Skip to main content
SpringerLink
Log in

A multifunctional cholesterol-free liposomal platform based on protopanaxadiol for alopecia therapy

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

Liposome could form a long-term drug reservoir in the skin for sustained drug release, which is beneficial to improving efficacy and alleviating adverse effects. Thus, it has become a better option for anti-alopecia drugs delivery. However, cholesterol used as the fluidity buffer in conventional liposomes is a precursor for testosterone biosynthesis, which could convert to dihydrotestosterone, resulting in hair follicle damage and potentiating hair loss. To overcome the limitations, in this study we prepared a cholesterol-free liposome (PPD-Lip) using protopanaxadiol (PPD) instead of cholesterol to avoid the biosynthesis of testosterone which is adverse to alopecia therapy. PPD-Lip also worked as an active ingredient to facilitate hair growth by promoting dermal papilla cells proliferation and migration, upregulating mRNA levels of hair growth-related positive regulators, and accelerating angiogenesis in vitro. Meanwhile, it promoted hair regrowth in telogen and androgenetic alopecia mice models in vivo. In addition, our study showed that as the liposomal vehicle, PPD-Lip loaded with dutasteride exerted a stronger efficacy in the treatment of androgenetic alopecia and such a strategy could extend to other anti-alopecia agents. To the best of our knowledge, being easy for clinical transformation, the PPD-based liposomal delivery system provides a promising and multifunctional alternative platform for the delivery of alopecia treatment agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Zito, P. M.; Raggio, B. S. Hair Transplantation; StatPearls Publishing: Treasure Island, 2022.

    Google Scholar 

  2. Jamerson, T. A.; Aguh, C. An approach to patients with alopecia. Med. Clin. North Am. 2021, 105, 599–610.

    Article  Google Scholar 

  3. Asghar, F.; Shamim, N.; Farooque, U.; Sheikh, H.; Aqeel, R. Telogen effluvium: A review of the literature. Cureus 2020, 12, e8320.

    Google Scholar 

  4. Gupta, A. K.; Talukder, M.; Venkataraman, M.; Bamimore, M. A. Minoxidil: A comprehensive review. J. Dermatolog. Treat., in press, https://doi.org/10.1080/09546634.2021.1945527.

  5. Randolph, M.; Tosti, A. Oral minoxidil treatment for hair loss: A review of efficacy and safety. J. Am. Acad. Dermatol. 2021, 84, 737–746.

    Article  CAS  Google Scholar 

  6. Beach, R. A.; McDonald, K. A.; Barrett, B. M.; Abdel-Qadir, H. Side effects of low-dose oral minoxidil for treating alopecia. J. Am. Acad. Dermatol. 2021, 84, e239–e240.

    Article  CAS  Google Scholar 

  7. Ashique, S.; Sandhu, N. K.; Haque, S. N.; Koley, K. A systemic review on topical marketed formulations, natural products, and oral supplements to prevent androgenic alopecia: A review. Nat. Prod. Bioprospect. 2020, 10, 345–365.

    Article  Google Scholar 

  8. Yang, G.; Chen, Q.; 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 Nano 2019, 13, 4354–4360.

    Article  CAS  Google Scholar 

  9. Martinez-Lopez, A.; Montero-Vilchez, T.; Sierra-Sánchez, Á.; Molina-Leyva, A.; Arias-Santiago, S. Advanced medical therapies in the management of non-scarring alopecia: Areata and androgenic alopecia. Int. J. Mol. Sci. 2020, 21, 8390.

    Article  CAS  Google Scholar 

  10. Salim, S.; Kamalasanan, K. Controlled drug delivery for alopecia: A review. J. Control. Release. 2020, 325, 84–99.

    Article  CAS  Google Scholar 

  11. Zhou, S.; Li, J. B.; Yu, J.; Yang, L. Y.; Kuang, X.; Wang, Z. J.; Wang, Y. L.; Liu, H. Z.; Lin, G. M.; He, Z. G. et al. A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect. Acta Pharm. Sin. B 2021, 11, 258–270.

    Article  CAS  Google Scholar 

  12. Roberts, M. S.; Cheruvu, H. S.; Mangion, S. E.; Alinaghi, A.; Benson, H. A. E.; Mohammed, Y.; Holmes, A.; van der Hoek, J.; Pastore, M.; Grice, J. E. Topical drug delivery: History, percutaneous absorption, and product development. Adv. Drug Deliv. Rev. 2021, 177, 113929.

    Article  CAS  Google Scholar 

  13. Oliveira, P. M.; Alencar-Silva, T.; Pires, F. Q.; Cunha-Filho, M.; Gratieri, T.; Carvalho, J. L.; Gelfuso, G. M. Nanostructured lipid carriers loaded with an association of minoxidil and latanoprost for targeted topical therapy of alopecia. Eur. J. Pharm. Biopharm. 2022, 172, 78–88.

    Article  CAS  Google Scholar 

  14. Xia, J. X.; Ma, S. J.; Zhu, X.; Chen, C.; Zhang, R.; Cao, Z. L.; Chen, X.; Zhang, L. L.; Zhu, Y.; Zhang, S. Y. et al. Versatile ginsenoside Rg3 liposomes inhibit tumor metastasis by capturing circulating tumor cells and destroying metastatic niches. Sci. Adv. 2022, 8, eabj1262.

    Article  CAS  Google Scholar 

  15. Kong, J.; Qiang, W. D.; Jiang, J. Y.; Hu, X. L.; Chen, Y. N.; Guo, Y. X.; Liu, H. X.; Sun, S. M.; Gao, H. T.; Zhang, Y. et al. Safflower oil body nanoparticles deliver hFGF10 to hair follicles and reduce microinflammation to accelerate hair regeneration in androgenetic alopecia. Int. J. Pharm. 2022, 616, 121537.

    Article  CAS  Google Scholar 

  16. Cao, S. S.; Wang, Y. X.; Wang, M.; Yang, X. Y.; Tang, Y. J.; Pang, M. L.; Wang, W. X.; Chen, L. L.; Wu, C. B.; Xu, Y. H. Microneedles mediated bioinspired lipid nanocarriers for targeted treatment of alopecia. J. Control. Release. 2021, 329, 1–15.

    Article  CAS  Google Scholar 

  17. Palmer, M. A.; Smart, E.; Haslam, I. S. Localisation and regulation of cholesterol transporters in the human hair follicle: Mapping changes across the hair cycle. Histochem. Cell. Biol. 2021, 155, 529–545.

    Article  CAS  Google Scholar 

  18. Palmer, M. A.; Blakeborough, L.; Harries, M.; Haslam, I. S. Cholesterol homeostasis: Links to hair follicle biology and hair disorders. Exp. Dermatol. 2020, 29, 299–311.

    Article  Google Scholar 

  19. Sadgrove, N. J. The “bald” phenotype (androgenetic alopecia) is caused by the high glycaemic, high cholesterol and low mineral “western diet”. Trends Food Sci. Technol. 2021, 116, 1170–1178.

    Article  CAS  Google Scholar 

  20. Hong, C.; Liang, J. M.; Xia, J. X.; Zhu, Y.; Guo, Y. Z.; Wang, A. N.; Lu, C. Y.; Ren, H. W.; Chen, C.; Li, S. Y. et al. One stone four birds: A novel liposomal delivery system multi-functionalized with ginsenoside Rh2 for tumor targeting therapy. Nanomicro Lett. 2020, 12, 129.

    CAS  Google Scholar 

  21. Sun, D.; Guo, S. Y.; Yang, L.; Wang, Y. R.; Wei, X. H.; Song, S.; Yang, Y. W.; Gan, Y.; Wang, Z. T. Silicone elastomer gel impregnated with 20(S)-protopanaxadiol-loaded nanostructured lipid carriers for ordered diabetic ulcer recovery. Acta Pharmacol. Sin. 2020, 41, 119–128.

    Article  CAS  Google Scholar 

  22. Park, J. Y.; You, H.; Lee, D.; Huh, W.; Hwang, G. S.; No, K. T.; Kim, K. H.; Ham, J.; Yamabe, N.; Kim, Y. et al. Comparison of the wound-healing effects of ginsenosides, their metabolites, and aglycones. Bull. Korean Chem. Soc. 2016, 37, 52–55.

    Article  CAS  Google Scholar 

  23. Zhang, E. Y.; Gao, B.; Shi, H. L.; Huang, L. F.; Yang, L.; Wu, X. J.; Wang, Z. T. 20(S)-protopanaxadiol enhances angiogenesis via HIF-1α-mediated VEGF secretion by activating p70S6 kinase and benefits wound healing in genetically diabetic mice. Exp. Mol. Med. 2017, 49, e387.

    Article  CAS  Google Scholar 

  24. Deng, Z. L.; Chen, M. T.; Liu, F. F.; Wang, Y. Y.; Xu, S.; Sha, K.; Peng, Q. Q.; Wu, Z.; Xiao, W. Q.; Liu, T. X. L. et al. Androgen receptor-mediated paracrine signaling induces regression of blood vessels in the dermal papilla in androgenetic alopecia. J. Invest. Dermatol., in press, https://doi.org/10.1016/j.jid.2022.01.003.

  25. Fu, D. L.; Huang, J. F.; Li, K. T.; Chen, Y. X.; He, Y.; Sun, Y.; Guo, Y. L.; Du, L. J.; Qu, Q.; Miao, Y. et al. Dihydrotestosterone-induced hair regrowth inhibition by activating androgen receptor in C57Bl6 mice simulates androgenetic alopecia. Biomed. Pharmacother. 2021, 137, 111247.

    Article  CAS  Google Scholar 

  26. Chen, C. L.; Huang, W. Y.; Wang, E. H. C.; Tai, K. Y.; Lin, S. J. Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration. J. Biomed. Sci. 2020, 27, 43.

    Article  Google Scholar 

  27. Uitto, J. Genetic susceptibility to alopecia. N. Engl. J. Med. 2019, 380, 873–876.

    Article  Google Scholar 

  28. Ohn, J.; Kim, K. H.; Kwon, O. Evaluating hair growth promoting effects of candidate substance: A review of research methods. J. Dermatol. Sci. 2019, 93, 144–149.

    Article  CAS  Google Scholar 

  29. Madaan, A.; Verma, R.; Singh, A. T.; Jaggi, M. Review of hair follicle dermal papilla cells as in vitro screening model for hair growth. Int. J. Cosmet. Sci. 2018, 40, 429–450.

    Article  CAS  Google Scholar 

  30. Nilforoushzadeh, M. A.; Aghdami, N.; Taghiabadi, E. Effects of adipose-derived stem cells and platelet-rich plasma exosomes on the inductivity of hair dermal papilla cells. Cell J. 2021, 23, 576–583.

    Google Scholar 

  31. Ji, S. F.; Zhu, Z. Y.; Sun, X. Y.; Fu, X. B. Functional hair follicle regeneration: An updated review. Signal Transduct. Target. Ther. 2021, 6, 66.

    Article  Google Scholar 

  32. Vasserot, A. P.; Geyfman, M.; Poloso, N. J. Androgenetic alopecia: Combing the hair follicle signaling pathways for new therapeutic targets and more effective treatment options. Expert Opin. Ther. Targets 2019, 23, 755–771.

    Article  CAS  Google Scholar 

  33. Yuan, A. R.; Xia, F.; Bian, Q.; Wu, H. B.; Gu, Y. T.; Wang, T.; Wang, R. X.; Huang, L. L.; Huang, Q. L.; Rao, Y. F. et al. Ceria nanozyme-integrated microneedles reshape the perifollicular microenvironment for androgenetic alopecia treatment. ACS Nano 2021, 15, 13759–13769.

    Article  CAS  Google Scholar 

  34. Wisuitiprot, V.; Ingkaninan, K.; Chakkavittumrong, P.; Wisuitiprot, W.; Neungchamnong, N.; Chantakul, R.; Waranuch, N. Effects of Acanthus ebracteatus Vahl. Extract and verbascoside on human dermal papilla and murine macrophage. Sci. Rep. 2022, 12, 1491.

    Article  CAS  Google Scholar 

  35. Müller-Röver, S.; Foitzik, K.; Paus, M. R.; Handjiski, B.; van der Veen, C.; Eichmüller, S.; McKay, I. A.; Stenn, K. S. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest. Dermatol. 2001, 117, 3–15.

    Article  Google Scholar 

  36. Abreu, C. M.; Marques, A. P. Recreation of a hair follicle regenerative microenvironment: Successes and pitfalls. Bioeng. Transl. Med. 2022, 7, e10235.

    Article  Google Scholar 

  37. Taghiabadi, E.; Nilforoushzadeh, M. A.; Aghdami, N. Maintaining hair inductivity in human dermal papilla cells: A review of effective methods. Skin Pharmacol. Physiol. 2020, 33, 280–292.

    Article  CAS  Google Scholar 

  38. Pindado-Ortega, C.; Saceda-Corralo, D.; Moreno-Arrones, Ó. M.; Rodrigues-Barata, A. R.; Hermosa-Gelbard, Á.; Jaén-Olasolo, P.; Vañó-Galván, S. Effectiveness of dutasteride in a large series of patients with frontal fibrosing alopecia in real clinical practice. J. Am. Acad. Dermatol. 2021, 84, 1285–1294.

    Article  CAS  Google Scholar 

  39. Ben-Eltriki, M.; Deb, S.; Hassona, M.; Meckling, G.; Fazli, L.; Chin, M. Y.; Lallous, N.; Yamazaki, T.; Jia, W.; Rennie, P. S. et al. 20(S)-protopanaxadiol regio-selectively targets androgen receptor: Anticancer effects in castration-resistant prostate tumors. Oncotarget 2018, 9, 20965–20978.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 81973264, 82104080, and 81773659), Guangdong Basic and Applied Basic Research Foundation (Nos. 2020A1515010593, 2019A1515011954, and 2021A1515012621), and Guangdong Provincial Key Laboratory of Construction Foundation (No. 2019B030301005).

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Xuefei Zhang, Shuxuan Li, Yating Dong, Hehui Rong, Junke Zhao & Haiyan Hu

  2. School of Traditional Dai-Thai Medicine, West Yunnan University of Applied Sciences, Jinghong, 666100, China

    Xuefei Zhang

  3. Guangdong Provincial Key Laboratory of Chiral Molecules and Drug Discovery, Sun Yat-sen University, Guangzhou, 510006, China

    Haiyan Hu

Authors
  1. Xuefei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuxuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yating Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hehui Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junke Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haiyan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haiyan Hu.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Li, S., Dong, Y. et al. A multifunctional cholesterol-free liposomal platform based on protopanaxadiol for alopecia therapy. Nano Res. 15, 9498–9510 (2022). https://doi.org/10.1007/s12274-022-4710-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-022-4710-y

Keywords

Search

Navigation