Effects of Membrane PEGylation on Entry and Location of Antifungal Drug Itraconazole and Their Pharmacological Implications
Language English Country United States Media print-electronic
Document type Journal Article
- Keywords
- cryo-TEM, itraconazole, lipid bilayer, molecular dynamics simulations, polyethylene glycol (PEG), sterically stabilized liposomes,
- MeSH
- Antifungal Agents chemistry MeSH
- Chemistry, Pharmaceutical methods MeSH
- Fluorescence MeSH
- Phosphatidylcholines chemistry MeSH
- Itraconazole chemistry MeSH
- Drug Delivery Systems methods MeSH
- Lipid Bilayers chemistry MeSH
- Liposomes chemistry MeSH
- Membranes chemistry MeSH
- Protective Agents chemistry MeSH
- Polyethylene Glycols chemistry MeSH
- Polymers chemistry MeSH
- Surface Properties MeSH
- Solubility MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Browser
- Antifungal Agents MeSH
- Phosphatidylcholines MeSH
- Itraconazole MeSH
- Lipid Bilayers MeSH
- Liposomes MeSH
- Protective Agents MeSH
- Polyethylene Glycols MeSH
- Polymers MeSH
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.
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
Faculty of Chemistry Jagiellonian University Ingardena 3 30 060 Kraków Poland
MEMPHYS Center for Biomembrane Physics University of Southern Denmark Odense Denmark
Université de Grenoble Alpes CNRS Institut Albert Bonniot UMR 5309 38042 CEDEX 9 Grenoble France
References provided by Crossref.org
Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery
