{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T17:41:44Z","timestamp":1789839704759,"version":"4.0.1"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T00:00:00Z","timestamp":1659484800000},"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>Candida albicans is a common fungal pathogen. Biofilm formation on various surfaces is an important determinant of C. albicans pathogenicity. Our previous results demonstrated the high potential of cannabidiol (CBD) to affect C. albicans biofilms. Based on these data, we investigated the possibility of incorporating CBD and\/or triclosan (an antimicrobial agent that is widely utilized in dentistry) in a sustained-release varnish (SRV) (SRV-CBD, SRV-triclosan) to increase their pharmaceutical potential against C. albicans biofilm, as well as that of the mixture of the agents into SRV (SRV-CBD\/triclosan). The study was conducted in a plastic model, on agar, and in an ex vivo tooth model. Our results demonstrated strong antibiofilm activity of SRV-CBD and SRV-triclosan against C. albicans in all tested models. Both formulations were able to inhibit biofilm formation and to remove mature fungal biofilm. In addition, SRV-CBD and SRV-triclosan altered C. albicans morphology. Finally, we observed a dramatic enhancement of antibiofilm activity when combined SRV-CBD\/triclosan was applied. In conclusion, we propose that incorporation of CBD or triclosan into SRV is an effective strategy to fight fungal biofilms. Importantly, the data demonstrate that our CBD\/triclosan varnish is safe, and is not cytotoxic for normal mammalian cells. Furthermore, we propose that CBD and triclosan being in mixture in SRV exhibit complementary antibiofilm activity, and thus can be explored for further development as a potential treatment against fungal infections.<\/jats:p>","DOI":"10.3390\/pharmaceutics14081624","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T23:33:01Z","timestamp":1659569581000},"page":"1624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Potential Combinatory Effect of Cannabidiol and Triclosan Incorporated into Sustained Release Delivery System against Oral Candidiasis"],"prefix":"10.3390","volume":"14","author":[{"given":"Mark","family":"Feldman","sequence":"first","affiliation":[{"name":"Biofilm Research Laboratory, Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irith","family":"Gati","sequence":"additional","affiliation":[{"name":"The Institute for Drug Research, Medical Faculty, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2978-5943","authenticated-orcid":false,"given":"Ronit Vogt","family":"Sionov","sequence":"additional","affiliation":[{"name":"Biofilm Research Laboratory, Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharonit","family":"Sahar-Helft","sequence":"additional","affiliation":[{"name":"Department of Endodontics, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Department of Endodontics, School of Graduate Dentistry, Rambam Health Care Center, Faculty of Medicine, Technion\u2014Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Friedman","sequence":"additional","affiliation":[{"name":"The Institute for Drug Research, Medical Faculty, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doron","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Biofilm Research Laboratory, Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4161\/viru.22913","article-title":"Candida albicans pathogenicity mechanisms","volume":"4","author":"Mayer","year":"2013","journal-title":"Virulence"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Feldman, M., Al-Quntar, A., Polacheck, I., Friedman, M., and Steinberg, D. (2014). Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093225"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1128\/CMR.00029-06","article-title":"Epidemiology of invasive candidiasis: A persistent public health problem","volume":"20","author":"Pfaller","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.mib.2006.10.003","article-title":"How to build a biofilm: A fungal perspective","volume":"9","author":"Blankenship","year":"2006","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Feldman, M., Sionov, R.V., Mechoulam, R., and Steinberg, D. (2021). Anti-biofilm activity of cannabidiol against Candida albicans. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020441"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1128\/AAC.04212-14","article-title":"Sustained release of a novel anti-quorum-sensing agent against oral fungal biofilms","volume":"59","author":"Feldman","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejim.2018.01.004","article-title":"Practical considerations in medical cannabis administration and dosing","volume":"49","author":"MacCallum","year":"2018","journal-title":"Eur. J. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1146\/annurev-pharmtox-010818-021441","article-title":"Beyond THC and endocannabinoids","volume":"60","author":"Pacher","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.pharmthera.2017.02.041","article-title":"Cannabidiol: State of the art and new challenges for therapeutic applications","volume":"175","author":"Pisanti","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3389\/fcimb.2019.00324","article-title":"Cannabidiol is a novel modulator of bacterial membrane vesicles","volume":"9","author":"Kosgodage","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_11","first-page":"e6809","article-title":"Comparison of Efficacy of Cannabinoids versus Commercial Oral Care Products in Reducing Bacterial Content from Dental Plaque: A Preliminary Observation","volume":"12","author":"Stahl","year":"2020","journal-title":"Cureus"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.1038\/s41598-020-60952-0","article-title":"Cannabidiol is an effective helper compound in combination with bacitracin to kill Gram-positive bacteria","volume":"10","author":"Wassmann","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Karas, J.A., Wong, L.J., Paulin, O.K., Mazeh, A.C., Hussein, M.H., Li, J., and Velkov, T. (2020). The antimicrobial activity of cannabinoids. Antibiotics, 9.","DOI":"10.3390\/antibiotics9070406"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bruni, N., Della Pepa, C., Oliaro-Bosso, S., Pessione, E., Gastaldi, D., and Dosio, F. (2018). Cannabinoid delivery systems for pain and inflammation treatment. Molecules, 23.","DOI":"10.3390\/molecules23102478"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sionov, R.V., and Steinberg, D. (2022). Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030631"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1021\/np8002673","article-title":"Antibacterial cannabinoids from Cannabis sativa: A structure-activity study","volume":"71","author":"Appendino","year":"2008","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1111\/clr.13363","article-title":"Effects of a toothpaste containing 0.3% triclosan in the maintenance phase of peri-implantitis treatment: 2-Year randomized clinical trial","volume":"29","author":"Stewart","year":"2018","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/JPER.17-0302","article-title":"Impact of a triclosan-containing toothpaste during the progression of experimental peri-implant mucositis: Clinical parameters and local pattern of osteo-immunoinflammatory mediators in peri-implant fluid","volume":"89","author":"Ribeiro","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1007\/s00784-019-03121-6","article-title":"Triclosan toothpaste as an adjunct therapy to plaque control in children from periodontitis families: A crossover clinical trial","volume":"24","author":"Monteiro","year":"2020","journal-title":"Clin. Oral Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1007\/s10856-010-4126-1","article-title":"Antibacterial activity of a triclosan-containing resin composite matrix against three common oral bacteria","volume":"21","author":"Rathke","year":"2010","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1002\/jbm.b.30266","article-title":"Sustained-release delivery systems of triclosan for treatment of Streptococcus mutans biofilm","volume":"77","author":"Steinberg","year":"2006","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S1773-2247(09)50055-X","article-title":"Sustained release of doxycycline as matrix metalloproteinase inhibitor for treatment of chronic periodontal diseases: In vitro evaluation","volume":"19","author":"Grin","year":"2009","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1615\/CritRevTherDrugCarrierSyst.v21.i5.10","article-title":"Modeling of drug release from polymeric delivery systems\u2014A review","volume":"21","author":"Kanjickal","year":"2004","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s40265-019-01127-8","article-title":"Adverse effects associated with long-term administration of azole antifungal agents","volume":"79","author":"Benitez","year":"2019","journal-title":"Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.ijantimicag.2017.09.002","article-title":"The antifungal arsenal: Alternative drugs and future targets","volume":"51","author":"Wiederhold","year":"2018","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"178","DOI":"10.4103\/0972-124X.75913","article-title":"Chlorhexidine varnishes effectively inhibit Porphyromonas gingivalis and Streptococcus mutans\u2014An in vivo study","volume":"14","author":"George","year":"2010","journal-title":"J. Indian Soc. Periodontol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/jac\/48.2.241","article-title":"Testing a degradable topical varnish of cetylpyridinium chloride in an experimental dental biofilm model","volume":"48","author":"Steinberg","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1159\/000066539","article-title":"Formulation, development and characterization of sustained release varnishes containing amine and stannous fluorides","volume":"36","author":"Steinberg","year":"2002","journal-title":"Caries Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s00784-009-0275-3","article-title":"A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis","volume":"14","author":"Czerninski","year":"2010","journal-title":"Clin. Oral Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00784-014-1259-5","article-title":"Comparison of the efficacy of a novel sustained release clotrimazole varnish and clotrimazole troches for the treatment of oral candidiasis","volume":"19","author":"Czerninski","year":"2015","journal-title":"Clin. Oral Investig."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sionov, R.V., Gati, I., Kirmayer, D., Friedman, M., Steinberg, D., and Gross, M. (2021). Voice Prosthesis Coated with Sustained Release Varnish Containing Clotrimazole Shows Long-Term Protection against Candida albicans: An In Vitro Study. Molecules, 26.","DOI":"10.3390\/molecules26175395"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.37358\/RC.17.12.5983","article-title":"Preventive and Therapeutic Effects of Chlorhexidine Containing Varnish on Candida Biofilm","volume":"68","author":"Mensch","year":"2017","journal-title":"Rev. Chim."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"215","DOI":"10.18363\/rbo.v74n3.p.215","article-title":"Treatment of denture stomatitis: Literature review","volume":"74","author":"Martins","year":"2017","journal-title":"Rev. Bras. Odontol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1099\/mic.0.064097-0","article-title":"Shuttle vectors for facile gap repair cloning and integration into a neutral locus in Candida albicans","volume":"159","author":"Zacchi","year":"2013","journal-title":"Microbiology"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Feldman, M., Tanabe, S., Howell, A., and Grenier, D. (2012). Cranberry proanthocyanidins inhibit the adherence properties of Candida albicans and cytokine secretion by oral epithelial cells. BMC Complement. Altern. Med., 12.","DOI":"10.1186\/1472-6882-12-6"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1128\/IAI.00480-10","article-title":"Development and validation of an in vivo Candida albicans biofilm denture model","volume":"78","author":"Nett","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/j.archoralbio.2011.04.006","article-title":"Bioactivity and cellular structure of Candida albicans and Candida glabrata biofilms grown in the presence of fluconazole","volume":"56","author":"Gomes","year":"2011","journal-title":"Arch. Oral Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1080\/08927014.2010.534552","article-title":"Efficacy of surface-generated nitric oxide against Candida albicans adhesion and biofilm formation","volume":"26","author":"Privett","year":"2010","journal-title":"Biofouling"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1089\/088922299309658","article-title":"Clinical Perspective Oropharyngeal Candidiasis in Patients with HIV: Suggested Guidelines for Therapy","volume":"15","author":"Powderly","year":"1999","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s007840050008","article-title":"Miconazole lacquer in the treatment of denture stomatitis: Clinical and microbiological findings in Chinese patients","volume":"1","author":"Dias","year":"1997","journal-title":"Clin.Oral Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0722.1994.tb01484.x","article-title":"Miconazole lacquer compared with gel in treatment of denture stomatitis","volume":"102","author":"Parvinen","year":"1994","journal-title":"Eur. J. Oral Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/prd.12341","article-title":"Sustained-release delivery of antimicrobial drugs for the treatment of periodontal diseases: Fantasy or already reality?","volume":"84","author":"Steinberg","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1023\/A:1015898717936","article-title":"Sustained-release delivery systems for treatment of dental diseases","volume":"7","author":"Friedman","year":"1990","journal-title":"Pharm. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1080\/17425247.2016.1213239","article-title":"Sustained-release drug delivery of antimicrobials in controlling of supragingival oral biofilms","volume":"14","author":"Steinberg","year":"2017","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E177","DOI":"10.1208\/pt0801026","article-title":"Development of a peptide-containing chewing gum as a sustained release antiplaque antimicrobial delivery system","volume":"8","author":"Faraj","year":"2007","journal-title":"AAPS PharmSciTech"},{"key":"ref_46","first-page":"348647","article-title":"Propolis varnish: Antimicrobial properties against cariogenic bacteria, cytotoxicity, and sustained-release profile","volume":"2014","author":"Franca","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1056\/NEJMra1315399","article-title":"Invasive candidiasis","volume":"373","author":"Kullberg","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.5455\/annalsmedres.2020.05.478","article-title":"Investigation of antifungal, antibiofilm and anti-filamentation activities of biocides against Candida isolates","volume":"27","author":"Ozturk","year":"2020","journal-title":"Ann. Med. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1128\/AAC.45.9.2475-2479.2001","article-title":"Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms","volume":"45","author":"Ramage","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1128\/AAC.39.9.2128","article-title":"Resistance of Candida albicans biofilms to antifungal agents in vitro","volume":"39","author":"Hawser","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.mib.2007.04.001","article-title":"Infection-related gene expression in Candida albicans","volume":"10","author":"Brown","year":"2007","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3510124","DOI":"10.1155\/2017\/3510124","article-title":"A sustained-release membrane of thiazolidinedione-8: Effect on formation of a Candida\/Bacteria mixed biofilm on hydroxyapatite in a continuous flow model","volume":"2017","author":"Feldman","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Cervi, V.F., Saccol, C.P., da Rosa Pinheiro, T., Santos, R.C.V., Sari, M.H.M., and Cruz, L. (2022). A novel nanotechnological mucoadhesive and fast-dissolving film for vaginal delivery of clotrimazole: Design, characterization, and in vitro antifungal action. Drug Deliv. Transl. Res.","DOI":"10.1007\/s13346-022-01154-1"},{"key":"ref_54","first-page":"85","article-title":"Physical chemical analysis of percutaneous absorption process from creams and ointments","volume":"11","author":"Higuchi","year":"1960","journal-title":"J. Soc. Cosmet. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/jps.2600501018","article-title":"Rate of release of medicaments from ointment bases containing drugs in suspension","volume":"50","author":"Higuchi","year":"1961","journal-title":"J. Pharm. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/8\/1624\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:03:28Z","timestamp":1760141008000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/8\/1624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,3]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["pharmaceutics14081624"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14081624","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,3]]}}}