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A novel chitosan nanocapsule for enhanced skin penetration of cyclosporin A and effective hair growth in vivo

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Abstract

Hair loss due to medical conditions, such as alopecia, male pattern baldness, and cancer chemotherapy treatment, has been a common problem for many individuals. Cyclosporin A (CsA), a fungal metabolite, has been reported to be a hair growth modulatory agent and is a potential drug for hair regeneration. However, the effect of topical application of CsA is limited by its poor water solubility. Several delivery systems developed to enhance its solubility still showed poor skin penetration. To overcome these limitations, in this study, we have developed a novel chitosan nanocapsule platform using Pluronic F127 and chitosan without any chemical crosslinking or complicated preparation steps for the enhanced water solubility and high transdermal penetration of CsA. The chitosan nanocapsules (ChiNCs) optimized in terms of structural stability by using chitosan with various molecular weights ranging from 3 to 100 kDa enhanced the skin permeation of CsA through human cadaver skin in vitro. Topical administration of the CsA loaded ChiNCs increased the hair follicles by c.a. 7 times higher than that of the control group, and effectively induced hair growth in C57BL/6 mice in vivo. These results suggest that ChiNCs could be used as a platform for effective transdermal delivery of various hydrophobic drugs.

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References

  1. Borel, J. F.; Feurer, C.; Gubler, H. U.; Stähelin H. Biological effects of cyclosporin A: A new antilymphocytic agent. Agents Actions.1994, 43, 179–186.

    CAS  Google Scholar 

  2. de Arriba, G.; Calvino, M.; Benito, S.; Parra T. Cyclosporine A-induced apoptosis in renal tubular cells is related to oxidative damage and mitochondrial fission. Toxicol. Lett.2013, 218, 30–38.

    CAS  Google Scholar 

  3. N’Guessan, B. B.; Sanchez, H.; Zoll, J.; Ribera, F.; Dufour, S.; Lampert, E.; Kindo, M.; Geny, B.; Ventura-Clapier, R.; Mettauer B. Oxidative capacities of cardiac and skeletal muscles of heart transplant recipients: Mitochondrial effects of cyclosporin-A and its vehicle Cremophor-EL. Fundam. Clin. Pharmacol.2014, 28, 151–160.

    Google Scholar 

  4. Jiang, H.; Yamamoto, S.; Kato, R. Induction of anagen in telogen mouse skin by topical application of FK506, a potent immunosuppressant. J. Invest. Dermatol.1995, 104, 523–525.

    CAS  Google Scholar 

  5. Maurer, M.; Handjiski, B.; Paus, R. Hair growth modulation by topical immunophilin ligands: Induction of anagen, inhibition of massive catagen development, and relative protection from chemotherapy-induced alopecia. Am. J. Pathol.1997, 150, 1433–1441.

    CAS  Google Scholar 

  6. Paus, R.; Stenn, K. S.; Link, R. E. The induction of anagen hair growth in telogen mouse skin by cyclosporine A administration. Lab. Invest.1989, 60, 365–369.

    CAS  Google Scholar 

  7. Horsley, V.; Aliprantis, A. O.; Polak, L.; Glimcher, L. H.; Fuchs, E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell.2008, 132, 299–310.

    CAS  Google Scholar 

  8. Paus, R.; Handjiski, B.; Eichmuller, S.; Czarnetzki, B. M. Chemotherapy-induced alopecia in mice. Induction by cyclophosphamide, inhibition by cyclosporine A, and modulation by dexamethasone. Am. J. Pathol.1994, 144, 719–734.

    CAS  Google Scholar 

  9. Sawada, M.; Terada, N.; Taniguchi, H.; Tateishi, R.; Mori, Y. Cyclosporin A stimulates hair growth in nude mice. Lab. Invest.1987, 56, 684–686.

    CAS  Google Scholar 

  10. Yamamoto, S.; Kato, R. Hair growth-stimulating effects of cyclosporin A and FK506, potent immunosuppressants. J. Dermatol. Sci.1994, 7, S47–S54.

    Google Scholar 

  11. Xu, W. R.; Fan, W. X.; Yao, K. Cyclosporine A stimulated hair growth from mouse vibrissae follicles in an organ culture model. J. Biomed. Mater. Res.2012, 26, 372–380.

    CAS  Google Scholar 

  12. Ezure, T.; Suzuki, Y. Involvement of sonic hedgehog in cyclosporine A induced initiation of hair growth. J. Dermatol. Sci.2007, 47, 168–170.

    CAS  Google Scholar 

  13. Lan, S. W.; Liu, F. L.; Zhao, G. F.; Zhou, T.; Wu, C. L.; Kou, J. N.; Fan, R. R.; Qi, X. J.; Li, Y. H.; Jiang, Y. X. et al. Cyclosporine A increases hair follicle growth by suppressing apoptosis-inducing factor nuclear translocation: A new mechanism. Fundam. Clin. Pharmacol.2015, 29, 191–203.

    CAS  Google Scholar 

  14. González, A.; Ravassa, S.; Beaumont, J.; López, B.; Díez, J. New targets to treat the structural remodeling of the myocardium. J. Am. Coll. Cardiol.2011, 58, 1833–1843.

    Google Scholar 

  15. Polster, B. M.; Basañez, G.; Etxebarria, A.; Hardwick, J. M.; Nicholls, D. G. Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J. Biol. Chem.2005, 280, 6447–6454.

    CAS  Google Scholar 

  16. Jain, S.; Mittal, A.; Jain, A. K.; Mahajan, R. R.; Singh, D. Cyclosporin a loaded PLGA nanoparticle: Preparation, optimization, in-vitro characterization and stability studies. Curr. Nanosci.2010, 6, 422–431.

    CAS  Google Scholar 

  17. Watanabe, S.; Mochizuki, A.; Wagatsuma, K.; Kobayashi, M.; Kawa, Y.; Takahashi, H. Hair growth on nude mice due to cyclosporin A. J. Dermatol.1991, 18, 714–719.

    CAS  Google Scholar 

  18. Onoue, S.; Sato, H.; Kawabata, Y.; Mizumoto, T.; Hashimoto, N.; Yamada, S. In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy. J. Control. Release2009, 138, 16–23.

    CAS  Google Scholar 

  19. Al-Meshal, M. A.; Khidr, S. H.; Bayomi, M. A.; Al-Angary, A. A. Oral administration of liposomes containing cyclosporine: A pharmacokinetic study. Int. J. Pharm.1998, 168, 163–168.

    CAS  Google Scholar 

  20. Müller, R. H.; Runge, S. A.; Ravelli, V.; Thünemann, A. F.; Mehnert, W.; Souto, E. B. Cyclosporine-loaded solid lipid nanoparticles (SLN®): Drug-lipid physicochemical interactions and characterization of drug incorporation. Eur. J. Pharm. Biopharm.2008, 68, 535–544.

    Google Scholar 

  21. Italia, J. L.; Bhatt, D. K.; Bhardwaj, V.; Tikoo, K.; Ravi Kumar M. N. V. PLGA nanoparticles for oral delivery of cyclosporine: Nephrotoxicity and pharmacokinetic studies in comparison to Sandimmune Neoral®. J. Control. Release2007, 119, 197–206.

    CAS  Google Scholar 

  22. Wu, J.; Zhao, L. L.; Xu, X. D.; Bertrand, N. C.; Choi, W. I.; Yameen, B. S.; Shi, J. J.; Shah, V.; Mulvale, M.; MacLean, J. L. et al. Hydrophobic cysteine poly(disulfide)-based redox-hypersensitive nanoparticle platform for cancer theranostics. Angew. Chem., Int. Ed.2015, 54, 9218–9223.

    CAS  Google Scholar 

  23. Zheng, Y. H.; You, X. R.; Guan, S. Y.; Huang, J.; Wang, L. Y.; Zhang, J. A.; Wu, J. Poly(Ferulic Acid) with an anticancer effect as a drug nanocarrier for enhanced colon cancer therapy. Adv. Funct. Mater.2019, 29, 1808646

    Google Scholar 

  24. Choi, W. I.; Lee, J. H.; Kim, J. Y.; Kim, J. C.; Kim, Y. H.; Tae, G. Efficient skin permeation of soluble proteins via flexible and functional nano-carrier. J. Control. Release2012, 157, 272–278.

    CAS  Google Scholar 

  25. Sapra, B.; Jain, S.; Tiwary, A. K. Effect of Asparagus racemosus extract on transdermal delivery of carvedilol: A mechanistic study. AAPS PharmSciTech.2009, 10, 199–210.

    CAS  Google Scholar 

  26. Smith, J.; Wood, E.; Dornish, M. Effect of chitosan an epithelial cell tight junctions. Pharm. Res.2004, 21, 43–49.

    CAS  Google Scholar 

  27. He, W.; Guo, X. X.; Zhang, M. Transdermal permeation enhancement of N-trimethyl chitosan for testosterone. Int. J. Pharm.2008, 356, 82–87.

    CAS  Google Scholar 

  28. Biruss, B.; Valenta, C. Skin permeation of different steroid hormones from polymeric coated liposomal formulation. Eur. J. Pharm. Biopharm.2006, 62, 210–219.

    CAS  Google Scholar 

  29. Mohammed, M. A.; Syeda, J. T. M.; Wasan, K. M.; Wasan, E. K. An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics2017, 9, 53.

    Google Scholar 

  30. Tu, Y.; Wang, X.; Lu, Y.; Zhang, H.; Yu, Y.; Chen, Y.; Liu, J.; Sun, Z.; Cui, L.; Gao, J. et al. Promotion of the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles combined with polypropylene electret. Int. J. Nanomedicine2016, 11, 5549–5561.

    CAS  Google Scholar 

  31. He, W.; Guo, X. X.; Xiao, L. H.; Feng, M. Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers. Int. J. Pharm.2009, 382, 234–243.

    CAS  Google Scholar 

  32. Alishahi, A.; Mirvaghefi, A.; Tehrani, M. R.; Farahmand, H.; Koshio, S.; Dorkoosh, F. A.; Elsabee, M. Z. Chitosan nanoparticle to carry vitamin C through the gastrointestinal tract and induce the non-specific immunity system of rainbow trout (Oncorhynchus mykiss). Carbohydr. Polym.2011, 86, 142–146.

    CAS  Google Scholar 

  33. Hembram, K. C.; Prabha, S.; Chandra, R.; Ahmed, B.; Nimesh, S. Advances in preparation and characterization of chitosan nanoparticles for therapeutics. Artif. Cells Nanomed. Biotechnol.2016, 44, 305–314.

    Google Scholar 

  34. Zhuo, Y.; Han, J.; Tang, L.; Liao, N.; Gui, G. F.; Chai, Y. Q.; Yuan, R. Quenching of the emission of peroxydisulfate system by ferrocene functionalized chitosan nanoparticles: A sensitive “signal off” electro-chemiluminescence immunosensor. Sens. Actuators, B: Chem.2014, 192, 791–795.

    CAS  Google Scholar 

  35. Chen, Y.; Mohanraj, V. J.; Wang, F.; Benson, H. A. E. Designing chitosandextran sulfate nanoparticles using charge ratios. AAPS PharmSciTech2007, 8, 131–139.

    CAS  Google Scholar 

  36. Tiyaboonchai, W. Chitosan nanoparticles: A promising system for drug delivery. Naresuan Univ. J.2003, 11, 51–66.

    Google Scholar 

  37. Niwa, T.; Takeuchi, H.; Hino, T.; Kunou, N.; Kawashima, Y. Preparations of biodegradable nanospheres of water-soluble and insoluble drugs with D, L-lactide/glycolide copolymer by a novel spontaneous emulsification solvent diffusion method, and the drug release behavior. J. Control. Release1993, 25, 89–98.

    CAS  Google Scholar 

  38. Vila, A.; Sánchez, A.; Tobío, M.; Calvo, P.; Alonso, M. J. Design of biodegradable particles for protein delivery. J. Control. Release2002, 78, 15–24.

    CAS  Google Scholar 

  39. Choi, W. I.; Kamaly, N.; Riol-Blanco, L.; Lee, I. H.; Wu, J.; Swami, A.; Vilos, C.; Yameen, B.; Yu, M.; Shi, J. J. et al. A solvent-free thermosponge nanoparticle platform for efficient delivery of labile proteins. Nano Lett.2014, 14, 6449–6455.

    CAS  Google Scholar 

  40. Cheon, J. W.; Shim, C. K.; Chung, S. J.; Kim, D. D. Effect of tripolyphosphate (TPP) on the controlled release of cyclosporin a from chitosan-coated lipid microparticles. J. Korean Pharm. Invest.2009, 39, 59–63.

    CAS  Google Scholar 

  41. Kapoor, Y.; Dixon, P.; Sekar, P.; Chauhan, A. Incorporation of drug particles for extended release of Cyclosporine A from poly-hydroxyethyl methacrylate hydrogels. Eur. J. Pharm. Biopharm.2017, 120, 73–79.

    CAS  Google Scholar 

  42. MacCuspie, R. I. Colloidal stability of silver nanoparticles in biologically relevant conditions. J. Nanopart. Res.2011, 13, 2893–2908.

    CAS  Google Scholar 

  43. Huang, M.; Khor, E.; Lim, L. Y. Uptake and cytotoxicity of chitosan molecules and nanoparticles: Effects of molecular weight and degree of deacetylation. Pharm. Res.2004, 21, 344–353.

    CAS  Google Scholar 

  44. Wikramanayake, T. C.; Amini, S.; Simon, J.; Mauro, L. M.; Elgart, G.; Schachner, L. A.; Jimenez, J. J. A novel rat model for chemotherapy-induced alopecia. Clin. Exp. Dermatol.2012, 37, 284–289.

    CAS  Google Scholar 

  45. Lin, W. H.; Xiang, L. J.; Shi, H. X.; Zhang, J.; Jiang, L. P.; Cai, P. T.; Lin, Z. L.; Lin, B. B.; Huang, Y.; Zhang, H. L. et al. Fibroblast growth factors stimulate hair growth through β-catenin and Shh expression in C57BL/6 mice. BioMed Res. Int.2015, 2015, 730139.

    Google Scholar 

  46. Tong, T.; Kim, N.; Park, T. Topical application of oleuropein induces anagen hair growth in telogen mouse skin. PLoS One2015, 10, e0129578.

    Google Scholar 

  47. del Pozo-Rodríguez, A.; Solinís, M. A.; Gascón, A. R.; Pedraz, J. L. Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur. J. Pharm. Biopharm.2009, 71, 181–189.

    Google Scholar 

  48. Norouzi, M.; Boroujeni, S. M.; Omidvarkordshouli, N.; Soleimani, M. Advances in skin regeneration: Application of electrospun scaffolds. Adv. Healthc. Mater.2015, 4, 1114–1133.

    CAS  Google Scholar 

  49. Hasanovic, A.; Zehl, M.; Reznicek, G.; Valenta, C. Chitosan-tripolyphosphate nanoparticles as a possible skin drug delivery system for aciclovir with enhanced stability. J. Pharm. Pharmacol.2009, 61, 1609–1616.

    CAS  Google Scholar 

  50. Nair, S. S. Chitosan-based transdermal drug delivery systems to overcome skin barrier functions. J. Drug Deliv. Ther.2019, 9, 266–270.

    CAS  Google Scholar 

  51. Sezer, A. D.; Cevher, E. Topical drug delivery using chitosan nano- and microparticles. Expert Opin. Drug Deliv.2012, 9, 1129–1146.

    CAS  Google Scholar 

  52. Roy, M. K.; Takenaka, M.; Kobori, M.; Nakahara, K.; Isobe, S.; Tsushida, T. Apoptosis, necrosis and cell proliferation -inhibition by cyclosporine A in U937 cells (a human monocytic cell line). Pharmacol. Res.2006, 53, 293–302.

    CAS  Google Scholar 

  53. Wongmekiat, O.; Gomonchareonsiri, S.; Thamprasert, K. Caffeic acid phenethyl ester protects against oxidative stress-related renal dysfunction in rats treated with cyclosporin A. Fundam. Clin. Pharmacol.2011, 25, 619–626.

    CAS  Google Scholar 

  54. Yang, G. A.; Chen, Q. A.; Wen, D.; Chen, Z. W.; Wang, J. Q.; Chen, G. J.; Wang, Z. J.; Zhang, X. D.; Zhang, Y. Q.; Hu, Q. Y. et al. A therapeutic microneedle patch made from hair-derived keratin for promoting hair regrowth. ACS Nano2019, 13, 4354–4360.

    CAS  Google Scholar 

  55. Begum, S.; Gu, L. J.; Lee, M. R.; Li, Z.; Li, J. J.; Hossain, M. J.; Wang, Y. B.; Sung, C. K. In vivo hair growth-stimulating effect of medicinal plant extract on BALB/c nude mice. Pharm. Biol.2015, 53, 1098–1103.

    Google Scholar 

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Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (Nos. NRF-2018R1D1A1B07043620 and 2018R1A4A1024963) and the grant of Korea Institute of Ceramic Engineering and Technology (KICET).

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  1. Jin Sil Lee and Youngmin Hwang contributed equally to this work.

Authors and Affiliations

  1. Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea

    Jin Sil Lee, Hyeryeon Oh, Sunghyun Kim & Won Il Choi

  2. School of Materials Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju, 61005, Republic of Korea

    Jin Sil Lee, Youngmin Hwang, Hyeryeon Oh & Giyoong Tae

  3. SKINMED Co., Ltd., Daejeon, 34028, Republic of Korea

    Jin-Hwa Kim, Jeung-Hoon Lee & Yong Chul Shin

  4. Amicogen, Inc., 64 Dongburo 1259, Jinsung, Jinju, 52621, Republic of Korea

    Yong Chul Shin

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  1. Jin Sil Lee
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Correspondence to Giyoong Tae or Won Il Choi.

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Lee, J.S., Hwang, Y., Oh, H. et al. A novel chitosan nanocapsule for enhanced skin penetration of cyclosporin A and effective hair growth in vivo. Nano Res. 12, 3024–3030 (2019). https://doi.org/10.1007/s12274-019-2546-x

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