drug. Deliv. 2020, 17(4) 312-323.

6. Alekseeva A., Kapkaeva M., Shcheglovitova O., Boldyrev I., Pazynina G., Bovin N., Vodovozova E. Interactions of antitumour Sialyl Lewis X-liposomes with vascular endothelial cells. Biochim. Biophys. Acta - Biomembranes 2015, 1848, 1099–1110.

7. Kuznetsova N.R., Sevrin C., Lespineux D., Bovin N.V., Vodovozova E.L., Mészáros T., Szebeni J., Grandfils C. Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer. J. Control. Release 2012, 160 (2), 394-400.

8. Кузнецова Н.Р., Водовозова Е.Л. Дифференциальное связывание белков плазмы крови липосомами, несущими в бислое липофильные пролекарства метотрексата и мелфалана. Биохимия 2014, 79 (8), 999–1008.

9. D.S. Tretiakova, N.R. Onishchenko, A.G. Vostrova, E.L. Vodovozova. Interactions of liposomes carrying lipophilic prodrugs in the bilayer with blood plasma proteins. Russ. J. Bioorg. Chem. 2017, 43, 678-689.

10. Tretiakova D.S., Khaidukov S.V., Babayants A.A., Frolova I.S., Shcheglovitova O.N., Onishchenko N.R., Vodovozova E.L. Lipophilic Prodrug of Methotrexate in the Membrane of Liposomes Promotes Their Uptake by Human Blood Phagocytes. Acta Naturae 2020,12(1) 99-109.

11. Tretiakova D., Onishchenko N., Boldyrev I., Mikhalyov I., Tuzikov A., Bovin N., Evtushenko E., Vodovozova E. Influence of stabilizing components on the integrity of antitumor liposomes loaded with lipophilic prodrug in the bilayer. Colloids and Surfaces B: Biointerfaces 2018, 166, 45–53.