posted on 2017-02-24, 00:00authored byMonika Dzieciuch-Rojek, Chetan Poojari, Jan Bednar, Alex Bunker, Bartłomiej Kozik, Maria Nowakowska, Ilpo Vattulainen, Paweł Wydro, Mariusz Kepczynski, Tomasz Róg
Itraconazole (ITZ) is an antifungal
agent used clinically to treat
mycotic infections. However, its therapeutic effects are limited by
low solubility in aqueous media. Liposome-based delivery systems (LDS)
have been proposed as a delivery mechanism for ITZ to alleviate this
problem. Furthermore, PEGylation, the inclusion in the formulation
of a protective “stealth sheath” of poly(ethylene glycol)
around carrier particles, is widely used to increase circulation time
in the bloodstream and hence efficacy. Together, these themes highlight
the importance of mechanistic and structural understanding of ITZ
incorporation into liposomes both with and without PEGylation because
it can provide a potential foundation for the rational design of LDS-based
systems for delivery of ITZ, using alternate protective polymers or
formulations. Here we have combined atomistic simulations, cryo-TEM,
Langmuir film balance, and fluorescence quenching experiments to explore
how ITZ interacts with both pristine and PEGylated liposomes. We found
that the drug can be incorporated into conventional and PEGylated
liposomes for drug concentrations up to 15 mol % without phase separation.
We observed that, in addition to its protective properties, PEGylation
significantly increases the stability of liposomes that host ITZ.
In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
(POPC) bilayer without PEGylation, ITZ was found to reside inside
the lipid bilayer between the glycerol and the double-bond regions
of POPC, adopting a largely parallel orientation along the membrane
surface. In a PEGylated liposome, ITZ partitions mainly to the PEG
layer. The results provide a solid basis for further development of
liposome-based delivery systems.