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Differential binding of plasma proteins by liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the bilayer

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Abstract

Immediately upon contact with blood, nanosized drug delivery systems become coated with a so-called protein corona. The quantitative and qualitative composition of the corona defines not only the behavior of the nanocarrier in the circulation but, ultimately, the pharmacokinetics and biodistribution of the encapsulated drug as well. In turn, the composition of the protein corona depends on the surface properties of the nanoparticles, such as size and distribution of charge and functional groups on the particle surface. Liposomes belong to the most bio- and hemocompatible drug delivery systems feasible for intravenous route of administration required in chemotherapy of metastasizing tumors. However, knowledge on the interactions of liposomes of various compositions with blood plasma proteins remains fragmentary. Moreover, all nanosized drug delivery systems are potential targets for the innate immunity system, primarily the complement (C) system, which underlies frequent cases of hypersensitivity reactions. Recently, in a panel of in vitro hemocompatibility tests, we demonstrated that liposomes built of natural phospholipids — egg phosphatidylcholine and phosphatidylinositol from Saccharomyces cerevisiae — and loaded with diglyceride conjugates of anticancer drugs melphalan and methotrexate, did not affect the morphology and numbers of the main blood cell types. While preparations with melphalan prodrug were also inert in coagulation and C activation tests, methotrexate-loaded liposomes caused impaired coagulation and C activation. The aim of this work was to study the interactions of liposomes carrying prodrugs of melphalan and methotrexate with blood plasma proteins in vitro. Data on protein binding capacity of liposomes obtained with classical gel permeation chromatography techniques allowed for prediction of rather rapid elimination of the liposomes from circulation. A number of differences revealed through immunoblotting of the liposome-bound proteins agree with the previously obtained data on C activation. The possible mechanism of C activation by methotrexate-containing liposomes is discussed.

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Abbreviations

C:

complement

Mlph-DOG:

diglyceride conjugate of melphalan

Mlph-L:

liposomes loaded with Mlph-DOG

MTX-DOG:

diglyceride conjugate of methotrexate

MTX-L:

liposomes loaded with MTX-DOG

PB :

protein binding

PBS:

phosphate buffered saline

PC:

phosphatidylcholine

PI:

phosphatidylinositol

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Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997, Moscow, Russia

    N. R. Kuznetsova & E. L. Vodovozova

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  1. N. R. Kuznetsova
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  2. E. L. Vodovozova
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Correspondence to E. L. Vodovozova.

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Published in Russian in Biokhimiya, 2014, Vol. 79, No. 8, pp. 999–1008.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM14-078, June 22, 2014.

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Kuznetsova, N.R., Vodovozova, E.L. Differential binding of plasma proteins by liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the bilayer. Biochemistry Moscow 79, 797–804 (2014). https://doi.org/10.1134/S0006297914080070

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  • DOI: https://doi.org/10.1134/S0006297914080070

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