Phosphatidylinositol stabilizes fluid-phase liposomes loaded with a melphalan lipophilic prodrug

Daria Tretiakova, Irina Le-Deigen, Natalia Onishchenko, Judith Kuntsche, Elena Kudryashova, Elena Vodovozova*

*Kontaktforfatter for dette arbejde

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Previously, a liposomal formulation of a chemotherapeutic agent melphalan (Mlph) incorporated in a fluid lipid bilayer of natural phospholipids in the form of dioleoylglyceride ester (MlphDG) was developed and the antitumor effect was confirmed in mouse models. The formulation composed of egg phosphatidylcholine (ePC), soybean phosphatidylinositol (PI), and MlphDG (8:1:1, by mol) showed stability in human serum for at least 4–5 h. On the contrary, replacing PI with pegy-lation of the liposomes, promoted fast dissociation of the components from the bilayer. In this work, interactions of MlphDG-liposomes with the most abundant plasma protein—albumin—in function of the presence of PI in the formulation were explored using Fourier transform infrared spectroscopy. The release of MlphDG from the liposomes was studied by asymmetrical flow field-flow fractionation (AF4) using micelles formed by a polyethylene glycol conjugate with phosphatidylethanolamine to mimic the physiological lipid sink like lipoproteins. Our results show that PI actually protects the membrane of MlphDG-liposomes from the protein penetration, presumably due to pairing between the positively charged MlphDG and negatively charged PI, which compensates for the heterogeneity of the lipid bilayer. The AF4 technique also evidences high stability of the formulation as a drug carrier.

Udgave nummer4
Antal sider19
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
Funding: The research was supported by the Russian Science Foundation, project number 21-74-20177. Asymmetrical flow-field-flow fractionation experiments were supported by an FEBS short-term fellowship.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


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