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Development of amphotericin B-loaded fibroin nanoparticles: a novel approach for topical ocular application

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Abstract

Fungal keratitis (FK), the major cause of ocular morbidity worldwide, is commonly treated with the amphotericin B (AmB) eye drops extemporaneously prepared from marketed parenteral formulations. However, these in-house prepared AmB eye drops have the drawbacks of poor ocular bioavailability and eye irritation. The aim of this study was to develop AmB-loaded fibroin nanoparticles (AmB-FNPs), in combination with the polymer PEG 400, as ready-to-use eye drops for FK. The AmB-FNPs were prepared by desolvation method. All AmB-FNPs exhibited homogeneous spherical particles with a mean size of ~ 270 nm, the zeta potential of ~ − 17 mV, and an entrapment efficiency of ~ 65%. Using X-ray diffraction and UV analysis, AmB demonstrated amorphous molecular dispersion and monomeric form when entrapped in the FNPs. Interestingly, in dissolution studies, although AmB-FNPs showed no detectable drug release in sink condition, they still possessed good antifungal activity against Candida albicans. Potentially, AmB-FNPs showed less cytotoxicity in human corneal epithelial cell line compared to the marketed AmB deoxycholate.

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References

  1. Gallis HA, Drew RH, Pickard WW (1990) Amphotericin B: 30 years of clinical experience. Rev Infect Dis 12(2):308–329

    CAS  Google Scholar 

  2. Tuli SS (2011) Fungal keratitis. Clin Ophthalmol 5:275–279

    Google Scholar 

  3. Thomas PA, Kaliamurthy J (2013) Mycotic keratitis: epidemiology, diagnosis and management. Clin Microbiol Infect 19(3):210–220

    CAS  Google Scholar 

  4. Chhonker YS, Prasad YD, Chandasana H, Vishvkarma A, Mitra K, Shukla PK, Bhatta RS (2015) Amphotericin-B entrapped lecithin/chitosan nanoparticles for prolonged ocular application. Int J Biol Macromol 72:1451–1458

    CAS  Google Scholar 

  5. Morand K, Bartoletti AC, Bochot A, Barratt G, Brandely ML, Chast F (2007) Liposomal amphotericin B eye drops to treat fungal keratitis: physico-chemical and formulation stability. Int J Pharm 344(1–2):150–153

    CAS  Google Scholar 

  6. Fu T, Yi J, Lv S, Zhang B (2017) Ocular amphotericin B delivery by chitosan-modified nanostructured lipid carriers for fungal keratitis-targeted therapy. J Liposome Res 27(3):228–233

    CAS  Google Scholar 

  7. Suresh PK, Sah AK (2014) Nanocarriers for ocular delivery for possible benefits in the treatment of anterior uveitis: focus on current paradigms and future directions. Expert Opin Drug Deliv 11(11):1747–1768

    CAS  Google Scholar 

  8. Baranowski Przemysław, Karolewicz Bożena, Gajda Maciej, Pluta J (2014) Ophthalmic drug dosage forms: characterisation and research methods. Sci World J 2014:14

    Google Scholar 

  9. Das S, Suresh PK (2011) Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B. Nanomedicine 7(2):242–247

    CAS  Google Scholar 

  10. Gratieri T, Gelfuso GM, Lopez RFV, Souto EB (2010) Current efforts and the potential of nanomedicine in treating fungal keratitis. Expert Rev Ophthalmol 5(3):365–384

    CAS  Google Scholar 

  11. Sharma A, Taniguchi J (2017) Review: emerging strategies for antimicrobial drug delivery to the ocular surface: Implications for infectious keratitis. Ocul Surf 15(4):670–679

    Google Scholar 

  12. Zhou W, Wang Y, Jian J, Song S (2013) Self-aggregated nanoparticles based on amphiphilic poly(lactic acid)-grafted-chitosan copolymer for ocular delivery of amphotericin B. Int J Nanomed 8:3715–3728

    Google Scholar 

  13. Soliman GM (2017) Nanoparticles as safe and effective delivery systems of antifungal agents: achievements and challenges. Int J Pharm 523(1):15–32

    CAS  Google Scholar 

  14. Chaiyasan W, Srinivas SP, Tiyaboonchai W (2015) Crosslinked chitosan-dextran sulfate nanoparticle for improved topical ocular drug delivery. Mol Vis 21:1224–1234

    CAS  Google Scholar 

  15. Chen Y-C, Su C-Y, Jhan H-J, Ho H-O, Sheu M-T (2015) Physical characterization and in vivo pharmacokinetic study of self-assembling amphotericin B-loaded lecithin-based mixed polymeric micelles. Int J Nanomed 10:7265–7274

    CAS  Google Scholar 

  16. Das S, Suresh PK, Desmukh R (2010) Design of Eudragit RL 100 nanoparticles by nanoprecipitation method for ocular drug delivery. Nanomedicine 6(2):318–323

    CAS  Google Scholar 

  17. Xu Z, Shi L, Yang M, Zhu L (2019) Preparation and biomedical applications of silk fibroin-nanoparticles composites with enhanced properties—a review. Mater Sci Eng C 95:302–311

    CAS  Google Scholar 

  18. Lozano-Perez AA, Rodriguez-Nogales A, Ortiz-Cullera V, Algieri F, Garrido-Mesa J, Zorrilla P, Rodriguez-Cabezas ME, Garrido-Mesa N et al (2014) Silk fibroin nanoparticles constitute a vector for controlled release of resveratrol in an experimental model of inflammatory bowel disease in rats. Int J Nanomed 9:4507–4520

    Google Scholar 

  19. Pham DT, Saelim N, Tiyaboonchai W (2018) Crosslinked fibroin nanoparticles using EDC or PEI for drug delivery: physicochemical properties, crystallinity and structure. J Mater Sci 53(20):14087–14103. https://doi.org/10.1007/s10853-018-2635-3

    Article  CAS  Google Scholar 

  20. Sharma S, Bano S, Ghosh AS, Mandal M, Kim H-W, Dey T, Kundu SC (2016) Silk fibroin nanoparticles support in vitro sustained antibiotic release and osteogenesis on titanium surface. Nanomed (NBM) 12(5):1193–1204

    CAS  Google Scholar 

  21. Zhang YQ, Ma Y, Xia YY, Shen WD, Mao JP, Zha XM, Shirai K, Kiguchi K (2006) Synthesis of silk fibroin-insulin bioconjugates and their characterization and activities in vivo. J Biomed Mater Res B Appl Biomater 79(2):275–283

    Google Scholar 

  22. Pham DT, Saelim N, Tiyaboonchai W (2018) Design of experiments model for the optimization of silk fibroin based nanoparticles. Int J Appl Pharm 10(5):195–201

    CAS  Google Scholar 

  23. Pham DT, Saelim N, Tiyaboonchai W (2019) Alpha mangostin loaded crosslinked silk fibroin-based nanoparticles for cancer chemotherapy. Colloids Surf B Biointerfaces 181:705–713

    CAS  Google Scholar 

  24. Zhao Z, Li Y, Xie MB (2015) Silk fibroin-based nanoparticles for drug delivery. Int J Mol Sci 16(3):4880–4903

    CAS  Google Scholar 

  25. Nimtrakul Pataranapa, Tiyaboonchai Waree, Lamlertthon S (2019) Amphotericin B loaded nanostructured lipid carriers for parenteral delivery: characterization, antifungal and in vitro toxicity assessment. Curr Drug Deliv 16(7):645–653

    CAS  Google Scholar 

  26. Wong SSW, Kao RYT, Yuen KY, Wang Y, Yang D, Samaranayake LP, Seneviratne CJ (2014) In vitro and in vivo activity of a novel antifungal small molecule against candida infections. PLoS ONE 9(1):e85836

    Google Scholar 

  27. Rodriguez-Tudela JL, Cuenca-Estrella M, Diaz-Guerra TM, Mellado E (2001) Standardization of antifungal susceptibility variables for a semiautomated methodology. J Clin Microbiol 39(7):2513–2517

    CAS  Google Scholar 

  28. Takahashi Y, Koike M, Honda H, Ito Y, Sakaguchi H, Suzuki H, Nishiyama N (2008) Development of the short time exposure (STE) test: an in vitro eye irritation test using SIRC cells. Toxicol In Vitro 22(3):760–770

    CAS  Google Scholar 

  29. Chanburee S, Tiyaboonchai W (2017) Mucoadhesive nanostructured lipid carriers (NLCs) as potential carriers for improving oral delivery of curcumin. Drug Dev Ind Pharm 43(3):432–440

    CAS  Google Scholar 

  30. Niamprem P, Srinivas SP, Tiyaboonchai W (2018) Development and characterization of indomethacin-loaded mucoadhesive nanostructured lipid carriers for topical ocular delivery. Int J Appl Pharm 10(2):91–96

    CAS  Google Scholar 

  31. Schuerer N, Stein E, Inic-Kanada A, Pucher M, Hohenadl C, Bintner N, Ghasemian E, Montanaro J et al (2017) Implications for ophthalmic formulations: ocular buffers show varied cytotoxic impact on human corneal-limbal and human conjunctival epithelial cells. Cornea 36(6):712–718

    Google Scholar 

  32. Barwicz J, Christian S, Gruda I (1992) Effects of the aggregation state of amphotericin B on its toxicity to mice. Antimicrob Agents Chemother 36(10):2310–2315

    CAS  Google Scholar 

  33. Churchill DN, Seely J (1977) Nephrotoxicity associated with combined gentamicin-amphotericin B therapy. Nephron 19(3):176–181

    CAS  Google Scholar 

  34. Adams ML, Kwon GS (2003) Relative aggregation state and hemolytic activity of amphotericin B encapsulated by poly(ethylene oxide)-block–poly(N-hexyl-l-aspartamide)-acyl conjugate micelles: effects of acyl chain length. J Control Release 87(1):23–32

    CAS  Google Scholar 

  35. Barwicz J, Tancrède P (1997) The effect of aggregation state of amphotericin-B on its interactions with cholesterol- or ergosterol-containing phosphatidylcholine monolayers. Chem Phys Lipids 85(2):145–155

    CAS  Google Scholar 

  36. 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 Nanomed 10:1769–1790

    CAS  Google Scholar 

  37. Lemke A, Kiderlen AF, Kayser O (2005) Amphotericin B. Appl Microbiol Biotechnol 68(2):151–162

    CAS  Google Scholar 

  38. Torrado JJ, Espada R, Ballesteros MP, Torrado-Santiago S (2008) Amphotericin B formulations and drug targeting. J Pharm Sci 97(7):2405–2425

    CAS  Google Scholar 

  39. Merisko-Liversidge E, Liversidge GG, Cooper ER (2003) Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci 18(2):113–120

    CAS  Google Scholar 

  40. Dizaj SM, Vazifehasl Z, Salatin S, Adibkia K, Javadzadeh Y (2015) Nanosizing of drugs: effect on dissolution rate. Res Pharm Sci 10(2):95–108

    Google Scholar 

  41. Tiyaboonchai W, Limpeanchob N (2007) Formulation and characterization of amphotericin B–chitosan–dextran sulfate nanoparticles. Int J Pharm 329(1):142–149

    CAS  Google Scholar 

  42. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ (2002) Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother 46:834–840

    CAS  Google Scholar 

  43. Hartsel SC, Bauer E, Kwong EH, Wasan KM (2001) The effect of serum albumin on amphotericin B aggregate structure and activity. Pharm Res 18(9):1305–1309

    CAS  Google Scholar 

  44. Casa DM, Karam TK, Alves Ade C, Zgoda AA, Khalil NM, Mainardes RM (2015) Bovine serum albumin nanoparticles containing amphotericin B: characterization, cytotoxicity and in vitro antifungal evaluation. J Nanosci Nanotechnol 15(12):10183–10188

    CAS  Google Scholar 

  45. Bang JY, Song CE, Kim C, Park WD, Cho KR, Kim PI, Lee SR, Chung WT et al (2008) Cytotoxicity of amphotericin B-incorporated polymeric micelles composed of poly(dl-lactide-co-glycolide)/dextran graft copolymer. Arch Pharm Res 31(11):1463–1469

    CAS  Google Scholar 

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Acknowledgements

The author would like to thank Miss Manisha Bangar of UCL School of Pharmacy, University College London for her assistance in conducting the experiments.

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Correspondence to Waree Tiyaboonchai.

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Chomchalao, P., Nimtrakul, P., Pham, D.T. et al. Development of amphotericin B-loaded fibroin nanoparticles: a novel approach for topical ocular application. J Mater Sci 55, 5268–5279 (2020). https://doi.org/10.1007/s10853-020-04350-x

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