{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:25:53Z","timestamp":1790357153042,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The development of resistance to traditional antifungal therapies has necessitated the exploration of alternative treatment strategies to effectively manage fungal infections, particularly those induced by Candida albicans (C. albicans). This research investigates the possibility of integrating silver nanoparticles (AgNPs) with Terbinafine to improve antifungal effectiveness. Terbinafine, while potent, faces challenges with specific fungal strains, highlighting the need for strategies to enhance its treatment efficacy. Silver nanoparticles were produced through a light-activated, gelatin-based method, resulting in particle sizes ranging from 56.8 nm to 66.2 nm, confirmed by dynamic light scattering and scanning electron microscopy. Stability studies indicated that AgNPs produced with 30 mg of silver nitrate (AgNO\u2083) exhibited the greatest stability over 60 days across different temperature conditions. The analysis through UV-visible spectrophotometry revealed a notable shift in the absorption spectra as AgNO\u2083 concentrations increased, which was associated with a strengthening of plasmon resonance. The effectiveness of the AgNPs and Terbinafine combination was assessed against three strains of C. albicans (ATCC 10231, ATCC 90028, and ATCC 18804). Terbinafine demonstrated strong antifungal properties with minimum inhibitory concentrations (MIC) values ranging from 2\u20134 \u00b5g\/mL, whereas AgNPs on their own displayed moderate effectiveness. The integrated formulation notably enhanced effectiveness, especially against strain ATCC 90028, revealing a synergistic effect (FIFi = 0.369). These results were complemented by the findings of the time-to-kill assay, where the same strain showed a 3.2 log\u2081\u2080 CFU\/mL decrease in viable cell count. The process by which AgNPs boost activity entails the disruption of the fungal cell membrane and its internal components, probably as a result of silver ion release and the generation of free radicals. The results indicate that the combination of Terbinafine and AgNPs may act as a powerful alternative for addressing resistant fungal infections, presenting an encouraging direction for future antifungal treatments.<\/jats:p>","DOI":"10.3390\/pharmaceutics17010125","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T03:33:02Z","timestamp":1737084782000},"page":"125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Synergistic Antifungal Activity of Terbinafine in Combination with Light-Activated Gelatin\u2013Silver Nanoparticles Against Candida albicans Strains"],"prefix":"10.3390","volume":"17","author":[{"given":"Atif","family":"Ullah","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Kohat University of Science and Technology, Kohat 26000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fawad","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kohat University of Science and Technology, Kohat 26000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farman","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kohat University of Science and Technology, Kohat 26000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajid Khan","family":"Sadozai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kohat University of Science and Technology, Kohat 26000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5606-2719","authenticated-orcid":false,"given":"Saeed Ahmed","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kohat University of Science and Technology, Kohat 26000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajid","family":"Hussain","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kohat University of Science and Technology, Kohat 26000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3761-6656","authenticated-orcid":false,"given":"Abdulwahed Fahad","family":"Alrefaei","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 2455, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0696-3057","authenticated-orcid":false,"given":"Sajid","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Horticulture and Life Science, Yeungnam University, Gyeongsan 38541, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"ref_1","unstructured":"Muruganathan, B. (2020). Manual of Hypertension, Jaypee Brothers Medical Publishers."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R.O., and Denning, D.W. (2017). Global and multi-national prevalence of fungal diseases\u2014Estimate precision. J. Fungi, 3.","DOI":"10.3390\/jof3040057"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101574","DOI":"10.1016\/j.jddst.2020.101574","article-title":"Ketoconazole-loaded PLGA nanoparticles and their synergism against Candida albicans when combined with silver nanoparticles","volume":"56","author":"Sadozai","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_4","first-page":"189","article-title":"Candida albicans the main opportunistic pathogenic fungus in humans","volume":"55","year":"2023","journal-title":"Rev. Argent. de Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Talapko, J., Juzba\u0161i\u0107, M., Matijevi\u0107, T., Pustijanac, E., Beki\u0107, S., Kotris, I., and \u0160krlec, I. (2021). Candida albicans\u2014The virulence factors and clinical manifestations of infection. J. Fungi, 7.","DOI":"10.3390\/jof7020079"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sadozai, S.K., Khan, S.A., Baseer, A., Ullah, R., Zeb, A., and Schneider, M. (2022). In vitro, ex vivo, and in vivo evaluation of nanoparticle-based topical formulation against Candida albicans infection. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.909851"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1080\/14656566.2021.1873951","article-title":"Current and promising pharmacotherapeutic options for candidiasis","volume":"22","author":"Scorzoni","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_8","first-page":"5806","article-title":"The future of antifungal drug therapy: Novel compounds and targets","volume":"65","author":"Regeimbal","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.2174\/1574885517666220328141054","article-title":"A detailed insight onto the molecular and cellular mechanism of action of the antifungal drugs used in the treatment of superficial fungal infections","volume":"17","author":"Wal","year":"2022","journal-title":"Curr. Drug Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fioriti, S., Brescini, L., Pallotta, F., Canovari, B., Morroni, G., and Barchiesi, F. (2022). Antifungal combinations against Candida species: From bench to bedside. J. Fungi, 8.","DOI":"10.3390\/jof8101077"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.mycmed.2006.07.004","article-title":"In vitro activity of terbinafine against Indian clinical isolates of Candida albicans and non-albicans using a macrodilution method","volume":"16","author":"Garg","year":"2006","journal-title":"J. Mycol. M\u00e9dicale"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"449","DOI":"10.3892\/br.2016.608","article-title":"Sensitization of Candida albicans to terbinafine by berberine and berberrubine","volume":"4","author":"Lam","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e383","DOI":"10.1016\/S1473-3099(17)30316-X","article-title":"The global problem of antifungal resistance: Prevalence, mechanisms, and management","volume":"17","author":"Perlin","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Atriwal, T., Azeem, K., Husain, F.M., Hussain, A., Khan, M.N., Alajmi, M.F., and Abid, M. (2021). Mechanistic understanding of Candida albicans biofilm formation and approaches for its inhibition. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.638609"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e00074-23","DOI":"10.1128\/cmr.00074-23","article-title":"Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease","volume":"37","author":"Hoenigl","year":"2024","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"More, P.R., Pandit, S., De Filippis, A., Franci, G., Mijakovic, I., and Galdiero, M. (2023). Silver nanoparticles: Bactericidal and mechanistic approach against drug resistant pathogens. Microorganisms, 11.","DOI":"10.3390\/microorganisms11020369"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kaiser, K.G., Delattre, V., Frost, V.J., Buck, G.W., Phu, J.V., Fernandez, T.G., and Pavel, I.E. (2023). Nanosilver: An old antibacterial agent with great promise in the fight against antibiotic resistance. Antibiotics, 12.","DOI":"10.3390\/antibiotics12081264"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.nano.2009.04.006","article-title":"Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: A study against gram-positive and gram-negative bacteria","volume":"6","author":"Fayaz","year":"2010","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8840","DOI":"10.1021\/acs.est.6b00998","article-title":"Mechanistic study of the synergistic antibacterial activity of combined silver nanoparticles and common antibiotics","volume":"50","author":"Deng","year":"2016","journal-title":"Environ. Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Matras, E., Gorczyca, A., Przemieniecki, S.W., and O\u0107wieja, M. (2022). Surface properties-dependent antifungal activity of silver nanoparticles. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-22659-2"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Abd-Elsalam, K.A. (2022). Nanosynthetic and ecofriendly approaches to produce green silver nanoparticles. Green Synthesis of Silver Nanomaterials, Elsevier.","DOI":"10.1016\/B978-0-12-824508-8.00022-8"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1177\/0958305X21989883","article-title":"Nanobiotechnology: Nature-inspired silver nanoparticles towards green synthesis","volume":"32","author":"Rosman","year":"2021","journal-title":"Energy Environ."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Dikshit, P.K., Kumar, J., Das, A.K., Sadhu, S., Sharma, S., Singh, S., Gupta, P.K., and Kim, B.S. (2021). Green synthesis of metallic nanoparticles: Applications and limitations. Catalysts, 11.","DOI":"10.3390\/catal11080902"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1039\/D1NR08144F","article-title":"Green approaches for the synthesis of metal and metal oxide nanoparticles using microbial and plant extracts","volume":"14","author":"Jeevanandam","year":"2022","journal-title":"Nanoscale"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"569","DOI":"10.2147\/IJN.S16867","article-title":"Green synthesis and characterization of gelatin-based and sugar-reduced silver nanoparticles","volume":"6","author":"Darroudi","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ullah, H., Ullah, I., Rehman, G., Hamayun, M., Ali, S., Rahman, A., and Lee, I.-J. (2022). Magnesium and zinc oxide nanoparticles from datura alba improve cognitive impairment and blood brain barrier leakage. Molecules, 27.","DOI":"10.3390\/molecules27154753"},{"key":"ref_27","first-page":"221","article-title":"Mini-Review: Opportunities and challenges in the techniques used for preparation of gelatin nanoparticles","volume":"33","author":"Khan","year":"2020","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1002\/mabi.201400214","article-title":"Stabilization of gelatin nanoparticles without crosslinking","volume":"14","author":"Khan","year":"2014","journal-title":"Macromol. Biosci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Babick, F. (2020). Dynamic light scattering (DLS). Characterization of Nanoparticles, Elsevier.","DOI":"10.1016\/B978-0-12-814182-3.00010-9"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jddst.2017.04.027","article-title":"SEM-image textural features and drug release behavior of Eudragit-based matrix pellets","volume":"42","author":"Concheiro","year":"2017","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.scitotenv.2017.04.055","article-title":"A rapid approach for measuring silver nanoparticle concentration and dissolution in seawater by UV\u2013Vis","volume":"618","author":"Sikder","year":"2018","journal-title":"Sci. Total Environ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"84172","DOI":"10.1039\/C5RA10187E","article-title":"Impact of storage conditions and storage time on silver nanoparticles' physicochemical properties and implications for their biological effects","volume":"5","author":"Huk","year":"2015","journal-title":"Rsc. Adv."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Arif, H., Qayyum, S., Akhtar, W., Fatima, I., Kayani, W.K., Rahman, K.U., and Ali, S. (2023). Synthesis and Characterization of Zinc Oxide Nanoparticles at Different pH Values from Clinopodium vulgare L. and Their Assessment as an Antimicrobial Agent and Biomedical Application. Micromachines, 14.","DOI":"10.3390\/mi14071285"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.2174\/0113816128319010240730115613","article-title":"Biological and Photocatalytic Activities of Silver Nanoparticles Synthesized from the Leaf Extract of Euphorbia royleana Boiss","volume":"30","author":"Begum","year":"2024","journal-title":"Curr. Pharm. Des."},{"key":"ref_35","unstructured":"da Silva, P.J.F. (2015). Screening of Biotechnological Potential of Osmundea Pinnatifida: Cultivation Trials and Biological Activities. [Master\u2019s Thesis, Universidade de Coimbra]."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3101324","DOI":"10.1155\/2020\/3101324","article-title":"Antifungal activity of the essential oil of Echinops kebericho Mesfin: An in vitro study","volume":"2020","author":"Beressa","year":"2020","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Alqahtani, A., Marrez, D.A., Aleraky, M., Fagir, N.A., Alqahtani, O., Othman, S., El Raey, M.A., and Attia, H.G. (2022). Characterization and Isolation of the Major Biologically Active Metabolites Isolated from Ficus retusa and Their Synergistic Effect with Tetracycline against Certain Pathogenic-Resistant Bacteria. Pharmaceuticals, 15.","DOI":"10.3390\/ph15121473"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2","DOI":"10.31080\/ASMI.2021.04.0825","article-title":"Protocol to evaluate antibacterial activity MIC, FIC and time kill method","volume":"4","author":"Alshareef","year":"2021","journal-title":"Acta Sci. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"378280","DOI":"10.1155\/2014\/378280","article-title":"Evaluation of antifungal activity and mechanism of action of citral against Candida albicans","volume":"2014","author":"Leite","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.biopha.2018.12.009","article-title":"Current antifungal drugs and immunotherapeutic approaches as promising strategies to treatment of fungal diseases","volume":"110","author":"Nami","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sousa, F., Ferreira, D., Reis, S., and Costa, P. (2020). Current insights on antifungal therapy: Novel nanotechnology approaches for drug delivery systems and new drugs from natural sources. Pharmaceuticals, 13.","DOI":"10.3390\/ph13090248"},{"key":"ref_42","first-page":"481","article-title":"The effects of different ionic liquid coatings and the length of alkyl chain on antimicrobial and cytotoxic properties of silver nanoparticles","volume":"12","author":"Abbaszadegan","year":"2017","journal-title":"Iran. Endod. J."},{"key":"ref_43","unstructured":"Lanza Bayona, G.A. (2023). Nanoparticles Applications in Time-Temperature Indicators (TTIs) for Cold Chain Validation of Fruits in Cundinamarca Region, Universidad de los Andes Repository."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1021\/acs.chemrev.8b00341","article-title":"Stabilization of silver and gold nanoparticles: Preservation and improvement of plasmonic functionalities","volume":"119","author":"Kang","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"103312","DOI":"10.1016\/j.jksus.2024.103312","article-title":"Utilizing Cinnamomum verum extract for green synthesis of silver nanoparticles: Exploring optical properties, morphology, and potential applications","volume":"36","author":"Alanazi","year":"2024","journal-title":"J. King Saud Univ. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1021\/acssuschemeng.3c04907","article-title":"Preparation and Application of Sustained-Release Antibacterial Alginate Hydrogels by Loading Plant-Mediated Silver Nanoparticles","volume":"12","author":"Dai","year":"2024","journal-title":"ACS Sustain. Chem. Eng."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bayat, M., Zargar, M., Chudinova, E., Astarkhanova, T., and Pakina, E. (2021). In vitro evaluation of antibacterial and antifungal activity of biogenic silver and copper nanoparticles: The first report of applying biogenic nanoparticles against Pilidium concavum and Pestalotia sp. fungi. Molecules, 26.","DOI":"10.3390\/molecules26175402"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Chen, D., Cheng, Y., Shi, L., Gao, X., Huang, Y., and Du, Z. (2024). Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane. Molecules, 29.","DOI":"10.3390\/molecules29174124"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1166\/jnn.2016.10934","article-title":"Synergy between polyvinylpyrrolidone-coated silver nanoparticles and azole antifungal against drug-resistant Candida albicans","volume":"16","author":"Sun","year":"2016","journal-title":"J. Nanosci. Nanotechnol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/1\/125\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:30:26Z","timestamp":1759919426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/1\/125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,17]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["pharmaceutics17010125"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17010125","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,17]]}}}