{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T09:22:05Z","timestamp":1783761725420,"version":"3.55.0"},"reference-count":118,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2015,12,24]],"date-time":"2015-12-24T00:00:00Z","timestamp":1450915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/molecules21010006","type":"journal-article","created":{"date-parts":[[2015,12,24]],"date-time":"2015-12-24T10:03:53Z","timestamp":1450951433000},"page":"6","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Solubilization Behavior of Polyene Antibiotics in Nanomicellar System: Insights from Molecular Dynamics Simulation of the Amphotericin B and Nystatin Interactions with Polysorbate 80"],"prefix":"10.3390","volume":"21","author":[{"given":"Meysam","family":"Mobasheri","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Attar","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran"},{"name":"Tofigh Daru Research and Engineering Company (TODACO), Tehran 1397116359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed","family":"Rezayat Sorkhabadi","sequence":"additional","affiliation":[{"name":"Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 1417755469, Iran"},{"name":"Department of Toxicology and Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran 193956466, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Khamesipour","sequence":"additional","affiliation":[{"name":"Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran 1416613675, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3908-6828","authenticated-orcid":false,"given":"Mahmoud","family":"Jaafari","sequence":"additional","affiliation":[{"name":"Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box: 91775-1365, Mashhad 917751365, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S0304-4157(00)00012-5","article-title":"Surface active drugs: Self-association and interaction with membranes and surfactants. Physicochemical and biological aspects","volume":"1508","author":"Schreier","year":"2000","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1517\/17425240903380446","article-title":"Overcoming the barriers in micellar drug delivery: Loading efficiency, in vivo stability, and micelle\u2013cell interaction","volume":"7","author":"Kim","year":"2009","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"555","DOI":"10.2174\/1568026614666140121112118","article-title":"Self-assembly drugs: From micelles to nanomedicine","volume":"14","author":"Messina","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5603","DOI":"10.1128\/AAC.00612-12","article-title":"Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan","volume":"56","author":"Kagan","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kleinberg, M. (2006). What is the current and future status of conventional amphotericin B?. Int. J. Antimicrob. Agents, 2712\u20132716.","DOI":"10.1016\/j.ijantimicag.2006.03.013"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1046\/j.1365-3156.2001.00778.x","article-title":"Drug resistance in Indian visceral leishmaniasis","volume":"6","author":"Sundar","year":"2001","journal-title":"Trop. Med. Int. Health."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1365-3156.2010.02520.x","article-title":"Household cost-of-illness of visceral leishmaniasis in Bihar, India","volume":"15","author":"Sundar","year":"2010","journal-title":"Trop. Med. Int. Health."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.bbrc.2011.11.023","article-title":"A novel mechanism for an old drug: Amphotericin B in the treatment of visceral leishmaniasis","volume":"416","author":"Chattopadhyay","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s40265-013-0069-4","article-title":"Amphotericin B Formulations: A comparative review of efficacy and toxicity","volume":"73","author":"Hamill","year":"2013","journal-title":"Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1128\/br.37.2.166-196.1973","article-title":"Chemistry and biology of the polyene macrolide antibiotics","volume":"37","year":"1973","journal-title":"Bacteriol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1093\/jac\/dks117","article-title":"Pharmacokinetics, tissue distribution and immunomodulatory effect of intralipid formulation of nystatin in mice","volume":"67","author":"Semis","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1093\/jac\/44.3.397","article-title":"In-vitro antifungal activity of liposomal nystatin in comparison with nystatin, amphotericin B cholesteryl sulphate, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B desoxycholate, fluconazole and itraconazole","volume":"44","author":"Tur","year":"1999","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1128\/JCM.40.4.1406-1412.2002","article-title":"In vitro activity of nystatin compared with those of liposomal nystatin, amphotericin B, and fluconazole against clinical candida isolates","volume":"40","author":"Arikan","year":"2002","journal-title":"J. Clin. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1128\/AAC.42.6.1412","article-title":"Comparison of in vitro antifungal activities of free and liposome-encapsulated nystatin with those of four amphotericin B formulations","volume":"42","author":"Johnson","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/toxsci\/53.2.421","article-title":"The reproductive and developmental toxicity of the antifungal drug Nyotran\u00ae (liposomal nystatin) in rats and rabbits","volume":"53","author":"Larson","year":"2000","journal-title":"Toxicol. Sci."},{"key":"ref_16","unstructured":"Lemke, T.L., and Williams, D.A. (2012). Foye\u2019s Principles of Medicinal Chemistry, Wolters Kluwer Health. [6th ed.]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1128\/AAC.36.10.2310","article-title":"Effects of the aggregation state of amphotericin B on its toxicity to mice","volume":"36","author":"Barwicz","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0009-3084(96)02652-7","article-title":"The effect of aggregation state of amphotericin-B on its interactions with cholesterol- or ergosterol-containing phosphatidylcholine monolayers","volume":"85","author":"Barwicz","year":"1997","journal-title":"Chem. Phys. Lipids."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ijpharm.2008.05.013","article-title":"Effect of aggregation state on the toxicity of different amphotericin B preparations","volume":"361","author":"Espada","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1128\/AAC.36.11.2518","article-title":"Effects of aggregation and solvent on the toxicity of amphotericin B to human erythrocytes","volume":"36","author":"Legrand","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1021\/mp300143n","article-title":"Toward Understanding of Toxic Side Effects of a polyene antibiotic amphotericin B: Fluorescence spectroscopy reveals widespread formation of the specific supramolecular structures of the drug","volume":"9","author":"Wasko","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1011-1344(02)00405-0","article-title":"Dimers of polyene antibiotic amphotericin B detected by means of fluorescence spectroscopy: Molecular organization in solution and in lipid membranes","volume":"69","author":"Gruszecki","year":"2003","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1006\/jcis.1993.1230","article-title":"Spontaneous organization of amphotericin B in aqueous medium","volume":"158","author":"Barwicz","year":"1993","journal-title":"J. Colloid. Interface Sci."},{"key":"ref_24","first-page":"161","article-title":"Organization of antibiotic amphotericin B in model lipid membranes. A mini review","volume":"8","author":"Gruszecki","year":"2003","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1016\/S0006-3495(95)80125-6","article-title":"Self-association of the polyene antibiotic nystatin in dipalmitoylphosphatidylcholine vesicles: A time-resolved fluorescence study","volume":"69","author":"Coutinho","year":"1995","journal-title":"Biophys. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5707","DOI":"10.1021\/bi00237a011","article-title":"One-sided action of amphotericin B on cholesterol-containing membranes is determined by its self-association in the medium","volume":"30","author":"Bolard","year":"1991","journal-title":"Biochemistry"},{"key":"ref_27","first-page":"2345","article-title":"Polysorbate 80 and Cremophor EL micelles deaggregate and solubilize nystatin at the core-corona interface","volume":"94","author":"Croy","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1128\/CMR.9.4.512","article-title":"Carrier effects on biological activity of amphotericin B","volume":"9","author":"Brajtburg","year":"1996","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jconrel.2003.11.003","article-title":"The effects of Pluronic block copolymers on the aggregation state of nystatin","volume":"95","author":"Croy","year":"2004","journal-title":"J. Control. Release"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ijpharm.2007.08.057","article-title":"Stable drug encapsulation in micelles and microemulsions","volume":"345","author":"Narang","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1023\/B:PHAM.0000016235.32639.23","article-title":"Solubilizing excipients in oral and injectable formulations","volume":"21","author":"Strickley","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1124\/pr.112.005660","article-title":"Strategies to address low drug solubility in discovery and development","volume":"65","author":"Williams","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0378-5173(03)00270-9","article-title":"Amphiphilic association systems for Amphotericin B delivery","volume":"260","author":"Esposito","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.ijpharm.2013.07.035","article-title":"Strategies for the design of orally bioavailable antileishmanial treatments","volume":"454","author":"Pham","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/355279a0","article-title":"Mixed micelles in drug delivery","volume":"355","author":"Lasic","year":"1992","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.3109\/03639045.2011.587431","article-title":"Niosomes as a potential drug delivery system for increasing the efficacy and safety of nystatin","volume":"37","author":"Abdelbary","year":"2011","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.colsurfa.2013.11.010","article-title":"A polysiloxane surfactant dissolves a poorly soluble drug (nystatin) in water","volume":"443","author":"Racles","year":"2014","journal-title":"Colloids. Surf. A. Physicochem. Eng. Asp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4482","DOI":"10.2174\/092986710794182935","article-title":"Computational simulation of drug delivery at molecular level","volume":"17","author":"Li","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.nano.2011.05.006","article-title":"Computational approaches to the rational design of nanoemulsions, polymeric micelles, and dendrimers for drug delivery","volume":"8","author":"Huynh","year":"2012","journal-title":"Nanomedicine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00466-013-0968-y","article-title":"Computational modeling of magnetic nanoparticle targeting to stent surface under high gradient field","volume":"53","author":"Wang","year":"2014","journal-title":"Comput. Mech."},{"key":"ref_41","first-page":"315","article-title":"The role of multiscale computational approaches for rational design of conventional and nanoparticle oral drug delivery systems","volume":"2","author":"Rickus","year":"2007","journal-title":"Int. J. Nanomed."},{"key":"ref_42","first-page":"S423","article-title":"In silico modelling of drug\u2013polymer interactions for pharmaceutical formulations","volume":"7","author":"Ahmad","year":"2010","journal-title":"Interface Focus"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9572","DOI":"10.3390\/ijms13089572","article-title":"Molecular dynamics simulation of palmitate ester self-assembly with diclofenac","volume":"13","author":"Basri","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1016\/j.bbamem.2012.07.029","article-title":"Aggregation behavior of ibuprofen, cholic acid and dodecylphosphocholine micelles","volume":"1818","author":"Prakash","year":"2012","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jconrel.2012.06.027","article-title":"pH-sensitive drug loading\/releasing in amphiphilic copolymer PAE\u2013PEG: Integrating molecular dynamics and dissipative particle dynamics simulations","volume":"162","author":"Luo","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/j.biomaterials.2012.11.024","article-title":"Molecular dynamics of paclitaxel encapsulated by salicylic acid-grafted chitosan oligosaccharide aggregates","volume":"34","author":"Wang","year":"2013","journal-title":"Biomaterials"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8471","DOI":"10.1021\/la501143z","article-title":"Molecular dynamics simulations of self-emulsifying drug-delivery systems (SEDDS): Influence of excipients on droplet nanostructure and drug localization","volume":"30","author":"Benson","year":"2014","journal-title":"Langmuir"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0301-4622(94)00114-Y","article-title":"Molecular dynamics of amphotericin B I. Single molecule in vacuum and water","volume":"54","author":"Mazerski","year":"1995","journal-title":"Biophys. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0301-4622(95)00062-7","article-title":"Molecular dynamics of amphotericin B. II. Dimer in water","volume":"57","author":"Mazerski","year":"1996","journal-title":"Biophys. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.bpc.2009.01.001","article-title":"Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives\u2014A molecular dynamics study","volume":"141","author":"Czub","year":"2009","journal-title":"Biophys. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1124\/mol.52.4.560","article-title":"Molecular properties of amphotericin b membrane channel: A molecular dynamics simulation","volume":"52","author":"Baginski","year":"1997","journal-title":"Mol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s002329900349","article-title":"Conformational analysis of amphotericin B\u2014cholesterol channel complex","volume":"162","author":"Silberstein","year":"1998","journal-title":"J. Membr. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16743","DOI":"10.1021\/jp061916g","article-title":"Modulation of amphotericin B membrane interaction by cholesterol and ergosterola molecular dynamics study","volume":"110","author":"Czub","year":"2006","journal-title":"J. Phys. Chem. B"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00894-004-0190-0","article-title":"Molecular aspects of the interaction between amphotericin B and a phospholipid bilayer: Molecular dynamics studies","volume":"10","author":"Sternal","year":"2004","journal-title":"J. Mol. Model."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0005-2736(02)00581-3","article-title":"Comparative molecular dynamics simulations of amphotericin B-cholesterol\/ergosterol membrane channels","volume":"1567","author":"Baginski","year":"2002","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0301-4622(01)00252-6","article-title":"Molecular modelling of amphotericin B\u2013ergosterol primary complex in water","volume":"95","author":"Baran","year":"2002","journal-title":"Biophys. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1080\/07391102.1995.10508790","article-title":"Molecular modeling studies on amphotericin B and its complex with phospholipid","volume":"12","author":"Anachi","year":"1995","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"15875","DOI":"10.1021\/jp905133f","article-title":"On the possibility of the amphotericin B-Sterol complex formation in cholesterol- and ergosterol-containing lipid bilayers: A molecular dynamics study","volume":"113","author":"Neumann","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1016\/j.bpj.2013.02.029","article-title":"The effect of sterols on amphotericin B self-aggregation in a lipid bilayer as revealed by free energy simulations","volume":"104","author":"Neumann","year":"2013","journal-title":"Biophys. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1016\/j.bbamem.2007.06.017","article-title":"Interactions of amphotericin B derivatives with lipid membranes\u2014A molecular dynamics study","volume":"1768","author":"Czub","year":"2007","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.bpc.2009.01.010","article-title":"Molecular modeling of amphotericin B-ergosterol primary complex in water II","volume":"141","author":"Baran","year":"2009","journal-title":"Biophys. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1023\/A:1008144208706","article-title":"Conformational properties of amphotericin B amide derivatives\u2014impact on selective toxicity","volume":"14","author":"Resat","year":"2000","journal-title":"J. Comput. Aided Mol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1002\/adma.201103192","article-title":"Nanoparticle shape improves delivery: Rational coarse grain molecular dynamics (rCG-MD) of taxol in worm-like PEG-PCL micelles","volume":"24","author":"Loverde","year":"2012","journal-title":"Adv. Mater."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1016\/S0040-4039(01)98622-8","article-title":"Chemical studies with amphotericin B III. The complete structure of the antibiotic","volume":"11","author":"Borowski","year":"1970","journal-title":"Tetrahedron Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ijpharm.2011.01.044","article-title":"Characterization of the colloidal properties, in vitro antifungal activity, antileishmanial activity and toxicity in mice of a distigmasterylhemisuccinoyl-glycero-phosphocholine liposome-intercalated amphotericin B","volume":"408","author":"Iman","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.ijpharm.2013.05.044","article-title":"Development of oil-in-water microemulsions for the oral delivery of amphotericin B","volume":"454","author":"Silva","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3109\/03639045.2013.771647","article-title":"Nanocarrier-based topical drug delivery for an antifungal drug","volume":"40","author":"Hussain","year":"2014","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_68","unstructured":"Hussain, A., Samad, A., Singh, S.K., Ahsan, M.N., Haque, M.W., Faruk, A., and Ahmed, F.J. (2015). Nanoemulsion gel-based topical delivery of an antifungal drug: In vitro activity and in vivo evaluation. Drug Deliv., 1\u201316."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ijpharm.2009.01.003","article-title":"Development and characterization of oral lipid-based Amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans","volume":"372","author":"Wasan","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"542","DOI":"10.2174\/15672018113109990001","article-title":"Oral bioavailability and stability study of a self-emulsifying drug delivery system (SEDDS) of amphotericin B","volume":"10","author":"Bhattacharyya","year":"2013","journal-title":"Curr. Drug Deliv."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7812","DOI":"10.1021\/jp071097f","article-title":"The MARTINI force field:\u2009 Coarse grained model for biomolecular simulations","volume":"111","author":"Marrink","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1021\/ct900313w","article-title":"Martini coarse-grained force field: Extension to carbohydrates","volume":"5","author":"Rzepiela","year":"2009","journal-title":"J. Chem. Theory. Comput."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Voth, G.A. (2008). Coarse-Graining of Condensed Phase and Biomolecular Systems, CRC Press.","DOI":"10.1201\/9781420059564"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1039\/C4SC00035H","article-title":"Aqueous solubilization of hydrophobic supramolecular metal-organic nanocapsules","volume":"5","author":"Kumari","year":"2014","journal-title":"Chem. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1039\/c0sm00965b","article-title":"Molecular dynamics simulation of a polysorbate 80 micelle in water","volume":"7","author":"Amani","year":"2011","journal-title":"Soft Matter"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev.pc.37.100186.002031","article-title":"Small angle neutron scattering studies of the structure and interaction in micellar and microemulsion systems","volume":"37","author":"Chen","year":"1986","journal-title":"Annu. Rev. Phys. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"12907","DOI":"10.1021\/jp507499k","article-title":"Molecular Dynamics simulations of structure\u2013property relationships of tween 80 surfactants in water and at interfaces","volume":"118","author":"Tang","year":"2014","journal-title":"J. Phys. Chem. B"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.jpba.2009.09.025","article-title":"Quantification of hydrophilic ethoxylates in polysorbate surfactants using diffusion NMR spectroscopy","volume":"51","author":"Verbrugghe","year":"2010","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"14071","DOI":"10.1021\/la203055t","article-title":"Sphere-to-rod transitions of nonionic surfactant micelles in aqueous solution modeled by molecular dynamics simulations","volume":"27","author":"Velinova","year":"2011","journal-title":"Langmuir"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3816","DOI":"10.1063\/1.1539048","article-title":"Sphere-to-rod transitions of micelles in model nonionic surfactant solutions","volume":"118","author":"Floriano","year":"2003","journal-title":"J. Chem. Phys."},{"key":"ref_81","unstructured":"Rosen, M.J. (1989). Surfactants and Interfacial Phenomena, Wiley-Interscience. [2nd ed.]."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1021\/mp900022m","article-title":"Flexible filaments for in vivo imaging and delivery: Persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage","volume":"6","author":"Christian","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1039\/b808701f","article-title":"Coarse-grained molecular modeling of non-ionic surfactant self-assembly","volume":"4","author":"Shinoda","year":"2008","journal-title":"Soft Matter"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/nature04162","article-title":"Interfaces and the driving force of hydrophobic assembly","volume":"437","author":"Chandler","year":"2005","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1021\/jp074310g","article-title":"Molecular dynamics simulation and thermodynamic modeling of the self-assembly of the triterpenoids asiatic acid and madecassic acid in aqueous solution","volume":"112","author":"Stephenson","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Attwood, D., and Florence, A.T. (1983). Surfactant Systems: Their Chemistry, Pharmacy and Biology, Chapman and Hall. [1st ed.].","DOI":"10.1007\/978-94-009-5775-6"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Mahato, R.I., and Narang, A.S. (2011). Pharmaceutical Dosage Forms and Drug Delivery, CRC Press. [2nd ed.].","DOI":"10.1201\/b12122"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1007\/BF02980276","article-title":"Mixed micellar nanoparticle of amphotericin b and poly styrene-block-poly ethylene oxide reduces nephrotoxicity but retains antifungal activity","volume":"30","author":"Han","year":"2007","journal-title":"Arch. Pharm. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0927-7765(98)00033-2","article-title":"Interaction of amphotericin B with polymeric colloids: A spectroscopic study","volume":"11","author":"Espuelas","year":"1998","journal-title":"Colloids. Surf. B Biointerfaces"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sun, Q., Radosz, M., and Shen, Y. (2012). Challenges in design of translational nanocarriers. J. Control. Release, 164156\u2013164169.","DOI":"10.1016\/j.jconrel.2012.05.042"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Amiji, M.M. (2006). Nanotechnology for Cancer Therapy, CRC Press.","DOI":"10.1201\/9781420006636"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1021\/ja513034e","article-title":"Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficiency","volume":"137","author":"Cai","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"11993","DOI":"10.1021\/ja036667d","article-title":"Interfacial solubilization of model amphiphilic molecules in block copolymer micelles","volume":"125","author":"Choucair","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9989","DOI":"10.1039\/c2sm26200b","article-title":"Can drug molecules diffuse into the core of micelles?","volume":"8","author":"Guo","year":"2012","journal-title":"Soft Matter"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0169-409X(02)00015-7","article-title":"Poly(ethylene oxide)-block-poly(l-amino acid) micelles for drug delivery","volume":"54","author":"Lavasanifar","year":"2002","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.addr.2006.09.002","article-title":"Liposomal drug transport: A molecular perspective from molecular dynamics simulations in lipid bilayers","volume":"58","author":"Xiang","year":"2006","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.1021\/ma971721u","article-title":"Release Kinetics studies of aromatic molecules into water from block polymer micelles","volume":"31","author":"Teng","year":"1998","journal-title":"Macromolecules"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6792","DOI":"10.1021\/la9904049","article-title":"Release of hydrophobic compounds from micellar solutions of hydrophobically modified polyelectrolytes","volume":"15","author":"Bromberg","year":"1999","journal-title":"Langmuir"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/10611860400011935","article-title":"Polymeric micelles for delivery of poorly soluble drugs: Preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids","volume":"13","author":"Wang","year":"2005","journal-title":"J. Drug Target"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1007\/s11095-006-9662-5","article-title":"Long circulating poly(ethylene glycol)-decorated lipid nanocapsules deliver docetaxel to solid tumors","volume":"23","author":"Khalid","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nrd4363","article-title":"Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies","volume":"13","author":"Mitragotri","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/2008-2231-21-57","article-title":"In-vitro\/In-vivo comparison of leuprolide acetate release from an in-situ forming plga system","volume":"21","author":"Mashayekhi","year":"2013","journal-title":"Daru"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1021\/mp700081v","article-title":"Effect of cholesterol on the release of Amphotericin B from PEG-phospholipid micelles","volume":"5","author":"Vakil","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/jbm.a.31504","article-title":"Amphotericin B-loaded poly(ethylene glycol)\u2013poly(lactide) micelles: Preparation, freeze-drying, and in vitro release","volume":"85A","author":"Yang","year":"2008","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1166\/jbt.2014.1160","article-title":"In-Vitro and In-Vivo Studies on Novel Chitosan-g-pluronic F-127 copolymer based nanocarrier of Amphotericin B for improved antifungal activity","volume":"4","author":"Kumar","year":"2014","journal-title":"J. Biomater. Tissue Eng."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s11095-011-0511-9","article-title":"Encapsulation and release of Amphotericin B from an ABC triblock fluorous copolymer","volume":"29","author":"Jee","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1021\/ma00118a014","article-title":"Solubilization of aromatic solutes in block copolymers","volume":"28","author":"Gadelle","year":"1995","journal-title":"Macromolecules"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.1021\/ja00800a003","article-title":"Structure and hydration of nonionic detergent micelles. High resolution nuclear magnetic resonance study","volume":"95","author":"Podo","year":"1973","journal-title":"J. Am. Chem. Soc."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1073\/pnas.78.2.676","article-title":"Molecular organization in micelles and vesicles","volume":"78","author":"Dill","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0168-3659(97)00245-9","article-title":"Polymeric micelles for drug delivery: Solubilization and haemolytic activity of amphotericin B","volume":"53","author":"Yu","year":"1998","journal-title":"J. Control. Release"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ijpharm.2005.11.031","article-title":"Encapsulation of amphotericin B in poly(ethylene glycol)-block-poly(\u03b5-caprolactone-co-trimethylenecarbonate) polymeric micelles","volume":"309","author":"Vandermeulen","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_112","first-page":"1","article-title":"Spectroscopic investigation of the aggregation state of amphotericin B during loading, freeze-drying, and reconstitution of polymeric micelles","volume":"7","author":"Adams","year":"2004","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1023\/A:1015127225021","article-title":"Block Copolymer micelles for the encapsulation and delivery of amphotericin B","volume":"19","author":"Lavasanifar","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0168-3659(02)00347-4","article-title":"Relative aggregation state and hemolytic activity of amphotericin B encapsulated by poly(ethylene oxide)-block\u2013poly(N-hexyl-l-aspartamide)-acyl conjugate micelles: Effects of acyl chain length","volume":"87","author":"Adams","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_115","unstructured":"Hezaveh, S. (2012). Study the Interaction Mechanisms of Block Copolymers with Biological Interfaces. [Ph.D. Thesis, The Jacobs University]."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/0005-2736(90)90305-8","article-title":"The effect of surfactants on the aggregation state of amphotericin B","volume":"1030","author":"Barwicz","year":"1990","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/1\/6\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:54:47Z","timestamp":1760216087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/1\/6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,24]]},"references-count":118,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,1]]}},"alternative-id":["molecules21010006"],"URL":"https:\/\/doi.org\/10.3390\/molecules21010006","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,24]]}}}