19-015-00499

Interactions of antitumor liposomes carrying lipophilic prodrugs in the bilayer with endothelial cells and blood plasma proteins under dynamic conditions: biomodelling in a microchannel of a microfluidic device

Liposomal drug delivery systems hold the leading position among nanomedicinal drugs for systemic administration. Due to their inherent low toxicity, they are suitable for chemotherapy of metastasizing tumors. However, upon contact with blood plasma, liposomes—similar to other nanoparticles—are instantly covered by proteins and their complexes with lipids, which constitute the so-called protein corona. Such corona modifies physicochemical properties of the carrier surface defining its behavior in circulation and ultimately determining pharmacokinetics and biodistribution of the encapsulated drug. Another important physiological barrier on the way of a drug vehicle to target cells and tissues are endothelial cells of blood vessels. The aim of the project is to study the effect of dynamic conditions of microflow on the interactions of liposomes carrying lipophilic prodrugs of an alkylating agent melphalan and a folic acid antimetabolite methotrexate, both indispensable agents in oncology, with endothelial cells and blood plasma proteins. To ensure transport to angiogenic endothelium of tumors, liposomes are equipped with a tetrasaccharide selectin ligand SiaLeX. Selectins are adhesion molecules expressed on activated leukocytes, platelets, and endothelial cells and play the key role in inflammation, tumor growth, and metastases. Earlier in vitro and in vivo assessment of liposomes under study produced promising rather. Here, we will use a unique microfluidic model of a microvessel providing for physiological conditions of endothelium functioning in terms of flow and sheer stress to study ways of hydrodynamic targeting of the liposomes to enhance the efficiency of drug delivery to specific parts of bloodstream. In frames of the project, microfluidic devices imitating key features of tumor vasculature will be created. Microfluidic approaches, together with computational hydrodynamics, will allow to produce new data on the effect of abnormal geometry of tumor vasculature on liposome distribution in endothelial layer and compare it to distribution in microchannels imitating normal bloodflow. Project aims include studies of liposomes of different compositions, particularly those carrying various stabilizing components. The project results are expected to promote development of optimized protocols for supramolecular antitumor carriers and correct their parameters for a more efficient delivery to target tissues.

List of publications

  1. Tretiakova DS, Khaidukov SV, Babayants AA, Frolova IS, Shcheglovitova ON, Onishchenko NR, Vodovozova EL (2020). Lipophilic Prodrug of Methotrexate in the Membrane of Liposomes Promotes Their Uptake by Human Blood Phagocytes. Acta Naturae 12 (1), 99–109
  2. Tuzikov AB, Ryabukhina EV, Paramonov AS, Chizhov AO, Bovin NV, Vodovozova EL (2021). A convenient route to conjugates of 1,2-diglycerides with functionalized oligoethylene glycol spacer arms. MENDELEEV COMMUN 31 (4), 538–541
  3. Onishchenko NR, Moskovtsev AA, Kobanenko MK, Tretiakova DS, Alekseeva AS, Kolesov DV, Mikryukova AA, Boldyrev IA, Kapkaeva MR, Shcheglovitova ON, Bovin NV, Kubatiev AA, Tikhonova OV, Vodovozova EL (2023). Protein Corona Attenuates the Targeting of Antitumor Sialyl Lewis X-Decorated Liposomes to Vascular Endothelial Cells under Flow Conditions. Pharmaceutics 15 (6), 1754