Laboratory of lipid chemistry

 

Laboratory of lipid chemistry was created in 1963 by Lev D. Bergelson. Over the decades research focus has migrated from methods to isolate lipids from natural sources and study their structure, through chemical synthesis of lipids and their analogues, particularly, fluorescent and photoreactive lipid probes, to the structure and function of biological membranes, the role of lipids in various pathologies, and development of lipid-based drug delivery systems.

 

Today, the laboratory of lipid chemistry is a center for development of lipid conjugates and supramolecular ensembles thereof. The studies are aimed at both creation of lipid constructs with preset properties and investigation of the interactions of these constructs with the environment, e.g. biological fluids.

NamePositionContacts
Elena Vodovozova, D.ScHead of lab.elvod@lipids.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
Ilya Mikhalyov, Ph.D.s. r. f.Ilya.Mikhalyov@gmail.com+7(495)330-66-10
Natalia Onishchenko, Ph.D.r. f.natalia@lipids.ibch.ru+7(495)330-66-10
Anna Vostrova, Ph.D.r. f.anna.vostrova@gmail.com+7(495)330-69-74
Anna Alekseeva, Ph.D.j. r. f.anna@lipids.ibch.ru+7(495)330-66-10
Daria Tretiakovaj. r. f.daria@lipids.ibch.ru+7(495)330-66-10
Ekaterina RyabukhinaPhD stud.miss.katringet@yandex.ru
Svetlana Volkovat. q. - lab. as.+7(495)335-32-00

Former members:

Lev Bergelson, corr. member of the RAShead
Galina Gayenko, Ph.D.s. r. f.GPG008@mail.ru
Galina Zhukovat. q. - lab. as.

All publications (show selected)

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Elena Vodovozova

Enzyme-responsive liposomes with phospholipidic colchicinoids

New phospholipidic prodrugs of colchicinoids were synthesized for incorporation into bilayer of enzyme-responsive liposomes. The prodrug design takes into account the structure of the substrate-binding site of target enzyme, phospholipase A2 (PLA2), and the lateral pressure profile inside the bilayer. This allowed for minimal distortions of the lipid packing by the colchicinoid prodrugs and submicromolar cytotoxicity of the liposome carriers.

Publications

  1. Shchegravina ES, Tretiakova DS, Alekseeva AS, Galimzyanov TR, Utkin YN, Ermakov YA, Svirshchevskaya EV, Negrebetsky VV, Karpechenko NY, Chernikov VP, Onishchenko NR, Vodovozova EL, Fedorov AY, Boldyrev IA (2019). Phospholipidic Colchicinoids as Promising Prodrugs Incorporated into Enzyme-Responsive Liposomes: Chemical, Biophysical, and Enzymological Aspects. Bioconjug Chem 30 (4), 1098–1113

Influence of stabilizing components in the lipid bilayer on the integrity of antitumor liposomes loaded with lipophilic prodrug, in human serum

In collaboration with Laboratory of Carbohydrates

We compared the effect of different amphiphiles in lipid bilayer on the integrity of 100-nm-liposomes loaded with lipophilic prodrug of chemotherapeutic agent melphalan, in human serum. Using fluorescence methods phosphatidylinositol was shown to protect fluid phase lipid bilayer based upon egg phosphatidylcholine at least for 4 hours, while ganglioside GM1 or a conjugate of carboxylated oligoglycine with phosphatidylethanolamine up to 24 hours. At the same time, polyethylene glycol (2000 Da) conjugated with dipalmitoylphosphatidylethanolamine (PEG-lipid) promoted degradation of liposomes, so that lipids began to exit fluid phase membrane, while gel phase membrane with less than 10 mol % of PEG-lipid was immediately cracked. Cholesterol-containing bilayers of condenced liquid ordered phase, supplemented with sufficient amounts of the PEG-lipid, showed good stability in serum. The above effects should be accounted when using lipophilic conjugates of PEG in the composition of supramolecular drug delivery systems devoid of covalent bonds, such as liposomes, lipid nanospheres, or micelles.

New fluorescent probes to research the structure and functions of membranes

In collaboration with Laboratory of molecular toxinology

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, 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

In collaboration with Laboratory of biotechnology

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.