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.

Self-assembled nanostructures of L-ascorbic acid alkyl esters support monomeric amphotericin B

“…AmB has been reported to have a hydrodynamic radius of 2.55 nm [ 63 ]. A film with such thickness would show reflectivity values of (5–6) x 10 −6 , depending on the assumed refraction index of the film (see Experimental Section).…”

“…The average reflectivity of those films is shown in Figure 8 . Note that the values reached for ASC16/AmB films (pH 8) falls below the expected reflectivity for a film with a thickness of 2.55 nm, the length of an AmB molecule in aqueous environment [ 63 ]. In films containing ASCn/AmB at a ratio of 20 (w/w), the images were similar to that for 8 (w/w) (not shown).…”

Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1: Drug Delivery

“…(1) behavior of the nanoparticle in the bloodstream and the protective polymer corona, (2) drug loading and release and (3) nanoparticle interaction with lipid membranes and entry into the cell. We would like to here alert the reader to the fact that there are other reviews of aspects of the use of computational Drugs, theirs applications, and references 5-flouracil -anti-cancer drug (Barraza et al, 2015;Kacar, 2019) Albendazole -anti-worm drug (Rodríguez-Hidalgo et al, 2011) Amphotercin B -antifungal drugs (Mobasheri et al, 2016) Anakinra -used in arthritis therapy (Liebner et al, 2014) Camptothecin -chemotherapy agent (Ansari et al, 2018;Alinejad et al, 2020) Carmustine -chemotherapy agent (Wolski et al, 2017a;Mortazavifar et al, 2019) Chlortetracycline -antibiotic (Dowlatabadi et al, 2019) Cisplatin -chemotherapy agent (Panczyk et al, 2013) Curcurbitacin drug families (Patel et al, 2010a) Cyclosporine -immunosuppressant (Tokarský et al, 2011) Dicolofenac -anti-inflammatory agents (Karjiban et al, 2012) Doxorubicin -chemotherapy agent (Guo et al, 2010(Guo et al, , 2012bYang et al, 2012;Yang C. et al, 2019;Yang Y.-L. et al, 2019;Zhang et al, 2012Zhang et al, , 2014Zhang et al, , 2018Nie et al, 2013;Shan et al, 2014;Izadyar et al, 2016;Rungrotmongkol and Poo-arporn, 2016;Wolski et al, 2017bWolski et al, , 2018Wolski et al, , 2019Hu et al, 2017;Mousavi et al, 2018;Kordzadeh et al, 2019;Alinejad et al, 2020;Exner and Ivanova, 2020;…”

Permeability Characteristics of a New Antifungal Topical Amphotericin B Formulation with γ-Cyclodextrins

“…The low solubility of AmB is one of the most important limitations to developing new formulations [2]. In order to increase the low AmB solubility, different approaches have been applied, such as solubilization with polysorbate 80 [3] or interactions with hydrophilic molecules. Some of the hydrophilic agents that have been combined with AmB are related to polyethylene glycol [4], chitosan [5,6,7], or cyclodextrins [8,9,10].…”