Laboratory of lipid chemistry

Laboratory studies a relationship between a structure and a function of lipids – the main component of the cell membrane. Basing on the study researchers create lipid conjugates with biologically active molecules (including drugs), surfactants, lipids which have reporter groups (lipid probes are unique instruments for scientific research) etc.

Fluorescent and photoaffinity lipid probes, designed taking into account the properties of lipid membranes, are developing by use of effective synthetic schemes. Today researchers are creating advanced drug delivery systems for nanomedicine.

The laboratory is equipped with everything necessary for analysis (HPLC and GC) and chemical synthesis of lipids (including rare devices for oxidation by singlet oxygen and ozonation).

In the field of synthesis, isolation and purification, study, and most importantly - the use of substances derived Lipid Laboratory collaborates with other laboratories of the IBCh RAS, as well as with the Moscow Technological University (MTU), Moscow State University (MSU), The Pirogov Russian National Research Medical University  (RNRMU), Saratov and Nizhny Novgorod Universities, N.F. Gamaleya Research Institute for Epidemiology and Microbiology, Gel'mgol'ts Institute of Ocular Diseases, N.N. Blokhin Russian Cancer Research Center, University of Umea (Sweden), Hormel Institute (USA), University of Liège (Belgium) and others.

Laboratory was created in 1963, just four years after the founding of the Institute. Lev D. Bergelson headed a new Laboratory. He was able to hold a tremendous amount of work to systematize methods of isolation of lipids from natural sources, study the structure and develop the chemical synthesis of lipids and their analogues. He also made a serious progress in the field of studying the structure and function of biological membranes, the role of lipids in various pathologies. In 1991 the Laboratory was headed by Julian G. Molotkovsky who contributed greatly to the development of fluorescent lipid probes. Since 2009 the Laboratory headed by Elena L. Vodovozova is mainly engaged in a pharmaceutical development.

Experience accumulated over 50 years, in fact, created over the years a scientific school, allows to finding unconventional solutions in the field of lipid chemistry and successfully deal with the challenges.

• Creating nanoscale systems of targeted delivery drugs based on liposomes, lipophilic prodrugs and lipophilic glycoconjugates (Figs. 1 and 2). Targeted liposomes surpassed original drugs and liposomes free of a carbohydrate ligand, in the antitumor effect (Fig. 3).

• Synthesis of new fluorescent lipid probes; studying structure and functions of membranes, and patterns of excitation energy transfer between the fluorophores using these probes (Figs. 4 and 5).

• Was realized the synthesis of unsaturated natural fatty acid based on stereochemistry of the Wittig reaction.

• Was found the phenomenon of dedifferentiation the lipid composition of organelles of cancer cells (L.D. Bergelson, E.V. Dyatlovitskaya).

• Was studied a spread and a role of a new class of diol lipid (L.D. Bergelson and V.A. Wawer).

• Was synthesized and proven a structure of bacterial lipoamino acids and performed the synthesis of unsaturated phosphatidylinositol (L.D. Bergelson and J.G. Molotkovsky).

• Was studied topology of membranes using NMR-spectroscopy (L.D. Bergelson and L.I. Barsukov in collaboration with V.F. Bystrov).

• Was discovered and proved the structure of a new class of bacterial ornithine-containing lipids (L.D. Bergelson and S.G. Batrakov).

• Was synthesized and used in biological studies a large range of fluorescent and photoaffinity lipid probes (L.D. Bergelson, J.G. Molotkovsky, E.L. Vodovozova, I.I. Mikhalyov, I.A. Boldyrev).

• Was developed a targeted liposomal delivery to the tumor of lipid-modified anti-cancer agents (J.G. Molotkovsky, E.L. Vodovozova, G.P. Gayenko in cooperation with N.V. Bovin).

• Was shown that the developed liposomal drugs are hemocompatible (N.R. Kuznetsova, E.L. Vodovozova in collaboration with the University of Liège and Nanomedicine Center in Budapest).

Was shown in vivo (in the model of Lewis lung carcinoma) that the antitumor effect of the 100 nm liposomes designed on the basis of natural phospholipids and lipophilic melphalan prodrug and bearing selectin ligand sialyl Lewis X (SiaLeX) tetrasaccharide, was caused by the specific antivasсular effect in tumor tissue (E.L. Vodovozova, N.R. Kuznetsova in cooperation with N.V. Bovin and N.N. Blokhin Russian Cancer Research Center).

• Was shown (on the model of human umbilical vein endothelial cells) that SiaLeX-liposomes loaded with a lipophilic melphalan prodrug selectively deliver drug to cells activated by tumor necrosis factor alpha (TNF-α) (A.S. Alekseev, E.L. Vodovozova in cooperation with the Institute N.F. Gamaleya Research Institute for Epidemiology and Microbiology).

• Was studied the function of the reopened ceramide-1-phosphate-transporting protein (C1P), widely distributed in mammalian tissues using a set of fluorescently-labeled phospholipids and glycolipids. Was shown that C1P modifies phospholipase A2 activity and mediates the biosynthesis of eicosanoids (J.G. Molotkovsky in collaboration with the Institute of Hormel and others).

Fig. 1. Structures of lipophilic prodrugs and glycoconjugates.

Fig. 2. Electron micrographs of the replicas of freeze fracture surfaces of (A, a) MTX-DG- and (B, b) Mlph-DG-containing liposomes.

Fig. 3. Weekly survival dynamics of BLRB mice with grafted mammary adenocarcinoma in different experimental groups (n=10). Mice were treated iv on the 3rd and 7th days after tumor cells inoculation. Groups: 1 — merphalan (sarcolysine); 2 — empty liposomes; 3 — liposomes + prodrug; 4 — liposomes + prodrug + SiaLeX-conjugate; 5 — liposomes + SiaLeX-conjugate; Control — physiological solution.

Fig. 4. Set of fluorescent probes for membrane studies across the bilayer. Plots in grey — order parameter profiles for the set in bilayers of different composition.

lipchem

Fig. 5. Structure of the BODIPY–FL–C3–GM1 ganglioside, the fluorescent raft marker.

Current Grants:

RNF № 14-15-00128 “«Gate» of blood-brain barrier: mechanisms of regulation, their dependence on the state of the body and age, methods of correction by supramolecular transport systems". Performers:  E.L. Vodovozova; leader institution: Saratov State University.

RFBR № 15-04-07415-a "Study of lipid-protein interactions in biological membranes and cells with a fluorescent lipid probes". Head: J.G. Molotkovsky.

RFBR № 16-04-01585-a "Studies of the fate of antitumor liposomes loaded in the bilayer with lipophilic prodrug of methotrexate in human plasma". Head: E.L. Vodovozova.

RFBR № 15-33-20523 "New fluorescent indicators of activity and substrate specificity of different types of phospholipase A2". Head: I.A. Boldyrev.

RFBR № 16-34-01237 "Study the mechanisms of penetration into cells and intracellular trafficking of liposomal forms of lipophilic methotrexate prodrug". Head: A.S. Alekseeva.

NamePositionContacts
Elena Vodovozova, D.Scdepart. dir.Elvod@ibch.ru+7(495)330-66-10
Julian Molotkovsky, D.Sc, professorpr. r. f.jgmol@ibch.ru+7(495)330-66-01
Ivan Boldyrev, Ph.D.s. r. f.ivan@lipids.ibch.ru+7(495)330-66-10, +7(926)224-68-06
Galina Gayenko, Ph.D.s. r. f.GPG008@mail.ru+7(495)330-66-83
Ilya Mikhalyov, Ph.D.s. r. f.Ilya.Mikhalyov@gmail.com+7(495)330-66-10
Anna Vostrova, Ph.D.r. f.anna.vostrova@gmail.com+7(495)330-69-74
Natalia Onishchenko (Kuznetsova), Ph.D.r. f.natalia@lipids.ibch.ru+7(495)330-66-10
Anna Alekseevaj. r. f.anna@lipids.ibch.ru+7(495)330-66-10
Daria TretiakovaPhD stud.daria@lipids.ibch.ru+7(495)330-66-10

Former members:

Lev Bergelson, corresponding member of the academy of sciencesdepart. dir.
Galina Zhukovat. q. - lab. as.

Selected publications

  1. Tretiakova D, Onishchenko N, Boldyrev I, Mikhalyov I, Tuzikov A, Bovin N, Evtushenko E, Vodovozova E (2018). Influence of stabilizing components on the integrity of antitumor liposomes loaded with lipophilic prodrug in the bilayer. Colloids Surf B Biointerfaces 166 (0), 45–53
  2. Koukalová A, Amaro M, Aydogan G, Gröbner G, Williamson PTF, Mikhalyov I, Hof M, Šachl R (2017). Lipid Driven Nanodomains in Giant Lipid Vesicles are Fluid and Disordered. Sci Rep 7 (1), 5460
  3. Alekseeva AA, Moiseeva EV, Onishchenko NR, Boldyrev IA, Singin AS, Budko AP, Shprakh ZS, Molotkovsky JG, Vodovozova EL (2017). Liposomal formulation of a methotrexate lipophilic prodrug: Assessment in tumor cells and mouse T-cell leukemic lymphoma. Int J Nanomedicine 12 (0), 3735–3749
  4. Galimzyanov TR, Lyushnyak AS, Aleksandrova VV, Shilova LA, Mikhalyov II, Molotkovskaya IM, Akimov SA, Batishchev OV (2017). Line Activity of Ganglioside GM1 Regulates the Raft Size Distribution in a Cholesterol-Dependent Manner. Langmuir 33 (14), 3517–3524
  5. Третьякова ДС, Онищенко НР, Вострова АГ, Водовозова ЕЛ (2017). Взаимодействия противоопухолевых липосом, несущих липофильные пролекарства в бислое, с белками плазмы крови. 43 (6), 661–673
  6. Zhai X, Gao YG, Mishra SK, Simanshu DK, Boldyrev IA, Benson LM, Bergen HR, Malinina L, Mundy J, Molotkovsky JG, Patel DJ, Brown RE (2017). Phosphatidylserine stimulates ceramide 1-phosphate (C1P) intermembrane transfer by C1P transfer proteins. J Biol Chem 292 (6), 2531–2541
  7. Amaro M, Šachl R, Aydogan G, Mikhalyov II, Vácha R, Hof M (2016). GM1Ganglioside Inhibits β-Amyloid Oligomerization Induced by Sphingomyelin. Angew Chem Int Ed Engl 55 (32), 9411–9415
  8. German SV, Navolokin NA, Kuznetsova NR, Zuev VV, Inozemtseva OA, Aniskov AA, Volkova EK, Bucharskaya AB, Maslyakova GN, Fakhrullin RF, Terentyuk GS, Vodovozova EL, Gorin DA (2015). Liposomes loaded with hydrophilic magnetite nanoparticles: Preparation and application as contrast agents for magnetic resonance imaging. Colloids Surf B Biointerfaces 135 (0), 109–115
  9. Šachl R, Amaro M, Aydogan G, Koukalová A, Mikhalyov II, Boldyrev IA, Humpolíčková J, Hof M (2015). On multivalent receptor activity of GM1 in cholesterol containing membranes. BIOCHIM BIOPHYS ACTA 1853 (4), 850–857
  10. Malinina L, Simanshu DK, Zhai X, Samygina VR, Kamlekar R, Kenoth R, Ochoa-Lizarralde B, Malakhova ML, Molotkovsky JG, Patel DJ, Brown RE (2015). Sphingolipid transfer proteins defined by the GLTP-fold. Q Rev Biophys 48 (3), 281–322
  11. Alekseeva A, Kapkaeva M, Shcheglovitova O, Boldyrev I, Pazynina G, Bovin N, Vodovozova E (2015). Interactions of antitumour Sialyl Lewis X liposomes with vascular endothelial cells. BIOCHIM BIOPHYS ACTA 1848 (5), 1099–1110
  12. Chugunov AO, Volynsky PE, Krylov NA, Boldyrev IA, Efremov RG (2014). Liquid but durable: Molecular dynamics simulations explain the unique properties of archaeal-like membranes. Sci Rep 4 (0), 7462
  13. Trusova VM, Molotkovsky JG, Kinnunen PKJ, Gorbenko GP (2014). Structural aspects of cytochrome c – cardiolipin interactions: Förster resonance energy transfer study.  (0), 173–223
  14. Zhai X, Boldyrev IA, Mizuno NK, Momsen MM, Molotkovsky JG, Brockman HL, Brown RE (2014). Nanoscale packing differences in sphingomyelin and phosphatidylcholine revealed by bodipy fluorescence in monolayers: Physiological implications. Langmuir 30 (11), 3154–3164
  15. Simanshu DK, Zhai X, Munch D, Hofius D, Markham JE, Bielawski J, Bielawska A, Malinina L, Molotkovsky JG, Mundy JW, Patel DJ, Brown RE (2014). Arabidopsis accelerated cell death 11, ACD11, Is a ceramide-1-phosphate transfer protein and intermediary regulator of phytoceramide levels. Cell Rep 6 (2), 388–399
  16. Trusova VM, Molotkovsky JG, Kinnunen PKJ, Gorbenko GP (2014). Structural aspects of cytochrome c-cardiolipin interactions: Förster resonance energy transfer study.  (0), 173–223
  17. Krasnov VP, Korolyova MA, Vodovozova EL (2013). Nano-sized melphalan and sarcolysine drug delivery systems: Synthesis and prospects of application. RUSS CHEM REV 82 (8), 783–814
  18. Simanshu DK, Kamlekar RK, Wijesinghe DS, Zou X, Zhai X, Mishra SK, Molotkovsky JG, Malinina L, Hinchcliffe EH, Chalfant CE, Brown RE, Patel DJ (2013). Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature 500 (7463), 463–467
  19. Zhai X, Momsen WE, Malakhov DA, Boldyrev IA, Momsen MM, Molotkovsky JG, Brockman HL, Brown RE (2013). GLTP-fold interaction with planar phosphatidylcholine surfaces is synergistically stimulated by phosphatidic acid and phosphatidylethanolamine. J Lipid Res 54 (4), 1103–1113
  20. Kamlekar RK, Simanshu DK, Gao YG, Kenoth R, Pike HM, Prendergast FG, Malinina L, Molotkovsky JG, Venyaminov SY, Patel DJ, Brown RE (2013). The glycolipid transfer protein (GLTP) domain of phosphoinositol 4-phosphate adaptor protein-2 (FAPP2): Structure drives preference for simple neutral glycosphingolipids. BIOCHIM BIOPHYS ACTA 1831 (2), 417–427
  21. Kuznetsova NR, Sevrin C, Lespineux D, Bovin NV, Vodovozova EL, Mészáros T, Szebeni J, Grandfils C (2012). Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer. J Control Release 160 (2), 394–400
  22. Samygina VR, Popov AN, Cabo-Bilbao A, Ochoa-Lizarralde B, Goni-De-Cerio F, Zhai X, Molotkovsky JG, Patel DJ, Brown RE, Malinina L (2011). Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein. Structure 19 (11), 1644–1654
  23. Alekseeva AS, Maslov MA, Antipova NV, Boldyrev IA (2011). Comparison of two lipid/DNA complexes of equal composition and different morphology. Colloids Surf B Biointerfaces 88 (1), 512–516
  24. Šachl R, Mikhalyov I, Gretskaya N, Olźyńska A, Hof M, ÅJohansson LBA (2011). Distribution of BODIPY-labelled phosphatidylethanolamines in lipid bilayers exhibiting different curvatures. Phys Chem Chem Phys 13 (24), 11694–11701
  25. Tuuf J, Kjellberg MA, Molotkovsky JG, Hanada K, Mattjus P (2011). The intermembrane ceramide transport catalyzed by CERT is sensitive to the lipid environment. BIOCHIM BIOPHYS ACTA 1808 (1), 229–235
  26. Kamlekar RK, Gao Y, Kenoth R, Molotkovsky JG, Prendergast FG, Malinina L, Patel DJ, Wessels WS, Venyaminov SY, Brown RE (2010). Human GLTP: Three distinct functions for the three tryptophans in a novel peripheral amphitropic fold. Biophys J 99 (8), 2626–2635
  27. Trusova VM, Gorbenko GP, Akopova I, Molotkovsky JG, Gryczynski I, Borejdo J, Gryczynski Z (2010). Morphological changes of supported lipid bilayers induced by lysozyme: Planar domain formation vs. multilayer stacking. Colloids Surf B Biointerfaces 80 (2), 219–226
  28. Mikhalyov I, Olofsson A, Gröbner G, Johansson LBA (2010). Designed fluorescent probes reveal interactions between amyloid-β(1-40) peptides and GM1gangliosides in micelles and lipid vesicles. Biophys J 99 (5), 1510–1519
  29. Achl R, Boldyrev I, Johansson LBA (2010). Localisation of BODIPY-labelled phosphatidylcholines in lipid bilayers. Phys Chem Chem Phys 12 (23), 6027–6034
  30. Kenoth R, Simanshu DK, Kamlekar RK, Pike HM, Molotkovsky JG, Benson LM, Bergen HR, Prendergast FG, Malinina L, Venyaminov SY, Patel DJ, Brown RE (2010). Structural determination and tryptophan fluorescence of heterokaryon incompatibility C2 protein (HET-C2), a fungal glycolipid transfer protein (GLTP), provide novel insights into glycolipid specificity and membrane interaction by the GLTP fold. J Biol Chem 285 (17), 13066–13078
  31. Trusova VM, Gorbenko GP, Molotkovsky JG, Kinnunen PKJ (2010). Cytochrome c-Lipid Interactions: New Insights from Resonance Energy Transfer. Biophys J 99 (6), 1754–1763
  32. Galkina SI, Stadnichuk VI, Molotkovsky JG, Romanova JM, Sudina GF, Klein T (2010). Microbial alkaloid staurosporine induces formation of nanometer-wide membrane tubular extensions (cytonemes, membrane tethers) in human neutrophils. Cell Adh Migr 4 (1), 32–38
  33. Kuznetsova N, Bovin N, Sevrin C, Lespineux D, Grandfils C, Vodovozova E (2010). Hemocompatibility of liposomes loaded with diglyceride esters of methotrexate and melphalan. Eur Cell Mater 20 (3), 152
  34. Shnyrova AV, Ayllon J, Mikhalyov II, Villar E, Zimmerberg J, Frolov VA (2007). Vesicle formation by self-assembly of membrane-bound matrix proteins into a fluidlike budding domain. J Biophys Biochem Cytol 179 (4), 627–633
  35. Nylund M, Fortelius C, Palonen EK, Molotkovsky JG, Mattjus P (2007). Membrane curvature effects on glycolipid transfer protein activity. Langmuir 23 (23), 11726–11733
  36. Boldyrev IA, Zhai X, Momsen MM, Brockman HL, Brown RE, Molotkovsky JG (2007). New BODIPY lipid probes for fluorescence studies of membranes. J Lipid Res 48 (7), 1518–1532
  37. Gorbenko GP, Molotkovsky JG, Kinnunen PKJ (2006). Cytochrome c interaction with cardiolipin/phosphatidylcholine model membranes: Effect of cardiolipin protonation. Biophys J 90 (11), 4093–4103
  38. Domanov YA, Molotkovsky JG, Gorbenko GP (2005). Coverage-dependent changes of cytochrome c transverse location in phospholipid membranes revealed by FRET. BIOCHIM BIOPHYS ACTA 1716 (1), 49–58
  39. Bergström F, Mikhalyov I, Hägglöf P, Wortmann R, Ny T, Johansson LBA (2002). Dimers of dipyrrometheneboron difluoride (BODIPY) with light spectroscopic applications in chemistry and biology. J Am Chem Soc 124 (2), 196–204
  40. Kalinin SV, Molotkovsky JG (2001). Anion binding to lipid bilayers: A study using fluorescent lipid probes. Cancer Biol Med 14 (6), 831–846
  41. Molotkovskaya IM, Kholodenko RV, Zelenova NA, Sapozhnikov AM, Mikhalev II, Molotkovsky JG (2000). Gangliosides induce cell apoptosis in the cytotoxic line CTLL-2, but not in the promyelocyte leukemia cell line HL-60. Cancer Biol Med 13 (6), 811–822
  42. Vodovozova EL, Moiseeva EV, Grechko GK, Gayenko GP, NifantEv NE, Bovin NV, Molotkovsky JG (2000). Antitumour activity of cytotoxic liposomes equipped with selectin ligand SiaLe(X), in a mouse mammary adenocarcinoma model. Eur J Cancer Clin Oncol 36 (7), 942–949
  43. Balakin KV, Korshun VA, Mikhalev II, Maleev GV, Malakhov AD, Prokhorenko IA, Berlin YA (1999). Erratum: Conjugates of oligonucleotides with polyaromatic fluorophores as promising DNA probes (Biosensors and Bioelectronics 13 (1998) (771-778) PII: S0956566398000414). Biosens Bioelectron 14 (6), 597
  44. Molotkovskaya IM, Zelenova NA, Lutsenko GV, Sapozhnikov AM, Mikhalyov II, Molotkovsky JG (1998). Immunosuppressive activity of glycosphingolipids. Influence of serum factors on ganglioside inhibition of IL-4-dependent cell proliferation. Cancer Biol Med 12 (6), 783–791
  45. Balakin KV, Korshun VA, Mikhalev II, Maleev GV, Malakhov AD, Prokhorenko IA, Berlin YA (1998). Conjugates of oligonucleotides with polyaromatic fluorophores as promising DNA probes. Biosens Bioelectron 13 (78), 771–778
  46. Bogen ST, Karolin J, Molotkovsky JG, Johansson LBA (1998). 1,32-dihydroxy-dotriacontane-bis(Rhodamine) 101 ester: A lipid membrane spanning bichromophoric molecule as revealed by intramolecular Donor-Donor Energy Migration (DDEM). 94 (16), 2435–2440
  47. Hernandez-Jimenez EI, Razinkov VI, Mikhalyov II, Kozminykh AV, Cohen FS, Molotkovsky JG (1997). Selective labeling of the inner liposome leaflet by fluorescent lipid probes, and studies of liposome fusion with influenza virus. Cancer Biol Med 11 (4), 515–527
  48. Polozov IV, Polozova AI, Molotkovsky JG, Epand RM (1997). Amphipathic peptide affects the lateral domain organization of lipid bilayers. BIOCHIM BIOPHYS ACTA 1328 (2), 125–139
  49. Johansson LBA, Bergström F, Edman P, Grechishnikova IV, Molotkovsky JG (1996). Electronic-energy migration and molecular rotation within bichromophoric macromolecules. Part 1. - Test of a model using bis(9-anthrylmethylphosphonate) bisteroid. 92 (9), 1563–1567
  50. UVAROV VY, SOTNICHENKO AI, VODOVOZOVA EL, MOLOTKOVSKY JG, KOLESANOVA EF, LYULKIN YA, STIER A, KRUEGER V, ARCHAKOV AI (1994). Determination of membrane‐bound fragments of cytochrome P‐450 2B4. FEBS J 222 (2), 483–489
  51. Medhage B, Mukhtar E, Kalman B, Johansson LBA, Molotkovsky JG (1992). Electronic energy transfer in anisotropic systems. Part 5. - Rhodamine-lipid derivatives in model membranes. 88 (19), 2845–2851
  52. Johansson LBA, Molotkovsky JG, Bergelson LD (1987). Fluorescence and Absorption Properties of Perylenyl and Perylenoyl Probe Molecules in Solvents and Liquid Crystals. J Am Chem Soc 109 (24), 7374–7381
  53. Bukrinskaya AG, Molotkovsky JG, Vodovozova EL, Manevich YM, Bergelson LD (1987). The molecular organization of the influenza virus surface. Studies using photoreactive and fluorescent labeled phospholipid probes. BIOCHIM BIOPHYS ACTA 897 (2), 285–292
  54. Manevich EM, Lakin KM, Archakov AI, Li VS, Molotkovsky JG, Bezuglov VV, Bergelson LD (1985). Influence of cholesterol and prostaglandin E1on the molecular organization of phospholipids in the erythrocyte membrane. A fluorescent polarization study with lipid-specific probes. BIOCHIM BIOPHYS ACTA 815 (3), 455–460
  55. Molotkovsky JG, Manevich YM, Babak VI, Bergelson LD (1984). Perylenoyl- and anthrylvinyl-labeled lipids as membrane probes. BIOCHIM BIOPHYS ACTA 778 (2), 281–288
  56. Molotkovsky JG, Manevich YM, Babak VI, Bergelson LD (1984). Perylenoyl- and anthrylvinyl-labeled lipids as membrane probes.  (778), 281–288
  57. MOLOTKOVSKY JG, MANEVICH YM, GERASIMOVA EN, MOLOTKOVSKAYA IM, POLESSKY VA, BERGELSON LD (1982). Differential Study of Phosphatidylcholine and Sphingomyelin in Human High‐Density Lipoproteins with Lipid‐Specific Fluorescent Probes. FEBS J 122 (3), 573–579
  58. Molotkovsky JG, Bergelson LD (1973). Synthesis of unsaturated mixed acid phosphatidylinositol of natural configuration. A new procedure for resolving racemic alcohols.  (11), 135–147

Elena Vodovozova

  • Russia, Moscow, Ul. Miklukho-Maklaya 16/10 — On the map
  • IBCh RAS, build. 34, office. 532
  • Phone: +7(495)330-66-10
  • E-mail: Elvod@ibch.ru

New fluorescent probes to research the structure and functions of membranes (2017-11-27)

The use of anthrylvinyl-perylenoyl FRET-pair of phospholipid probes revealed the existence of regulatory interaction site(s) on the surface of ceramide-1 phosphate transfer protein that are specific to the polar head groups of phosphoglycerides in the lipid membrane. This finding delineates new differences between Glycolipid Transfer Proteins superfamily members that are specific for C1P versus glycolipid [1]. By means of new BODIPY FRET-pair of phosphatidylcholine probes, it was shown that heterodimeric V. nikolskii phospholipases A2 induce aggregation and stacking of negatively charged lipid bilayers [2]; this may be one of the mechanisms of PLA2 biological activity. A novel combination of FRET between BODIPY-ganglioside probes and Monte Carlo simulations (MC-FRET) identified directly 10 nm large nanodomains (rafts) composed of sphingomyelin and cholesterol in liquid-disordered model membranes that mimic the cytoplasmic membrane; the nanodomains are also fluid and disordered [3].

Publications

  1. Alekseeva AS, Tretiakova DS, Chernikov VP, Utkin YN, Molotkovsky JG, Vodovozova EL, Boldyrev IA (2017). Heterodimeric V. nikolskii phospholipases A2 induce aggregation of the lipid bilayer. Toxicon 133 (0), 169–179
  2. Zhai X, Gao YG, Mishra SK, Simanshu DK, Boldyrev IA, Benson LM, Bergen HR, Malinina L, Mundy J, Molotkovsky JG, Patel DJ, Brown RE (2017). Phosphatidylserine stimulates ceramide 1-phosphate (C1P) intermembrane transfer by C1P transfer proteins. J Biol Chem 292 (6), 2531–2541
  3. Koukalová A, Amaro M, Aydogan G, Gröbner G, Williamson PTF, Mikhalyov I, Hof M, Šachl R (2017). Lipid Driven Nanodomains in Giant Lipid Vesicles are Fluid and Disordered. Sci Rep 7 (1), 5460

Liposomal formulation of a methotrexate lipophilic prodrug: interactions with tumor cells and studies in vivo (2017-11-27)

Previously, we developed a formulation of widely used cytostatic agent methotrexate incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug). Here, we first studied interactions of MTX-DG liposomes with various human and mouse tumor cell lines using fluorescence techniques. Liposomes were labeled with fluorescent analogues of phosphatidylcholine and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies with inhibitors of liposome uptake and processing by cells demonstrated that the formulation utilized multiple mechanisms to deliver the prodrug inside the cell. According to our data, undamaged liposomes fuse with the cell membrane only 1.5–2 h after binding to the cell surface and then the components of liposomal bilayer enter the cell separately. The study of the time course of plasma concentration in mice showed that the AUC (area under the curve) of methotrexate generated upon intravenous injection of MTX-DG liposomes exceeded that of intact methotrexate 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen (only four low to middle-dose injections) resulted in lower toxicity and retarded lymphoma growth rate as compared to methotrexate.