title: Effects of Membrane PEGylation on Entry and Location of Antifungal Drug Itraconazole and Their Pharmacological Implications.
abstract: 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.
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Dzieciuch-Rojek
authors.affiliation: Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.
authors.forename: Chetan
authors.initials: C
authors.lastname: Poojari
authors.affiliation: Université de Grenoble Alpes/CNRS, Institut Albert Bonniot , UMR 5309, 38042 CEDEX 9 Grenoble, France.|First Faculty of Medicine, Laboratory of Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, Charles University in Prague , KeKarlovu 2, 12800 Prague 2, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Bednar
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Alex
authors.initials: A
authors.lastname: Bunker
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Kozik
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Nowakowska
authors.affiliation: Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.|Department of Physics, University of Helsinki , P.O. Box 64, FI-00014 Helsinki, Finland.|MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark , Odense, Denmark.
authors.forename: Ilpo
authors.identifier: 0000-0001-7408-3214
authors.initials: I
authors.lastname: Vattulainen
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Wydro
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Mariusz
authors.identifier: 0000-0002-7304-6881
authors.initials: M
authors.lastname: Kepczynski
authors.affiliation: Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.|Department of Physics, University of Helsinki , P.O. Box 64, FI-00014 Helsinki, Finland.
authors.forename: Tomasz
authors.identifier: 0000-0001-6765-7013
authors.initials: T
authors.lastname: Róg
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D005453:Fluorescence; D017964:Itraconazole / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D008566:Membranes / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D020011:Protective Agents / Q000737:chemistry; D012995:Solubility; D013499:Surface Properties
chemical_list: D000935:Antifungal Agents; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D011108:Polymers; D020011:Protective Agents; D017964:Itraconazole; D011092:Polyethylene Glycols; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: cryo-TEM; itraconazole; lipid bilayer; molecular dynamics simulations; polyethylene glycol (PEG); sterically stabilized liposomes