Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lipid-based nanoparticles in the treatment of erectile dysfunction

Subjects

Abstract

Erectile dysfunction (ED) is a common disorder among men, with significant public health implications. Current therapies have certain limitations including efficacy and safety issues, necessitating the development of novel therapeutic strategies for ED. Nanotechnology-based drug delivery systems are being explored to overcome these limitations with promising in vitro and in vivo efficacies. In particular, lipid-based nanoparticles have generated considerable interest owing to their potential to enhance drug bioavailability, and decrease side effects and drug susceptibility to metabolism. This review summarizes the recent findings using lipid-based nanoparticles in ED therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. McCabe MP, Sharlip ID, Atalla E, Balon R, Fisher AD, Laumann E, et al. Definitions of sexual dysfunctions in women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. J Sex Med. 2016;13:135–43.

    Google Scholar 

  2. Gratzke C, Angulo J, Chitaley K, Dai YT, Kim NN, Paick JS, et al. Anatomy, physiology, and pathophysiology of erectile dysfunction. J Sex Med. 2010;7:445–75.

    CAS  Google Scholar 

  3. Sanchez-Cruz JJ, Cabrera-Leon A, Martin-Morales A, Fernandez A, Burgos R, Rejas J. Male erectile dysfunction and health-related quality of life. Eur Urol. 2003;44:245–53.

    CAS  Google Scholar 

  4. Aytac IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999;84:50–6.

    Google Scholar 

  5. Hatzimouratidis K, Giuliano F, Moncada I, Muneer A, Salonia A, Verze P, et al. EAU guidelines on male sexual dysfunction. 2018. https://uroweb.org/guideline/male-sexual-dysfunction/.

  6. Montorsi F, McCullough A. Efficacy of sildenafil citrate in men with erectile dysfunction following radical prostatectomy: a systematic review of clinical data. J Sex Med. 2005;2:658–67.

    CAS  Google Scholar 

  7. Carvalheira AA, Pereira NM, Maroco J, Forjaz V. Dropout in the treatment of erectile dysfunction with PDE5: a study on predictors and a qualitative analysis of reasons for discontinuation. J Sex Med. 2012;9:2361–9.

    Google Scholar 

  8. Lea AP, Bryson HM, Balfour JA. Intracavernous alprostadil. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in erectile dysfunction. Drugs Aging. 1996;8:56–74.

    CAS  Google Scholar 

  9. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med. 1996;334:873–7.

    CAS  Google Scholar 

  10. Coombs PG, Heck M, Guhring P, Narus J, Mulhall JP. A review of outcomes of an intracavernosal injection therapy programme. BJU Int. 2012;110:1787–91.

    CAS  Google Scholar 

  11. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol. 1996;155:802–15.

    CAS  Google Scholar 

  12. Leungwattanakij S, Flynn V, Hellstrom WJG. Intracavernosal injection and intraurethral therapy for erectile dysfunction. Urol Clin N. Am. 2001;28:343–54.

    CAS  Google Scholar 

  13. Padma-Nathan H, Hellstrom WJ, Kaiser FE, Labasky RF, Lue TF, Nolten WE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med. 1997;336:1–7.

    CAS  Google Scholar 

  14. Shabsigh R, Padma-Nathan H, Gittleman M, McMurray J, Kaufman J, Goldstein I. Intracavernous alprostadil alfadex is more efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: a comparative, randomized, crossover, multicenter study. Urology. 2000;55:109–13.

    CAS  Google Scholar 

  15. Engel JD, McVary KT. Transurethral alprostadil as therapy for patients who withdrew from or failed prior intracavernous injection therapy. Urology. 1998;51:687–92.

    CAS  Google Scholar 

  16. Hellstrom WJG, Bennett AH, Gesundheit N, Kaiser FE, Lue TF, PadmaNathan H, et al. A double-blind, placebo-controlled evaluation of the erectile response to transurethral alprostadil. Urology. 1996;48:851–6.

    CAS  Google Scholar 

  17. Antonini G, Busetto GM, De Berardinis E, Giovannone R, Vicini P, Del Giudice F, et al. Minimally invasive infrapubic inflatable penile prosthesis implant for erectile dysfunction: evaluation of efficacy, satisfaction profile and complications. Int J Impot Res. 2016;28:4–8.

    CAS  Google Scholar 

  18. Montague DK, Angermeier KW, Lakin MM. Penile prosthesis infections. Int J Impot Res. 2001;13:326–8.

    CAS  Google Scholar 

  19. Holloway FB, Farah RN. Intermediate term assessment of the reliability, function and patient satisfaction with the AMS700 Ultrex penile prosthesis. J Urol. 1997;157:1687–91.

    CAS  Google Scholar 

  20. Carson CC. Diagnosis, treatment and prevention of penile prosthesis infection. Int J Impot Res. 2003;15(Suppl 5):S139–46.

    Google Scholar 

  21. Han G, Tar M, Kuppam DSR, Friedman A, Melman A, Friedman J, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. J Sex Med. 2010;7:224–33.

    CAS  Google Scholar 

  22. Pryor JL, Redmon B. New therapies and delivery mechanisms for treatment of erectile dysfunction. Int J Impot Res. 2000;12:S158–S62.

    Google Scholar 

  23. Ahmed TA. Preparation of transfersomes encapsulating sildenafil aimed for transdermal drug delivery: Plackett-Burman design and characterization. J Liposome Res. 2015;25:1–10.

    CAS  Google Scholar 

  24. Gommersall L, Shergill IS, Ahmed HU, Hayne D, Arya M, Patel HR, et al. Nanotechnology and its relevance to the urologist. Eur Urol. 2007;52:368–75.

    CAS  Google Scholar 

  25. Caruthers SD, Wickline SA, Lanza GM. Nanotechnological applications in medicine. Curr Opin Biotechnol. 2007;18:26–30.

    CAS  Google Scholar 

  26. Thorley AJ, Tetley TD. New perspectives in nanomedicine. Pharm Ther. 2013;140:176–85.

    CAS  Google Scholar 

  27. Yu X, Trase I, Ren M, Duval K, Guo X, Chen Z. Design of nanoparticle-based carriers for targeted drug delivery. J Nanomater. 2016;1–15.

  28. Puri A, Loomis K, Smith B, Lee JH, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev Ther Drug. 2009;26:523–80.

    CAS  Google Scholar 

  29. Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H. Nanoparticles as drug delivery systems. Pharm Rep. 2012;64:1020–37.

    CAS  Google Scholar 

  30. Tawfik MA, Tadros MI, Mohamed MI. Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride. Pharm Dev Technol. 2018:1–10.

  31. Berko S, Zsiko S, Deak G, Gacsi A, Kovacs A, Budai-Szucs M, et al. Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction. Drug Des Dev Ther. 2018;12:2923–31.

    CAS  Google Scholar 

  32. Draganski A, Tar MT, Villegas G, Friedman JM, Davies KP. Topically applied curcumin-loaded nanoparticles treat erectile dysfunction in a rat model of Type-2 diabetes. J Sex Med. 2018;15:645–53.

    Google Scholar 

  33. Elnaggar YSR, El-Massik MA, Abdallah OY. Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles. Int J Nanomed. 2011;6:3195–205.

    CAS  Google Scholar 

  34. Fahmy UA, Ahmed OAA, Hosny KM. Development and evaluation of Avanafil self-nanoemulsifying drug delivery system with rapid onset of action and enhanced bioavailability. Aaps PharmSciTech. 2015;16:53–8.

    CAS  Google Scholar 

  35. Tar MT, Draganski A, Friedman J, Davies KP. Topical application of Sildenafil-nanoparticles (proximal and distal) improve erectile function in an aging-rat model of erectile dysfunction. J Sex Med. 2018;15:S138–S9.

    Google Scholar 

  36. Soliman KA, Ibrahim HK, Ghorab MM. Effects of different combinations of nanocrystallization technologies on avanafil nanoparticles: in vitro, in vivo and stability evaluation. Int J Pharm. 2017;517:148–56.

    CAS  Google Scholar 

  37. Parikh KJ, Sawant KK. Solubilization of vardenafil HCl in lipid-based formulations enhances its oral bioavailability in vivo: a comparative study using Tween-20 and Cremophor—EL. J Mol Liq. 2019;277:189–99.

    CAS  Google Scholar 

  38. Hosny KM, Aljaeid BM. Sildenafil citrate as oral solid lipid nanoparticles: a novel formula with higher bioavailability and sustained action for treatment of erectile dysfunction. Exp Opin Drug Del. 2014;11:1015–22.

    CAS  Google Scholar 

  39. Fahmy UA, Aljaeid BM. Tadalafil transdermal delivery with alpha-lipoic acid self nanoemulsion for treatment of erectile dysfunction by diabetes mellitus. Int J Pharmacol 2018;14:945–51.

    CAS  Google Scholar 

  40. Badr-Eldin SM, Ahmed OAA. Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation. Drug Des Dev Ther. 2016;10:1323–33.

    CAS  Google Scholar 

  41. Baek JS, Pham CV, Myung CS, Cho CW. Tadalafil-loaded nanostructured lipid carriers using permeation enhancers. Int J Pharm. 2015;495:701–9.

    CAS  Google Scholar 

  42. Chuang SY, Lin CH, Huang TH, Fang JY. Lipid-based nanoparticles as a potential delivery approach in the treatment of rheumatoid arthritis. Nanomaterials. 2018;8:E42. pii.

    Google Scholar 

  43. Shrestha H, Bala R, Arora S. Lipid-based drug delivery systems. J Pharm. 2014;2014:801820.

    Google Scholar 

  44. Pradhan M, Srivastava S, Singh D, Saraf S, Saraf S, Singh MR. Perspectives of lipid-based drug carrier systems for transdermal delivery. Crit Rev Ther Drug. 2018;35:331–67.

    Google Scholar 

  45. Elbardisy B, Galal S, Abdelmonsif DA, Boraie N. Intranasal Tadalafil nanoemulsions: formulation, characterization and pharmacodynamic evaluation. Pharm Dev Technol. 2019;24:1083–94.

    CAS  Google Scholar 

  46. Elnaggar YSR, El-Massik MA, Abdallah OY. Sildenafil citrate nanoemulsion vs. self-nanoemulsifying delivery systems: rational development and transdermal permeation. Int J Nanotechnol. 2011;8:749–63.

    CAS  Google Scholar 

  47. Cheng Y, Liu M, Hu H, Liu D, Zhou S. Development, optimization, and characterization of PEGylated nanoemulsion of Prostaglandin E1 for long circulation. Aaps PharmSciTech 2016;17:409–17.

    CAS  Google Scholar 

  48. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. 2013;8:102.

    Google Scholar 

  49. Gupta V, Barupal AK, Ramteke S. Formulation development and in vitro characterization of proliposomes for topical delivery of aceclofenac. Indian J Pharm Sci. 2008;70:768–75.

    Google Scholar 

  50. Zhou XL, Hao Y, Yuan LP, Pradhan S, Shrestha K, Pradhan O, et al. Nano-formulations for transdermal drug delivery: a review. Chin Chem Lett. 2018;29:1713–24.

    CAS  Google Scholar 

  51. Hua S. Lipid-based nano-delivery systems for skin delivery of drugs and bioactives. Front Pharmacol. 2015;6:219.

    Google Scholar 

  52. Ascenso A, Raposo S, Batista C, Cardoso P, Mendes T, Praca FG, et al. Development, characterization, and skin delivery studies of related ultradeformable vesicles: transfersomes, ethosomes, and transethosomes. Int J Nanomed. 2015;10:5837–51.

    CAS  Google Scholar 

  53. Romero EL, Morilla MJ. Highly deformable and highly fluid vesicles as potential drug delivery systems: theoretical and practical considerations. Int J Nanomed. 2013;8:3171–86.

    Google Scholar 

  54. Cevc G. Transfersomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery. Crit Rev Ther Drug. 1996;13:257–388.

    CAS  Google Scholar 

  55. Malakar J, Sen SO, Nayak AK, Sen KK. Formulation, optimization and evaluation of transferosomal gel for transdermal insulin delivery. Saudi Pharm J. 2012;20:355–63.

    Google Scholar 

  56. Pilch E, Musial W. Liposomes with an ethanol fraction as an application for drug delivery. Int J Mol Sci. 2018;19:E3806. pii.

    Google Scholar 

  57. Akhtar N. Vesicles: a recently developed novel carrier for enhanced topical drug delivery. Curr Drug Deliv. 2014;11:87–97.

    CAS  Google Scholar 

  58. Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–77.

    CAS  Google Scholar 

  59. Thukral DK, Dumoga S, Mishra AK. Solid lipid nanoparticles: promising therapeutic nanocarriers for drug delivery. Curr Drug Deliv. 2014;11:771–91.

    CAS  Google Scholar 

  60. Czajkowska-Kosnik A, Szekalska M, Winnicka K. Nanostructured lipid carriers: a potential use for skin drug delivery systems. Pharm Rep. 2019;71:156–66.

    CAS  Google Scholar 

  61. Solans C, Izquierdo P, Nolla J, Azemar N, Garcia-Celma MJ. Nano-emulsions. Curr Opin Colloid, 2005;10:102–10.

    CAS  Google Scholar 

  62. Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech. 2015;5:123–7.

    Google Scholar 

  63. Tayeb HH, Sainsbury F. Nanoemulsions in drug delivery: formulation to medical application. Nanomedicine. 2018;13:2507–25.

    CAS  Google Scholar 

  64. Zhou HF, Yue Y, Liu GL, Li Y, Zhang J, Gong Q, et al. Preparation and characterization of a lecithin nanoemulsion as a topical delivery system. Nanoscale Res Lett. 2010;5:224–30.

    CAS  Google Scholar 

  65. Gupta A, Eral HB, Hatton TA, Doyle PS. Nanoemulsions: formation, properties and applications. Soft Matter. 2016;12:2826–41.

    CAS  Google Scholar 

  66. Date AA, Desai N, Dixit R, Nagarsenker M. Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine. 2010;5:1595–616.

    CAS  Google Scholar 

  67. Kadam RS, Bourne DWA, Kompella UB. Nano-advantage in enhanced drug delivery with biodegradable nanoparticles: contribution of reduced clearance. Drug Metab Dispos. 2012;40:1380–8.

    CAS  Google Scholar 

  68. Kermanizadeh A, Powell LG, Stone V, Moller P. Nanodelivery systems and stabilized solid-drug nanoparticles for orally administered medicine: current landscape. Int J Nanomed. 2018;13:7575–605.

    CAS  Google Scholar 

  69. Jung SY, Seo YG, Kim GK, Woo JS, Yong CS, Choi HG. Comparison of the Solubility and Pharmacokinetics of Sildenafil Salts. Arch Pharm Res. 2011;34:451–4.

    CAS  Google Scholar 

  70. Rao QH, Qiu ZW, Huang DE, Lu TJ, ZYJS Zhang, Luo DD, et al. Enhancement of the apparent solubility and bioavailability of tadalafil nanoparticles via antisolvent precipitation. Eur J Pharm Sci. 2019;128:222–31.

    CAS  Google Scholar 

  71. Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil-review of the literature. Eur J Med Res. 2002;7:435–46.

    CAS  Google Scholar 

  72. Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res. 1998;10:69–73. discussion 73-4.

    CAS  Google Scholar 

  73. Wang AY, Podlasek CA. Role of nanotechnology in erectile dysfunction treatment. J Sex Med. 2017;14:36–43.

    CAS  Google Scholar 

  74. Meda H, Rao GD, Chowdary VH, Tej MB. Formulation and evaluation of nanosuspensions of tadalafil using different stabilizers. Eur Chem Bull. 2018;7:218–22.

    CAS  Google Scholar 

  75. Tawfik MA, Tadros MI, Mohamed MI. Lipomers (lipid-polymer hybrid particles) of Vardenafil hydrochloride: a promising dual platform for modifying the drug release rate and enhancing its oral bioavailability. Aaps PharmSciTech 2018;19:3650–60.

    CAS  Google Scholar 

  76. Limin M, Johnsen N, Hellstrom WJG. Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Exp Opin Investig Drug. 2010;19:1427–37.

    Google Scholar 

  77. Jung J, Choi S, Cho SH, Ghim JL, Hwang A, Kim U, et al. Tolerability and pharmacokinetics of avanafil, a phosphodiesterase Type 5 inhibitor: a single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers. Clin Ther. 2010;32:1178–87.

    CAS  Google Scholar 

  78. Burke RM, Evans JD. Avanafil for treatment of erectile dysfunction: review of its potential. Vasc Health Risk Manag. 2012;8:517–23.

    CAS  Google Scholar 

  79. Choi MK, Song IS. Characterization of efflux transport of the PDE5 inhibitors, vardenafil and sildenafil. J Pharm Pharm. 2012;64:1074–83.

    CAS  Google Scholar 

  80. Yap RL, McVary KT. Topical agents and erectile dysfunction: is there a place? Curr Urol Rep. 2002;3:471–6.

    Google Scholar 

  81. Pegoraro C, MacNeil S, Battaglia G. Transdermal drug delivery: from micro to nano. Nanoscale 2012;4:1881–94.

    CAS  Google Scholar 

  82. Cevc G. Lipid vesicles and other colloids as drug carriers on the skin. Adv Drug Deliv Rev. 2004;56:675–711.

    CAS  Google Scholar 

  83. Gruenwald I, Appel B, Massarwa O. Safety and feasibility of VL#FIA3-30- a new local topical agent for the treatment of erectile dysfunction. J Sex Med. 2017;14:e179.

    Google Scholar 

  84. Cuzin B. Alprostadil cream in the treatment of erectile dysfunction: clinical evidence and experience. Ther Adv Urol. 2016;8:249–56.

    CAS  Google Scholar 

  85. Mishra DK, Shandilya R, Mishra PK. Lipid based nanocarriers: a translational perspective. Nanomed-Nanotechnol. 2018;14:2023–50.

    CAS  Google Scholar 

  86. Sala M, Diab R, Elaissari A, Fessi H. Lipid nanocarriers as skin drug delivery systems: properties, mechanisms of skin interactions and medical applications. Int J Pharm. 2018;535:1–17.

    CAS  Google Scholar 

  87. Jain S, Patel N, Shah MK, Khatri P, Vora N. Recent advances in lipid-based vesicles and particulate carriers for topical and transdermal application. J Pharm Sci. 2017;106:423–45.

    CAS  Google Scholar 

  88. Hosny KM, Aldawsari HM. Avanafil liposomes as transdermal drug delivery for erectile dysfunction treatment: preparation, characterization, and in vitro, ex vivo vivo and in vivo studies. Trop J Pharm Res. 2015;14:559–65.

    CAS  Google Scholar 

  89. Fahmy UA. Nanoethosomal transdermal delivery of vardenafil for the treatment of erectile dysfunction: optimization, characterization, and in vivo evaluation. Drug Des Dev Ther. 2015;9:6129–37.

    CAS  Google Scholar 

  90. Hosny KM, Ahmed OAA, Fahmy UA, Alkhalidi HM. Nanovesicular systems loaded with a recently approved second generation type-5 phospodiesterase inhibitor (avanafil): I. Plackett–Burman screening and characterization. J Drug Deliv Sci Technol. 2018;43:154–9.

    CAS  Google Scholar 

  91. El Zaafarany GM, Awad GAS, Holayel SM, Mortada ND. Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery. Int J Pharm. 2010;397:164–72.

    CAS  Google Scholar 

  92. Ali MFM, Salem HF, Abdelmohsen HF, Attia SK. Preparation and clinical evaluation of nano-transferosomes for treatment of erectile dysfunction. Drug Des Dev Ther. 2015;9:2431–47.

    CAS  Google Scholar 

  93. Kurakula M, Ahmed OAA, Fahmy UA, Ahmed TA. Solid lipid nanoparticles for transdermal delivery of avanafil: optimization, formulation, in-vitro and ex vivo studies. J Liposome Res. 2016;26:288–96.

    CAS  Google Scholar 

  94. Nam E, Yoo S, Kim HY, Kim YR, Heo YJ. Transdermal water-in-oil nanocarriers of nitric oxide for triggering penile erection. Sci Rep. 2018;8:7312.

    Google Scholar 

  95. Bolzinger MA, Briancon S, Pelletier J, Chevalier Y. Penetration of drugs through skin, a complex rate-controlling membrane. Curr Opin Colloid. 2012;17:156–65.

    CAS  Google Scholar 

Download references

Acknowledgements

The author would like to thank Hacettepe Technology Transfer Center (HT-TTM) for providing the editing service for the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eylem Güven.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Güven, E. Lipid-based nanoparticles in the treatment of erectile dysfunction. Int J Impot Res 32, 578–586 (2020). https://doi.org/10.1038/s41443-020-0235-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41443-020-0235-7

This article is cited by

Search

Quick links