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.

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

“…PEGylation modulates the effect of cholesterol on the conformation and dynamics of lipid bilayers [ 153 ]. Their simulations also captured the insertion of hydrophobic drug or light-sensitizing molecules (e.g., porphyrins, indocyanine green, itraconazole, and piroxicam) to the PEG layer and the hydrophobic region of the bilayer ( Figure 6 ) [ 154 , 155 , 156 , 157 , 158 ]. Recently, they simulated linear and branched PEG chains grafted on lipid bilayers, showing that the architecture and length of PEG–lipid conjugates influence the structure and dynamics of membranes, in agreement with experimental results [ 159 ].…”

To Protect and to Preserve: Novel Preservation Strategies for Extracellular Vesicles

“…Advantages of PEG include the fact that it is non-fouling, well-tolerated by the body, can be obtained in a wide range of molecular weights and end-group chemistries and that it is FDA approved for a range of medical applications ( Hasan, 2017 ). There are many examples in which liposomes have been PEGylated, i.e., the PEG chains are incorporated within the lipid bilayer during synthesis (e.g., PEGlyated liposomes to incorporate itraconazole, antifungal agent, as well as dopamine-loaded PEGylated immunoliposomes; Kang et al, 2016 ; Dzieciuch-Rojek et al, 2017 ). Although effective, such a strategy is unsuitable for EV stabilization.…”

Nanoparticles with CD44 Targeting and ROS Triggering Properties as Effective in Vivo Antigen Delivery System

“…It has been demonstrated that PEG fragments not only increase the stability of NPs, but also reduce proteolysis, both of which result in increased circulation time and improved efficacy 20 .Since HA is a member of the mucopolysaccharide family with high viscosity that may attenuate protein release, we have also examined the protein releasing ability of the NPs (Fig. 1D).…”