The unit was disbanded in 2019. It is part of the unit Department of biotechnology.

Laboratory of biotechnology

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Anatoliy Miroshnikov

  • Russia, Moscow, Ul. Miklukho-Maklaya 16/10 — On the map
  • IBCh RAS, build. 53, office. 6601
  • Phone: +7(495)995-55-57#2005
  • E-mail: aiv@ibch.ru

Fax: +7 (495) 330-74-10

Liposomal formulation of a methotrexate lipophilic prodrug: interactions with tumor cells and studies in vivo

In collaboration with Laboratory of lipid chemistry

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.