posted on 2020-03-05, 17:34authored byChetan Poojari, Agata Zak, Monika Dzieciuch-Rojek, Alex Bunker, Mariusz Kepczynski, Tomasz Róg
Cholesterol
plays a crucial role in modulating the physicochemical
properties of biomembranes, both increasing mechanical strength and
decreasing permeability. Cholesterol is also a common component of
vesicle-based delivery systems, including liposome-based drug delivery
systems (LDSs). However, its effect on the partitioning of drug molecules
to lipid membranes is very poorly recognized. Herein, we performed
a combined experimental/computational study of the potential for the
use of the LDS formulation for the delivery of the antifungal drug
itraconazole (ITZ). We consider the addition of cholesterol to the
lipid membrane. Since ITZ is only weakly soluble in water, its bioavailability
is limited. Use of an LDS has thus been proposed. We studied lipid
membranes composed of cholesterol, 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), and ITZ using a combination of
computational molecular dynamics (MD) simulations of lipid bilayers
and Brewster angle microscopy (BAM) experiments of monolayers. Both
experimental and computational results show separation of cholesterol
and ITZ. Cholesterol has a strong preference to orient parallel to
the bilayer normal. However, ITZ, a long and relatively rigid molecule
with weakly hydrophilic groups along the backbone, predominantly locates
below the interface between the hydrocarbon chain region and the polar
region of the membrane, with its backbone oriented parallel to the
membrane surface; the orthogonal orientation in the membrane could
be the cause of the observed separation. In addition, fluorescence
measurements demonstrated that the affinity of ITZ for the lipid membrane
is decreased by the presence of cholesterol, which is thus probably
not a suitable formulation component of an LDS designed for ITZ delivery.