Dzieciuch-Rojek Monika, Poojari Chetan, Bednar Jan, Bunker Alex, Kozik Bartłomiej, Nowakowska Maria, Vattulainen Ilpo, Wydro Paweł, Kepczynski Mariusz, Róg Tomasz
Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.
Mol Pharm. 2017 Apr 3;14(4):1057-1070. doi: 10.1021/acs.molpharmaceut.6b00969. Epub 2017 Mar 7.
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.
伊曲康唑（ITZ）是一种临床上用于治疗真菌感染的抗真菌药物。然而，其治疗效果受到在水性介质中低溶解度的限制。基于脂质体的递送系统（LDS）已被提议作为ITZ的一种递送机制来缓解这一问题。此外，聚乙二醇化，即在载体颗粒周围的制剂中包含一层保护性的聚（乙二醇）“隐形鞘”，被广泛用于延长在血流中的循环时间从而提高疗效。总之，这些主题凸显了理解ITZ在有或没有聚乙二醇化的情况下掺入脂质体的机制和结构的重要性，因为这可以为合理设计基于LDS的ITZ递送系统提供潜在基础，该系统可使用替代的保护性聚合物或制剂。在这里，我们结合了原子模拟、冷冻透射电子显微镜、朗缪尔膜天平以及荧光猝灭实验，以探究ITZ如何与原始脂质体和聚乙二醇化脂质体相互作用。我们发现，对于高达15 mol%的药物浓度，该药物可以掺入常规脂质体和聚乙二醇化脂质体中而不发生相分离。我们观察到，除了其保护特性外，聚乙二醇化还显著提高了容纳ITZ的脂质体的稳定性。在没有聚乙二醇化的1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（POPC）双层膜中，发现ITZ位于POPC的甘油和双键区域之间的脂质双层内部，沿着膜表面采取大致平行的取向。在聚乙二醇化脂质体中，ITZ主要分配到聚乙二醇层。这些结果为基于脂质体的递送系统的进一步开发提供了坚实的基础。
