{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:02Z","timestamp":1787029262307,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004564","name":"Ministry of Education, Science and Technological Development of the Republic of Serbia","doi-asserted-by":"publisher","award":["451-03-68\/2022-14\/200042"],"award-info":[{"award-number":["451-03-68\/2022-14\/200042"]}],"id":[{"id":"10.13039\/501100004564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001704","name":"European Society of Clinical Microbiology and Infectious Diseases","doi-asserted-by":"publisher","award":["Research Grant 2015 (JNR)"],"award-info":[{"award-number":["Research Grant 2015 (JNR)"]}],"id":[{"id":"10.13039\/501100001704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Immobilizing antifungal polyenes such as nystatin (Nys) and amphotericin B (AmB) into biodegradable formulations is advantageous compared to free drug administration providing sustained release, reduced dosing due to localized targeting and overall reduced systemic drug toxicity. In this study, we encapsulated Nys and AmB in medium chain length polyhydroxyalkanoates (mcl-PHA) microspheres (7\u20138 \u00b5m in diameter). The obtained formulations have been validated for antifungal activity in vitro against a panel of pathogenic fungi including species of Candida, Aspergillus, Microsporum and Trichophyton genera and toxicity and efficacy in vivo using the zebrafish model of disseminated candidiasis. While free polyenes, especially AmB, were highly toxic to zebrafish embryos at the effective (MIC) doses, after their loading into mcl-PHA microspheres, inner organ toxicity and teratogenicity associated with both drugs were not observed, even at 100 \u00d7 MIC doses. The obtained mcl-PHA\/polyene formulations have successfully eradicated C. albicans infection and showed an improved therapeutic profile in zebrafish by enhancing infected embryos survival. This approach is contributing to the antifungal arsenal as polyenes, although the first broad-spectrum antifungals on the market are still the gold standard for treatment of fungal infections.<\/jats:p>","DOI":"10.3390\/pharmaceutics14040696","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T23:31:43Z","timestamp":1648164703000},"page":"696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model"],"prefix":"10.3390","volume":"14","author":[{"given":"Aleksandar","family":"Pavic","sequence":"first","affiliation":[{"name":"Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5989-0031","authenticated-orcid":false,"given":"Zoran","family":"Stojanovic","sequence":"additional","affiliation":[{"name":"Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1991-9634","authenticated-orcid":false,"given":"Marina","family":"Pekmezovic","sequence":"additional","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology, Hans Kn\u00f6ll Institute, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0110or\u0111e","family":"Veljovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-0076","authenticated-orcid":false,"given":"Kevin","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"BiOrbic Bioeconomy SFI Research Centre, Belfield, D04 V1W Dublin, Ireland"},{"name":"School of Biomolecular and Biomedical Sciences, University College Dublin, Belfield, D04 V1W Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Malagurski","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2553-977X","authenticated-orcid":false,"given":"Jasmina","family":"Nikodinovic-Runic","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5484","DOI":"10.1021\/acs.jmedchem.7b01413","article-title":"Emerging New Targets for the Treatment of Resistant Fungal Infections","volume":"61","author":"Liu","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.3390\/molecules19011085","article-title":"Invasive fungal infections in the ICU: How to approach, how to treat","volume":"19","author":"Paramythiotou","year":"2014","journal-title":"Molecules"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.bcp.2016.11.019","article-title":"Antifungals","volume":"133","author":"Campoy","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrd.2017.46","article-title":"The antifungal pipeline: A reality check. Nature reviews","volume":"16","author":"Perfect","year":"2017","journal-title":"Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ijantimicag.2011.02.016","article-title":"Candida bloodstream infections: Comparison of species distribution and resistance to echinocandin and azole antifungal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008\u20132009)","volume":"38","author":"Pfaller","year":"2011","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s40121-020-00382-7","article-title":"Sixty years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections","volume":"10","author":"Cavassin","year":"2021","journal-title":"Infect. Dis. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13584","DOI":"10.1038\/s41598-018-31801-y","article-title":"Nystatin-like Pseudonocardia polyene B1, a novel disaccharide-containing antifungal heptaene antibiotic","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Carolus, H., Pierson, S., Lagrou, K., and Van Dijck, P. (2020). Amphotericin B and Other Polyenes-Discovery, Clinical Use, Mode of Action and Drug Resistance. J. Fungi, 6.","DOI":"10.3390\/jof6040321"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"F429","DOI":"10.1136\/adc.2008.157123","article-title":"Oral nystatin prophylaxis and neonatal fungal infections","volume":"94","author":"Howell","year":"2009","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1055\/s-2007-999649","article-title":"Prophylactic oral nystatin and fungal infections in very-low-birthweight infants","volume":"5","author":"Sims","year":"1988","journal-title":"Am. J. Perinatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/S0079-6700(00)00035-6","article-title":"Synthesis, structure and properties of polyhydroxyalkanoates: Biological polyesters","volume":"25","author":"Sudesh","year":"2000","journal-title":"Prog. Polym. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/17434440.2019.1615439","article-title":"Polyhydroxyalkanoate (PHA): Applications in drug delivery and tissue engineering","volume":"16","author":"Elmowafy","year":"2019","journal-title":"Expert Rev. Med. Devices"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/pi.5282","article-title":"Polyhydroxyalkanoate-based drug delivery systems","volume":"66","author":"Michalak","year":"2017","journal-title":"Polym. Int."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pekmezovic, M., Kalagasidis Krusic, M., Malagurski, I., Milovanovic, J., St\u0119pie\u0144, K., Guzik, M., Charifou, R., Babu, R., O\u2019Connor, K., and Nikodinovic-Runic, J. (2021). Polyhydroxyalkanoate\/Antifungal Polyene Formulations with Monomeric Hydroxyalkanoic Acids for Improved Antifungal Efficiency. Antibiotics, 10.","DOI":"10.3390\/antibiotics10060737"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/jac\/dkh477","article-title":"Antimicrobial efficacy of a new antibiotic-loaded poly(hydroxybutyric-co-hydroxyvaleric acid) controlled release system","volume":"54","author":"Rossi","year":"2004","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e495","DOI":"10.1002\/term.2318","article-title":"Poly(3-hydroxyoctanoate), a promising new material for cardiac tissue engineering","volume":"12","author":"Bagdadi","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129100","DOI":"10.1016\/j.matlet.2020.129100","article-title":"Polyhydroxyoctanoate Films Reinforced With Titanium Dioxide Microfibers for Biomedical Application","volume":"285","author":"Malagurski","year":"2021","journal-title":"Mater. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47192","DOI":"10.1002\/app.47192","article-title":"Structural, topographical, and mechanical characteristics of purified polyhydroxyoctanoate polymer","volume":"136","author":"Barbasz","year":"2019","journal-title":"J. Appl. Polym. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1007\/s10856-013-4941-2","article-title":"Microparticles prepared from biodegradable polyhydroxyalkanoates as matrix for encapsulation of cytostatic drug","volume":"24","author":"Murueva","year":"2013","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.bbamem.2006.01.001","article-title":"Spectroscopic studies of amphotericin B solubilized in nanoscale bilayer membranes","volume":"1758","author":"Hargreaves","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s0021663550409","article-title":"Spectroscopic study on nystatin conformational modifications generated by its interaction with the solvent","volume":"355","author":"Lupan","year":"1996","journal-title":"Fresenius\u2019 J. Anal. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/BF00328721","article-title":"Isolation of the Candida albicans gene for orotidine-5\u2032-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations","volume":"198","author":"Gillum","year":"1984","journal-title":"Mol. Gen. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1469-0691.2006.01454.x","article-title":"European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing","volume":"12","author":"Kahlmeter","year":"2006","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.vascn.2012.10.003","article-title":"A zebrafish phenotypic assay for assessing drug-induced hepatotoxicity","volume":"67","author":"He","year":"2013","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.vascn.2016.12.002","article-title":"A rapid assessment for predicting drug-induced hepatotoxicity using zebrafish","volume":"84","author":"Zhang","year":"2017","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/j.1365-2958.2005.04557.x","article-title":"Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood","volume":"56","author":"Fradin","year":"2005","journal-title":"Mol. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jmbbm.2014.07.020","article-title":"Crystallization and its Effect on the Mechanical Properties of a Medium Chain Length Polyhydroxyalkanoate","volume":"39","author":"Vega","year":"2014","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jddst.2017.02.004","article-title":"Preparation and Physicochemical Characterization of the Nystatin-loaded Eudragit RS100\/PLGA Nanoparticles and Evaluation of their Anti-fungal Properties against Candida albicans","volume":"38","author":"Mohammadi","year":"2017","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1016\/j.bbamem.2010.07.037","article-title":"Spectroscopic Studies of Molecular Organization of Antibiotic Amphotericin B in Monolayers and Dipalmitoylphosphatidylcholine Lipid Multibilayers","volume":"1798","author":"Gagos","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Salevic, A., Stojanovic, D., Levic, S., Pantic, M., Djordjevic, V., Pesic, R., Bugarski, B., Pavlovic, V., Uskokovic, P., and Nedovic, V. (2022). The Structuring of Sage (Salvia officinalis L.) Extract-Incorporating Edible Zein-Based Materials with Antioxidant and Antibacterial Functionality by Solvent Casting versus Electrospinning. Foods, 11.","DOI":"10.3390\/foods11030390"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Brothers, K.M., and Wheeler, R.T. (2012). Non-invasive imaging of disseminated candidiasis in zebrafish larvae. J. Vis. Exp.","DOI":"10.3791\/4051"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"780","DOI":"10.3389\/fmicb.2016.00780","article-title":"Phenotypic plasticity regulates Candida albicans interactions and virulence in the vertebrate host","volume":"7","author":"Mallick","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1080\/14787210.2016.1199272","article-title":"Antifungal Agents and Liver Toxicity: A Complex Interaction","volume":"14","author":"Tverdek","year":"2016","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijpharm.2017.03.019","article-title":"Nanoparticles as safe and effective delivery systems of antifungal agents: Achievements and challenges","volume":"523","author":"Soliman","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s13167-010-0001-x","article-title":"Drug delivery systems: Advanced technologies potentially applicable in personalized treatments","volume":"1","author":"Coelho","year":"2010","journal-title":"EPMA J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.3390\/ijms12074294","article-title":"Controlled delivery of gentamicin using poly(3-hydroxybutyrate) microspheres","volume":"12","author":"Francis","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1007\/s10856-013-5012-4","article-title":"Tetracycline-encapsulated P(3HB) microsphere-coated 45S5 Bioglass(\u00ae)-based scaffolds for bone tissue engineering","volume":"24","author":"Meng","year":"2013","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3109\/02652049109071487","article-title":"Poly(hydroxybutyrate-hydroxyvalerate) microspheres containing progesterone: Preparation, morphology and release properties","volume":"8","author":"Gangrade","year":"1991","journal-title":"J. Microencapsul."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1007\/s00253-011-3101-1","article-title":"Sustained release of PI3K inhibitor from PHA nanoparticles and in vitro growth inhibition of cancer cell lines","volume":"89","author":"Lu","year":"2011","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.msec.2015.11.067","article-title":"Polymeric nanoparticles for targeted drug delivery system for cancer therapy","volume":"60","author":"Masood","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nrd4627","article-title":"Zebrafish as tools for drug discovery","volume":"14","author":"MacRae","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1021\/acs.chemrestox.9b00335","article-title":"Use of Zebrafish in Drug Discovery Toxicology","volume":"33","author":"Cassar","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.1177319","article-title":"Identification of a Primary Target of Thalidomide Teratogenicity","volume":"327","author":"Ito","year":"2010","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.reprotox.2011.07.001","article-title":"Developmental effects of coumarin and the anticoagulant coumarin derivative warfarin on zebrafish (Danio rerio) embryos","volume":"33","author":"Weigt","year":"2012","journal-title":"Reprod. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1128\/AAC.31.12.1901","article-title":"Toxicity and therapeutic effects in mice of liposome-encapsulated nystatin for systemic fungal infections","volume":"31","author":"Mehta","year":"1987","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s40265-016-0538-7","article-title":"Liposomal Amphotericin B (AmBisome(\u00ae)): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions","volume":"76","author":"Stone","year":"2016","journal-title":"Drugs"},{"key":"ref_47","first-page":"149","article-title":"Clinical hepatotoxicity associated with antifungal agents","volume":"16","author":"Kyriakidis","year":"2017","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1128\/AAC.01657-09","article-title":"Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection","volume":"54","author":"Wang","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3109\/03602532.2011.645578","article-title":"Comparisons between in vitro whole cell imaging and in vivo zebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development","volume":"44","author":"Hill","year":"2012","journal-title":"Drug Metab. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1128\/AAC.11.1.154","article-title":"Effects of Amphotericin B on Macrophages and Their Precursor Cells","volume":"11","author":"Lin","year":"1977","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/S1081-1206(10)61514-1","article-title":"Amphotericin-induced stridor: A review of stridor, amphotericin preparations, and their immunoregulatory effects","volume":"91","author":"Lowery","year":"2003","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"361","DOI":"10.2165\/00003495-200969030-00010","article-title":"Liposomal amphotericin B: A review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections","volume":"69","author":"Moen","year":"2009","journal-title":"Drugs"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3109\/13693786.2012.731712","article-title":"Mechanism of activity and toxicity of Nystatin-Intralipid","volume":"51","author":"Semis","year":"2013","journal-title":"Med. Mycol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"113858","DOI":"10.1016\/j.ejmech.2021.113858","article-title":"Combatting AMR: A molecular approach to the discovery of potent and non-toxic rhenium complexes active against C. albicans-MRSA co-infection","volume":"226","author":"Sovari","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"130006","DOI":"10.1016\/j.molstruc.2021.130006","article-title":"Improvement of the anti-Candida activity of itraconazole in the zebrafish infection model by its coordination to silver(I)","volume":"1232","author":"Vojnovic","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/jac\/dku355","article-title":"Antifungal drugs during pregnancy: An updated review","volume":"70","author":"Pilmis","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1080\/00365540310017069","article-title":"A Population-based Case-control Teratological Study of Oral Nystatin Treatment During Pregnancy","volume":"35","author":"Czeizel","year":"2003","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_58","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."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/4\/696\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:42:01Z","timestamp":1760136121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/4\/696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,24]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["pharmaceutics14040696"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14040696","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,24]]}}}