title: Solubilization Behavior of Polyene Antibiotics in Nanomicellar System: Insights from Molecular Dynamics Simulation of the Amphotericin B and Nystatin Interactions with Polysorbate 80.
abstract: Amphotericin B (AmB) and Nystatin (Nys) are the drugs of choice for treatment of systemic and superficial mycotic infections, respectively, with their full clinical potential unrealized due to the lack of high therapeutic index formulations for their solubilized delivery. In the present study, using a coarse-grained (CG) molecular dynamics (MD) simulation approach, we investigated the interaction of AmB and Nys with Polysorbate 80 (P80) to gain insight into the behavior of these polyene antibiotics (PAs) in nanomicellar solution and derive potential implications for their formulation development. While the encapsulation process was predominantly governed by hydrophobic forces, the dynamics, hydration, localization, orientation, and solvation of PAs in the micelle were largely controlled by hydrophilic interactions. Simulation results rationalized the experimentally observed capability of P80 in solubilizing PAs by indicating (i) the dominant kinetics of drugs encapsulation over self-association; (ii) significantly lower hydration of the drugs at encapsulated state compared with aggregated state; (iii) monomeric solubilization of the drugs; (iv) contribution of drug-micelle interactions to the solubilization; (v) suppressed diffusivity of the encapsulated drugs; (vi) high loading capacity of the micelle; and (vii) the structural robustness of the micelle against drug loading. Supported from the experimental data, our simulations determined the preferred location of PAs to be the core-shell interface at the relatively shallow depth of 75% of micelle radius. Deeper penetration of PAs was impeded by the synergistic effects of (i) limited diffusion of water; and (ii) perpendicular orientation of these drug molecules with respect to the micelle radius. PAs were solvated almost exclusively in the aqueous poly-oxyethylene (POE) medium due to the distance-related lack of interaction with the core, explaining the documented insensitivity of Nys solubilization to drug-core compatibility in detergent micelles. Based on the obtained results, the dearth of water at interior sites of micelle and the large lateral occupation space of PAs lead to shallow insertion, broad radial distribution, and lack of core interactions of the amphiphilic drugs. Hence, controlled promotion of micelle permeability and optimization of chain crowding in palisade layer may help to achieve more efficient solubilization of the PAs.
authors.affiliation: Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran. m.mobasheri@srbiau.ac.ir.
authors.forename: Meysam
authors.initials: M
authors.lastname: Mobasheri
authors.affiliation: Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran. attar.h@srbiau.ac.ir.|Tofigh Daru Research and Engineering Company (TODACO), Tehran 1397116359, Iran. attar.h@srbiau.ac.ir.
authors.forename: Hossein
authors.initials: H
authors.lastname: Attar
authors.affiliation: Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 1417755469, Iran. rezayat@sina.tums.ac.ir.|Department of Toxicology and Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran 193956466, Iran. rezayat@sina.tums.ac.ir.
authors.forename: Seyed Mehdi
authors.initials: SM
authors.lastname: Rezayat Sorkhabadi
authors.affiliation: Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran 1416613675, Iran. khamesipour@tums.ac.ir.
authors.forename: Ali
authors.initials: A
authors.lastname: Khamesipour
authors.affiliation: Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box: 91775-1365, Mashhad 917751365, Iran. jafarimr@mums.ac.ir.
authors.forename: Mahmoud Reza
authors.initials: MR
authors.lastname: Jaafari
mesh_terms: D000666:Amphotericin B / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009761:Nystatin / Q000737:chemistry*; D010316:Particle Size; D011090:Polyenes / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry*; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D008823:Micelles; D011090:Polyenes; D011136:Polysorbates; D013501:Surface-Active Agents; D009761:Nystatin; D000666:Amphotericin B
keywords: Amphotericin B; Nystatin; Polysorbate 80; drug delivery systems; drug formulation; molecular dynamics simulation; nanomedicine; polyene antibiotics; solubilization