Transdermal Delivery of Kidney-Targeting Nanoparticles Using Dissolvable Microneedles



Chronic kidney disease (CKD) affects approximately 13% of the world’s population and will lead to dialysis or kidney transplantation. Unfortunately, clinically available drugs for CKD show limited efficacy and toxic extrarenal side effects. Hence, there is a need to develop targeted delivery systems with enhanced kidney specificity that can also be combined with a patient-compliant administration route for such patients that need extended treatment. Towards this goal, kidney-targeted nanoparticles administered through transdermal microneedles (KNP/MN) is explored in this study.


A KNP/MN patch was developed by incorporating folate-conjugated micelle nanoparticles into polyvinyl alcohol MN patches. Rhodamine B (RhB) was encapsulated into KNP as a model drug and evaluated for biocompatibility and binding with human renal epithelial cells. For MN, skin penetration efficiency was assessed using a Parafilm model, and penetration was imaged via scanning electron microscopy. In vivo, KNP/MN patches were applied on the backs of C57BL/6 wild type mice and biodistribution, organ morphology, and kidney function assessed.


KNP showed high biocompatibility and folate-dependent binding in vitro, validating KNP’s targeting to folate receptors in vitro. Upon transdermal administration in vivo, KNP/MN patches dissolved within 30 min. At varying time points up to 48 h post-KNP/MN administration, higher accumulation of KNP was found in kidneys compared with MN that consisted of the non-targeting, control-NP. Histological evaluation demonstrated no signs of tissue damage, and kidney function markers, serum blood urea nitrogen and urine creatinine, were found to be within normal ranges, indicating preservation of kidney health.


Our studies show potential of KNP/MN patches as a non-invasive, self-administrable platform to direct therapies to the kidneys.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7


  1. 1.

    Abhang, P., et al. Transmucosal drug delivery-an overview. Drug Deliv. Lett. 2014.

    Article  Google Scholar 

  2. 2.

    Au-Poon, C., M. Au-Sarkar, and E. J. Au-Chung. Synthesis of monocyte-targeting peptide amphiphile micelles for imaging of atherosclerosis. JoVE 129:e56625, 2017.

    Google Scholar 

  3. 3.

    Black, K. A., et al. Biocompatibility and characterization of a peptide amphiphile hydrogel for applications in peripheral nerve regeneration. Tissue Eng Part A 21(7–8):1333–1342, 2015.

    Google Scholar 

  4. 4.

    Blair, H. A. Tolvaptan: a review in autosomal dominant polycystic kidney disease. Drugs 79(3):303–313, 2019.

    Google Scholar 

  5. 5.

    Brough, C., et al. Use of polyvinyl alcohol as a solubility enhancing polymer for poorly water-soluble drug delivery (part 2). AAPS PharmSciTech 17(1):180–190, 2016.

    MathSciNet  Google Scholar 

  6. 6.

    Brough, C., et al. Use of polyvinyl alcohol as a solubility-enhancing polymer for poorly water soluble drug delivery (part 1). AAPS PharmSciTech 17(1):167–179, 2016.

    MathSciNet  Google Scholar 

  7. 7.

    Chin, M. P., et al. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J. Cardiac Fail. 20(12):953–958, 2014.

    Google Scholar 

  8. 8.

    Chin, D. D., et al. Hydroxyapatite-binding micelles for the detection of vascular calcification in atherosclerosis. J. Mater. Chem. B 7(41):6449–6457, 2019.

    Google Scholar 

  9. 9.

    Chin, D. D., et al. Collagenase-cleavable peptide amphiphile micelles as a novel theranostic strategy in atherosclerosis. Adv. Ther. 3:1900196, 2020.

    Google Scholar 

  10. 10.

    Chu, H., et al. Detecting functional and accessible folate receptor expression in cancer and polycystic kidneys. Mol. Pharm. 16(9):3985–3995, 2019.

    Google Scholar 

  11. 11.

    Chung, E. J. Targeting and therapeutic peptides in nanomedicine for atherosclerosis. Exp. Biol. Med. (Maywood, N.J.) 241(9):891–898, 2016.

    Google Scholar 

  12. 12.

    Chung, E. J. Nanoparticle Strategies for Biomedical Applications: Reviews from the University of Southern California Viterbi School of Engineering. SLAS TECHNOLOGY: Transl. Life Sci. Innov. 24(2):135–136, 2019.

    Google Scholar 

  13. 13.

    Chung, E. J., et al. Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma. Biomaterials 35(4):1249–1256, 2014.

    Google Scholar 

  14. 14.

    Chung, E. J., et al. In vivo biodistribution and clearance of peptide amphiphile micelles. Nanomedicine: Nanotechnol. Biol. Med. 11(2):479–487, 2015.

    Google Scholar 

  15. 15.

    de Zeeuw, D., et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369(26):2492–2503, 2013.

    Google Scholar 

  16. 16.

    Delanaye, P., et al. Paricalcitol for reduction of albuminuria in diabetes. The Lancet 377(9766):635, 2011.

    Google Scholar 

  17. 17.

    Dong, Y., et al. Folate-conjugated nanodiamond for tumor-targeted drug delivery. RSC Adv. 5(101):82711–82716, 2015.

    Google Scholar 

  18. 18.

    Donnelly, R. F., T. R. Raj Singh, and A. D. Woolfson. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv. 17(4):187–207, 2010.

    Google Scholar 

  19. 19.

    Dunn, S. R., et al. Utility of endogenous creatinine clearance as a measure of renal function in mice. Kidney International 65(5):1959–1967, 2004.

    Google Scholar 

  20. 20.

    Flaten, G. E., et al. In vitro skin models as a tool in optimization of drug formulation. Eur. J. Pharm. Sci. 75:10–24, 2015.

    Google Scholar 

  21. 21.

    Gill, K. K., A. Kaddoumi, and S. Nazzal. PEG–lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication. Journal of Drug Targeting 23(3):222–231, 2015.

    Google Scholar 

  22. 22.

    Health, N.I.o., USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States., M.N.I.o.H. Bethesda, National Institute of Diabetes and Digestive and Kidney Diseases, Editor. 2018.

  23. 23.

    Hill, N. R., et al. Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS ONE 11(7):e0158765–e0158765, 2016.

    Google Scholar 

  24. 24.

    Ita, K. Transdermal delivery of drugs with microneedles-potential and challenges. Pharmaceutics 7(3):90–105, 2015.

    Google Scholar 

  25. 25.

    Ito, Y., et al. Two-layered dissolving microneedles formulated with intermediate-acting insulin. Int. J. Pharm. 436(1):387–393, 2012.

    Google Scholar 

  26. 26.

    Kipp, K. R., et al. Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an orthologous mouse model of polycystic kidney disease. Am. J. Physiol.-Renal Physiol. 315(2):F395–F405, 2018.

    Google Scholar 

  27. 27.

    Larrañeta, E., et al. A proposed model membrane and test method for microneedle insertion studies. Int. J. Pharm. 472(1):65–73, 2014.

    Google Scholar 

  28. 28.

    Lasagna-Reeves, C., et al. Bioaccumulation and toxicity of gold nanoparticles after repeated administration in mice. Biochem. Biophys. Res. Commun. 393(4):649–655, 2010.

    Google Scholar 

  29. 29.

    Lau, S., et al. Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery. J. Controlled Rel. 265:113–119, 2017.

    Google Scholar 

  30. 30.

    Lee, J. W., J.-H. Park, and M. R. Prausnitz. Dissolving microneedles for transdermal drug delivery. Biomaterials 29(13):2113–2124, 2008.

    Google Scholar 

  31. 31.

    Li, W., et al. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nature Biomedical Engineering 3(3):220–229, 2019.

    Google Scholar 

  32. 32.

    Lin, Y., et al. Targeted drug delivery to renal proximal tubule epithelial cells mediated by 2-glucosamine. J. Controlled Rel. 167(2):148–156, 2013.

    Google Scholar 

  33. 33.

    Liu, S., et al. The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. J. Controlled Rel. 161(3):933–941, 2012.

    Google Scholar 

  34. 34.

    Liu, Y. M., Y. Q. Shao, and Q. He. Sirolimus for treatment of autosomal-dominant polycystic kidney disease: a meta-analysis of randomized controlled trials. Transpl. Proc. 46(1):66–74, 2014.

    Google Scholar 

  35. 35.

    Lukyanov, A. N., et al. Polyethylene glycol-diacyllipid micelles demonstrate increased accumulation in subcutaneous tumors in mice. Pharm. Res. 19(10):1424–1429, 2002.

    Google Scholar 

  36. 36.

    Lutton, R. E. M., et al. A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays. Int. J. Pharm. 494(1):417–429, 2015.

    Google Scholar 

  37. 37.

    Maeda, H., et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Controlled Rel. 65(1):271–284, 2000.

    Google Scholar 

  38. 38.

    Mascari, T. M., and L. D. Foil. Evaluation of rhodamine B as an orally delivered biomarker for rodents and a feed-through transtadial biomarker for phlebotomine sand flies (Diptera: Psychodidae). J. Med. Entomol. 46(5):1131–1137, 2009.

    Google Scholar 

  39. 39.

    Matsuo, K., et al. A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens. J. Controlled Rel. 161(1):10–17, 2012.

    Google Scholar 

  40. 40.

    Moga, K. A., et al. Rapidly-dissolvable microneedle patches via a highly scalable and reproducible soft lithography approach. Adv. Mater. 25(36):5060–5066, 2013.

    Google Scholar 

  41. 41.

    Moretton, M. A., et al. Molecular implications in the nanoencapsulation of the anti-tuberculosis drug rifampicin within flower-like polymeric micelles. Colloids Surf. B: Biointerfaces 79(2):467–479, 2010.

    Google Scholar 

  42. 42.

    Murphy, D., et al. Trends in prevalence of chronic kidney disease in the United States. Ann. Internal Med. 165(7):473–481, 2016.

    Google Scholar 

  43. 43.

    Perez-Gomez, M. V., et al. Horizon 2020 in diabetic kidney disease: the clinical trial pipeline for add-on therapies on top of renin angiotensin system blockade. J. Clin. Med. 4(6):1325–1347, 2015.

    Google Scholar 

  44. 44.

    Poon, C., et al. Hybrid, metal oxide-peptide amphiphile micelles for molecular magnetic resonance imaging of atherosclerosis. J. Nanobiotechnol. 16(1):92, 2018.

    Google Scholar 

  45. 45.

    Prausnitz, M. R., S. Mitragotri, and R. Langer. Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov. 3(2):115–124, 2004.

    Google Scholar 

  46. 46.

    Rodrigues, W. F., C. B. Miguel, M. H. Napimoga, and C. J. F. Oliveira. Lazo-Chica JE (2014) Establishing standards for studying renal function in mice through measurements of body size-adjusted creatinine and urea levels. Biometr. Biosec. 872827:8, 2014.

    Google Scholar 

  47. 47.

    Rogers, E. S. Iris, fundamentals of chemistry: solubility. Wisconsin: Department of Chemistry, University of Wisconsin, 2000.

    Google Scholar 

  48. 48.

    Saigusa, T., and P. D. Bell. Molecular pathways and therapies in autosomal-dominant polycystic kidney disease. Physiology 30(3):195–207, 2015.

    Google Scholar 

  49. 49.

    Samant, P. P., and M. R. Prausnitz. Mechanisms of sampling interstitial fluid from skin using a microneedle patch. Proceedings of the National Academy of Sciences 115(18):4583, 2018.

    Google Scholar 

  50. 50.

    Sandoval, R. M., et al. Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy. Am. J. Physiol.-Cell Physiol. 287(2):C517–C526, 2004.

    Google Scholar 

  51. 51.

    Shi, H., et al. Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys. J. Controlled Rel. 293:113–125, 2019.

    Google Scholar 

  52. 52.

    Stenvinkel, P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J. Internal Med. 268(5):456–467, 2010.

    Google Scholar 

  53. 53.

    Torres, V. E., and P. C. Harris. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J. Am. Soc. Nephrol. 25(1):18, 2014.

    Google Scholar 

  54. 54.

    Trac, N. T., and E. J. Chung. Peptide-based targeting of immunosuppressive cells in cancer. Bioactive Mater. 5(1):92–101, 2020.

    Google Scholar 

  55. 55.

    Ueda, Y., et al. In vivo imaging of T cell lymphoma infiltration process at the colon. Sci. Rep. 8(1):3978, 2018.

    Google Scholar 

  56. 56.

    Vora, L. K., et al. Novel nanosuspension-based dissolving microneedle arrays for transdermal delivery of a hydrophobic drug. J. Interdiscip. Nanomed. 3(2):89–101, 2018.

    Google Scholar 

  57. 57.

    Walz, G., et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363(9):830–840, 2010.

    Google Scholar 

  58. 58.

    Wang, S., et al. Design and synthesis of [111In]DTPA−folate for use as a tumor-targeted radiopharmaceutical. Bioconjugate Chem. 8(5):673–679, 1997.

    Google Scholar 

  59. 59.

    Wang, J., J. J. Masehi-Lano, and E. J. Chung. Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease. Biomater. Sci. 5(8):1450–1459, 2017.

    Google Scholar 

  60. 60.

    Wang, J., et al. Design and in vivo characterization of kidney-targeting multimodal micelles for renal drug delivery. Nano Res. 11(10):5584–5595, 2018.

    Google Scholar 

  61. 61.

    Yoo, S. P., et al. Gadolinium-functionalized peptide amphiphile micelles for multimodal imaging of atherosclerotic lesions. ACS Omega 1(5):996–1003, 2016.

    Google Scholar 

  62. 62.

    Yuan, Z.-X., et al. Specific renal uptake of randomly 50% n-acetylated low molecular weight chitosan. Mol. Pharm. 6(1):305–314, 2009.

    MathSciNet  Google Scholar 

  63. 63.

    Zhang, Z., et al. The targeting of 14-succinate triptolide-lysozyme conjugate to proximal renal tubular epithelial cells. Biomaterials 30(7):1372–1381, 2009.

    Google Scholar 

  64. 64.

    Zhou, P., X. Sun, and Z. Zhang. Kidney–targeted drug delivery systems. Acta Pharmaceutica Sin. B 4(1):37–42, 2014.

    Google Scholar 

  65. 65.

    Zhu, Y.-H., et al. Incorporation of a rhodamine B conjugated polymer for nanoparticle trafficking both in vitro and in vivo. Biomater. Sci. 7(5):1933–1939, 2019.

    Google Scholar 

Download references


The authors would like to acknowledge the financial support from the Women in Science and Engineering (WiSE), Gabilan Assistant Professorship, L. K. Whittier Foundation, the National Heart, Lung, and Blood Institute (NHLBI, R00HL124279), and NIH New Innovator Award (DP2-DK121328) awarded to EJC. TEM images were taken with the aid of the USC Center of Excellence in Nano Imaging.

Conflict of interest

Nirmalya Tripathy, Jonathan Wang, Madelynn Tung, Claire Conway, and Eun Ji Chung have no conflicts of interest to disclose.

Animal Studies

All animal studies followed NIH guidelines for the care and use of laboratory animals and were conducted and approved by the University of Southern California’s Institutional Animal Care and Use Committee (Los Angeles, CA, USA).

Human Studies

No human studies were carried out by the authors for this article.

Author information



Corresponding author

Correspondence to Eun Ji Chung.

Additional information

Publisher's Note

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

Associate Editor Michael R. King oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOCX 2904 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tripathy, N., Wang, J., Tung, M. et al. Transdermal Delivery of Kidney-Targeting Nanoparticles Using Dissolvable Microneedles. Cel. Mol. Bioeng. 13, 475–486 (2020).

Download citation


  • Chronic kidney disease
  • Kidney-targeting
  • Nanoparticles
  • Folate
  • Microneedles