Abstract
Oral candidiasis or thrush is a fungal infection due to Candida albicans, causing discomfort in areas inside mouth or tongue. The clinical application of antifungal reagent amphotericin B (AMB), which is believed to offer a better treatment for oral candidiasis, is greatly compromised by its toxicities (mainly nephrotoxicity) and poor solubility. In order to overcome these issues, we characterized AMB-loaded MPEG-PCL micelles in vitro and in vivo. In addition, the antifungal activities of AMB/MPEG-PCL micelles-loaded buccal tablet were also evaluated in vitro. We found that micelles system could significantly improve the solubility of AMB yet reduce the overall toxicity, while the buccal tablet system is capable to suppress C. albicans biofilm formation. Furthermore, the toxicity of the buccal tablet system is also reduced compared with other standard preparations. Therefore, the prepared tablet with AMB-loaded MPEG-PCL micelles as oral topical preparations has the potential to improve current treatment of superficial oral C. albicans infections.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arantes PT, Sanita PV, Santezi C, Barbeiro CD, Reina BD, Vergani CE, Dovigo LN (2016) Reliability of the agar based method to assess the production of degradative enzymes in clinical isolates of Candida albicans. Med Mycol 54:266–274. https://doi.org/10.1093/mmy/myv103
Arce-Miranda JE, Sotomayor CE, Albesa I, Paraje MG (2011) Oxidative and nitrosative stress in Staphylococcus aureus biofilm. FEMS Microbiol Lett 315:23–29. https://doi.org/10.1111/j.1574-6968.2010.02164.x
Baginski M, Czub J (2009) Amphotericin B and its new derivatives-mode of action. Curr Drug Metab 10:459–469. https://doi.org/10.2174/138920009788898019
Banat IM, De Rienzo MA, Quinn GA (2014) Microbial biofilms: biosurfactants as antibiofilm agents. Appl Microbiol Biotechnol 98:9915–9929. https://doi.org/10.1007/s00253-014-6169-6
Barkalina N, Jones C, Coward K (2016) Nanomedicine and mammalian sperm: lessons from the porcine model. Theriogenology 85:74–82. https://doi.org/10.1016/j.theriogenology.2015.05.025
Barros PP, Ribeiro FC, Rossoni RD, Junqueira JC, Jorge AO (2016) Influence of Candida krusei and Candida glabrata on Candida albicans gene expression in in vitro biofilms. Arch Oral Biol 64:92–101. https://doi.org/10.1016/j.archoralbio.2016.01.005
Botero-Aguirre JP, Restrepo-Hamid AM (2015) Amphotericin B deoxycholate versus liposomal amphotericin B: effects on kidney function. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD010481.pub2
Botero MC, Puentes-Herrera M, Cortes JA (2014) Lipid formulations of amphotericin. Rev Chil Infectol 31:518–527. https://doi.org/10.4067/S0716-10182014000500002
Charvalos E, Tzatzarakis MN, Van Bambeke F, Tulkens PM, Tsatsakis AM, Tzanakakis GN, Mingeot-Leclercq MP (2006) Water-soluble amphotericin B-polyvinylpyrrolidone complexes with maintained antifungal activity against Candida spp. and Aspergillus spp. and reduced haemolytic and cytotoxic effects. J Antimicrob Chemother 57:236–244. https://doi.org/10.1093/jac/dki455
Chen YC, Su CY, Jhan HJ, Ho HO, Sheu MT (2015) Physical characterization and in vivo pharmacokinetic study of self-assembling amphotericin B-loaded lecithin-based mixed polymeric micelles. Int J Nanomedicine 10:7265–7274. https://doi.org/10.2147/IJN.S95194
Fanos V, Cataldi L (2000) Amphotericin B-induced nephrotoxicity: a review. J Chemother 12:463–470. https://doi.org/10.1179/joc.2000.12.6.463
Hamill RJ (2013) Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs 73:919–934. https://doi.org/10.1007/s40265-013-0069-4
Han YW, Shi W, Huang GT, Kinder-Haake S, Park NH, Kuramitsu H, Genco RJ (2000) Interactions between periodontal bacteria and human oral epithelial cells: fusobacterium nucleatum adheres to and invades epithelial cells. Infect Immun 68:3140–3146. https://doi.org/10.1128/IAI.68.6.3140-3146.2000
Hashemi M, Ayatollahi S, Parhiz H, Mokhtarzadeh A, Javidi S, Ramezani M (2015) PEGylation of polypropylenimine dendrimer with alkylcarboxylate chain linkage to improve DNA delivery and cytotoxicity. Appl Biochem Biotechnol 177:1–17. https://doi.org/10.1007/s12010-015-1723-y
He J, Chipot C, Shao XG, Cai WS (2014) Cooperative recruitment of amphotericin B mediated by a cyclodextrin dimer. J Phys Chem C 118:24173–24180. https://doi.org/10.1021/jp507325j
Homeyer DC, Sanchez CJ, Mende K, Beckius ML, Murray CK, Wenke JC, Akers KS (2015) In vitro activity of melaleuca alternifolia (tea tree) oil on filamentous fungi and toxicity to human cells. Med Mycol 53:285–294. https://doi.org/10.1093/mmy/myu072
Javed F, Samaranayake LP, Romanos GE (2014) Treatment of oral fungal infections using antimicrobial photodynamic therapy: a systematic review of currently available evidence. Photochem Photobiol Sci 13:726–734. https://doi.org/10.1039/c3pp50426c
Kaneo Y, Taguchi K, Tanaka T, Yamamoto S (2014) Nanoparticles of hydrophobized cluster dextrin as biodegradable drug carriers: solubilization and encapsulation of amphotericin B. J Drug Deliv Sci Tec 24:344–351. https://doi.org/10.1016/S1773-2247(14)50072-X
Kumar CG, Poornachandra Y (2015) Biodirected synthesis of Miconazole-conjugated bacterial silver nanoparticles and their application as antifungal agents and drug delivery vehicles. Colloid Surface B 125:110–119. https://doi.org/10.1016/j.colsurfb.2014.11.025
Lalla RV, Bensadoun RJ (2011) Miconazole mucoadhesive tablet for oropharyngeal candidiasis. Expert Rev Anti-Infect Ther 9:13–17. https://doi.org/10.1586/eri.10.152
Laredj-Bourezg F, Bolzinger MA, Pelletier J, Valour JP, Rovere MR, Smatti B, Chevalier Y (2015) Skin delivery by block copolymer nanoparticles (block copolymer micelles). Int J Pharm 496:1034–1046. https://doi.org/10.1016/j.ijpharm.2015.11.031
Lourbakos A, Potempa J, Travis J, D'Andrea MR, Andrade-Gordon P, Santulli R, Mackie EJ, Pike RN (2001) Arginine-specific protease from porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect Immun 69:5121–5130. https://doi.org/10.1128/IAI.69.8.5121-5130.2001
Lyu X, Zhao C, Z-m Y, Hua H (2016) Efficacy of nystatin for the treatment of oral candidiasis: a systematic review and meta-analysis. Drug Des Devel Ther 10:1161–1171. https://doi.org/10.2147/DDDT.S100795
Malik DS, Mital N, Kaur G (2016) Topical drug delivery systems: a patent review. Expert Opin Ther Pat 26:213–228. https://doi.org/10.1517/13543776.2016.1131267
Mansuri S, Kesharwani P, Jain K, Tekade RK, Jain NK (2016) Mucoadhesion: a promising approach in drug delivery system. React Funct Polym 100:151–172. https://doi.org/10.1016/j.reactfunctpolym.2016.01.011
Mesa-Arango AC, Trevijano-Contador N, Román E, Sánchez-Fresneda R, Casas C, Herrero E, Argüelles JC, Pla J, Cuenca-Estrella M, Zaragozaa O (2014) The production of reactive oxygen species is a universal action mechanism of amphotericin B against pathogenic yeasts and contributes to the fungicidal effect of this drug. Antimicrob Agents Chemother 58:6627–6638 doi:10.1128/AAC.03570-14
Mohamed-Ahmed HA, Les KA, Seifert K, Croft SL, Brocchini S (2013) Noncovalent complexation of amphotericin-B with Poly(α-glutamic acid). Mol Pharm 10:940–950. https://doi.org/10.1021/mp300339p
Mukherjee PK, Chen H, Patton LL, Evans S, Lee A, Kumwenda J, Hakim J, Masheto G, Sawe F, Pho M, Freedberg KA, Shiboski CH, Ghannoum MA, Salata RA (2017) Topical gentian violet compared with nystatin oral suspension for the treatment of oropharyngeal candidiasis in HIV-1 infected participants. Aids 31:8188. https://doi.org/10.1097/Qad.0000000000001286
O'Keeffe J, Doyle S, Kavanagh K (2003) Exposure of the yeast Candida albicans to the anti-neoplastic agent adriamycin increases the tolerance to amphotericin B. J Pharm Pharmacol 55:1629–1633. https://doi.org/10.1211/0022357022359
Patil S, Rao RS, Majumdar B, Anil S (2015) Clinical appearance of oral Candida infection and therapeutic strategies. Front Microbiol 6. https://doi.org/10.3389/fmicb.2015.01391
Patton LL (2016) Current strategies for prevention of oral manifestations of human immunodeficiency virus. Oral Surg Oral Med Oral Pathol 121:29–38. https://doi.org/10.1016/j.oooo.2015.09.004
Paula SB, Morey AT, Santos JP, Santos PM, Gameiro DG, Kerbauy G, Sena EM, Ueda LT, Carneiro M, Pinge-Filho P, Yamauchi LM, Yamada-Ogatta SF (2015) Oral Candida colonization in HIV-infected patients in Londrina-PR, Brazil: antifungal susceptibility and virulence factors. J Infect Dev Countr 9:1350–1359. https://doi.org/10.3855/jidc.6970
Rajendran R, Sherry L, Nile CJ, Sherriff LA, Johnson EM, Hanson MF, Williams C, Munro CA, Jones BJ, Ramage G (2016) Biofilm formation is a risk factor for mortality in patients with Candida albicans bloodstream infection-Scotland, 2012-2013. Clin Microbiol Infect 22:87–93. https://doi.org/10.1016/j.cmi.2015.09.018
Randhawa MA, Gondal MA, Al-Zahrani AJ, Rashid SG, Ali A (2015) Synthesis, morphology and antifungal activity of nano-particulated amphotericin-B, ketoconazole and thymoquinone against Candida albicans yeasts and Candida biofilm. J Environ Sci Heal A 50:119–124. https://doi.org/10.1080/10934529.2015.975042
Ruiz HK, Serrano DR, Dea-Ayuela MA, Bilbao-Ramos PE, Bolas-Fernandez F, Torrado JJ, Molero G (2014) New amphotericin B-gamma cyclodextrin formulation for topical use with synergistic activity against diverse fungal species and Leishmania spp. Int J Pharm 473:148–157. https://doi.org/10.1016/j.ijpharm.2014.07.004
Serrano-Fujarte I, Lopez-Romero E, Reyna-Lopez GE, Martinez-Gamez MA, Vega-Gonzalez A, Cuellar-Cruz M (2015) Influence of culture media on biofilm formation by Candida species and response of sessile cells to antifungals and oxidative stress. Biomed Res Int. https://doi.org/10.1155/2015/783639
Silva AE, Barratt G, Cheron M, Egito EST (2013) Development of oil-in-water microemulsions for the oral delivery of amphotericin B. Int J Pharm 454:641–648. https://doi.org/10.1016/j.ijpharm.2013.05.044
Siopi M, Neroutsos E, Zisaki K, Gamaletsou M, Pirounaki M, Tsirigotis P, Sipsas N, Dokoumetzidis A, Goussetis E, Zerva L, Valsami G, Meletiadis J (2016) Bioassay for determining voriconazole serum levels in patients receiving combination therapy with echinocandins. Antimicrob Agents Chemother 60:632–636. https://doi.org/10.1128/AAC.01688-15
Taborga L, Diaz K, Olea AF, Reyes-Bravo P, Flores ME, Pena-Cortes H, Espinoza L (2015) Effect of polymer micelles on antifungal activity of geranylorcinol compounds against Botrytis cinerea. J Agrlc Food Chem 63:6890–6896. https://doi.org/10.1021/acs.jafc.5b01920
Tang XL, Dai JJ, Xie J, Zhu YQ, Zhu M, Wang Z, Xie CM, Yao AX, Liu TT, Wang XY, Chen L, Jiang QL, Wang SL, Liang Y, Xu CJ (2015) Enhanced antifungal activity by ab-modified amphotericin B-loaded nanoparticles using a pH-responsive block copolymer. Nanoscale Res Lett 10:1–11. https://doi.org/10.1186/s11671-015-0969-1
Tian Y, Mao SR (2012) Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs. Expert Opin Drug Del 9:687–700. https://doi.org/10.1517/17425247.2012.681299
Vazquez J, Reboli AC, Pappas PG, Patterson TF, Reinhardt J, Chin-Hong P, Tobin E, Kett DH, Biswas P, Swanson R (2014) Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis 14. https://doi.org/10.1186/1471-2334-14-97
Vazquez JA, Sobel JD (2012) Miconazole mucoadhesive tablets: a novel delivery system. Clin Infect Dis 54:1480–1484. https://doi.org/10.1093/cid/cis205
Villegas NA, Baronetti J, Albesa I, Polifroni R, Parma A, Etcheverria A, Becerra M, Padola N, Paraje M (2013) Relevance of biofilms in the pathogenesis of Shiga-toxin-producing Escherichia coli infection. Sci World J 2013:607258. https://doi.org/10.1155/2013/607258
Wang K, Liu TT, Lin R, Liu B, Yang GD, Xin B, Wang WR, Zhang PP, Zhou L, Zhang JY (2014) Preparation and in vitro release of buccal tablets of naringenin-loaded MPEG-PCL nanoparticles. RSC Adv 4:33672–33679. https://doi.org/10.1039/c4ra04920a
Wang YJ, Gou ML, Gong CY, Wang C, Qian ZY, Lin YF, Luo F (2012) Pharmacokinetics and disposition of nanomedicine using biodegradable PEG/PCL polymers as drug carriers. Curr Drug Metab 13:338–353. https://doi.org/10.2174/138920012800166490
Zhang XW, Zhang TP, Zhou XT, Liu HM, Sun H, Ma ZG, Wu BJ (2014) Enhancement of oral bioavailability of tripterine through lipid nanospheres: preparation, characterization, and absorption evaluation. J Pharm Sci-US 103:1711–1719. https://doi.org/10.1002/jps.23967
Zhu YA, Yu JN, Tong SS, Wang L, Peng M, Cao X, Xu XM (2010) Preparation and in vitro evaluation of povidone-sodium cholate-phospholipid mixed micelles for the solubilization of poorly soluble drugs. Arch Pharm Res 33:911–917. https://doi.org/10.1007/s12272-010-0614-6
Zhu YY, Liao LM (2015) Applications of nanoparticles for anticancer drug delivery: a review. J Nanosci Nanotechnol 15:4753–4773. https://doi.org/10.1166/jnn.2015.10298
Zia Q, Khan AA, Swaleha Z, Owais M (2015) Self-assembled amphotericin B-loaded polyglutamic acid nanoparticles: preparation, characterization and in vitro potential against Candida albicans. Int J Nanomedicine 10:1769–1790. https://doi.org/10.2147/IJN.S63155
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 81402925, 81470549, 81400233, and 81270347). The authors would like to thank the editor for editing the manuscript and the anonymous reviewers for their detailed and helpful comments.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
The authors state that the animal experimental protocol was in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and was approved by the Institutional Animal Care Committee of Xi’an Jiaotong University.
Conflict of interest
The authors declare that they have no competing conflict of interest.
Electronic supplementary material
ESM 1
Supplementary data (the details of experimental methods, Tables and Figures associated with this article) are available in the online version of this article. (PDF 573 kb)
Rights and permissions
About this article
Cite this article
Zhang, P., Yang, X., He, Y. et al. Preparation, characterization and toxicity evaluation of amphotericin B loaded MPEG-PCL micelles and its application for buccal tablets. Appl Microbiol Biotechnol 101, 7357–7370 (2017). https://doi.org/10.1007/s00253-017-8463-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-017-8463-6