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    Interactions of anticancer drugs doxorubicin and idarubicin with lipid monolayers: New insight into the composition, structure and morphology

    Year: 2021

    Journal: J. Colloid Interface Sci., Volume 581, JAN 1, page 403–416

    Authors: Matyszewska, Dorota; Nazaruk, Ewa; Campbell, Richard A.

    Organizations: Polish National Science Centre [2016/23/D/ST4/03200]; European Union from the European Regional Development Fund under the Operational Program Innovative Economy, 2007-2013; FILL2030, a European Union project within the European Commission's Horizon 2020 Research and Innovation programme [731096]

    Keywords: Anthracycline drugs; Doxorubicin; Idarubicin; Lipid monolayers; Neutron reflectometry; Langmuir trough

    We quantify directly here for the first time the extents of interactions of two different anthracycline drugs with pure and mixed lipid monolayers with respect to the surface pressure and elucidate differences in the resulting interaction mechanisms. The work concerns interactions of doxorubicin (DOx) and idarubicin (IDA) with monolayers of the zwitterionic DMPC (1,2-dimyristoyl-sn-glycero-3-phospho choline) and negatively charged DMPS (1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (sodium salt)) as well as a 7:3 mixture of the two lipids. These drugs are used in current cancer treatments, while the lipid systems were chosen as phosphocholines are the major lipid component of healthy cell membranes, and phosphoserines are the major lipid component that is externalized into the outer leaflet of cancerous cell membranes. It is shown that DOx interacts with DMPS monolayers to a greater extent than with DMPC monolayers by lower limits of a factor of 5 at a surface pressure of 10 mN/m and a factor of 12 at 30 mN/m. With increasing surface pressure, the small amount of drug (similar to 0.3 mu mol/m(2)) bound to DMPC monolayers is excluded from the interface, yet its interaction with DMPS monolayers is enhanced until there is even more drug (similar to 3.2 mu mol/m(2)) than lipid (similar to 2.6 mu mol/m(2)) at the interface. Direct evidence is presented for all systems studied that upon surface area compression lipid is reproducibly expelled from the monolayer, which we infer to be in the form of drug-lipid aggregates, yet the nature of adsorption of material back to the monolayer upon expansion is system-dependent. At 30 mN/m, most relevant to human physiology, the interactions of DOx and IDA are starkly different. For DOx, there is a conformational change in the interfacial layer driven by aggregation, resulting in the formation of lateral domains that have extended layers of drug. For the more lipophilic IDA, there is penetration of the drug into the hydrophobic acyl chain region of the monolayer and no indication of lateral segregation. In addition to the Langmuir technique, these advances were made as a result of direct measurements of the interfacial composition, structure and morphology using two different implementations of neutron reflectometry and Brewster angle microscopy. The results provide new insight into key processes that determine the uptake of drugs such as limited drug penetration through cell membranes by passive diffusion as well as activation of drug removal mechanisms related to multidrug resistance. (C) 2020 The Authors. Published by Elsevier Inc.
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