Abstract
Introduction
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.
Methods
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.
Results
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.
Conclusions
Our studies show potential of KNP/MN patches as a non-invasive, self-administrable platform to direct therapies to the kidneys.
Similar content being viewed by others
References
Abhang, P., et al. Transmucosal drug delivery-an overview. Drug Deliv. Lett. 2014. https://doi.org/10.2174/22103031113039990011.
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.
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.
Blair, H. A. Tolvaptan: a review in autosomal dominant polycystic kidney disease. Drugs 79(3):303–313, 2019.
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.
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.
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.
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.
Chin, D. D., et al. Collagenase-cleavable peptide amphiphile micelles as a novel theranostic strategy in atherosclerosis. Adv. Ther. 3:1900196, 2020.
Chu, H., et al. Detecting functional and accessible folate receptor expression in cancer and polycystic kidneys. Mol. Pharm. 16(9):3985–3995, 2019.
Chung, E. J. Targeting and therapeutic peptides in nanomedicine for atherosclerosis. Exp. Biol. Med. (Maywood, N.J.) 241(9):891–898, 2016.
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.
Chung, E. J., et al. Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma. Biomaterials 35(4):1249–1256, 2014.
Chung, E. J., et al. In vivo biodistribution and clearance of peptide amphiphile micelles. Nanomedicine: Nanotechnol. Biol. Med. 11(2):479–487, 2015.
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.
Delanaye, P., et al. Paricalcitol for reduction of albuminuria in diabetes. The Lancet 377(9766):635, 2011.
Dong, Y., et al. Folate-conjugated nanodiamond for tumor-targeted drug delivery. RSC Adv. 5(101):82711–82716, 2015.
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.
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.
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.
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.
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.
Hill, N. R., et al. Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS ONE 11(7):e0158765–e0158765, 2016.
Ita, K. Transdermal delivery of drugs with microneedles-potential and challenges. Pharmaceutics 7(3):90–105, 2015.
Ito, Y., et al. Two-layered dissolving microneedles formulated with intermediate-acting insulin. Int. J. Pharm. 436(1):387–393, 2012.
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.
Larrañeta, E., et al. A proposed model membrane and test method for microneedle insertion studies. Int. J. Pharm. 472(1):65–73, 2014.
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.
Lau, S., et al. Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery. J. Controlled Rel. 265:113–119, 2017.
Lee, J. W., J.-H. Park, and M. R. Prausnitz. Dissolving microneedles for transdermal drug delivery. Biomaterials 29(13):2113–2124, 2008.
Li, W., et al. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nature Biomedical Engineering 3(3):220–229, 2019.
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.
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.
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.
Lukyanov, A. N., et al. Polyethylene glycol-diacyllipid micelles demonstrate increased accumulation in subcutaneous tumors in mice. Pharm. Res. 19(10):1424–1429, 2002.
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.
Maeda, H., et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Controlled Rel. 65(1):271–284, 2000.
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.
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.
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.
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.
Murphy, D., et al. Trends in prevalence of chronic kidney disease in the United States. Ann. Internal Med. 165(7):473–481, 2016.
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.
Poon, C., et al. Hybrid, metal oxide-peptide amphiphile micelles for molecular magnetic resonance imaging of atherosclerosis. J. Nanobiotechnol. 16(1):92, 2018.
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.
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.
Rogers, E. S. Iris, fundamentals of chemistry: solubility. Wisconsin: Department of Chemistry, University of Wisconsin, 2000.
Saigusa, T., and P. D. Bell. Molecular pathways and therapies in autosomal-dominant polycystic kidney disease. Physiology 30(3):195–207, 2015.
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.
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.
Shi, H., et al. Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys. J. Controlled Rel. 293:113–125, 2019.
Stenvinkel, P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J. Internal Med. 268(5):456–467, 2010.
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.
Trac, N. T., and E. J. Chung. Peptide-based targeting of immunosuppressive cells in cancer. Bioactive Mater. 5(1):92–101, 2020.
Ueda, Y., et al. In vivo imaging of T cell lymphoma infiltration process at the colon. Sci. Rep. 8(1):3978, 2018.
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.
Walz, G., et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363(9):830–840, 2010.
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.
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.
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.
Yoo, S. P., et al. Gadolinium-functionalized peptide amphiphile micelles for multimodal imaging of atherosclerotic lesions. ACS Omega 1(5):996–1003, 2016.
Yuan, Z.-X., et al. Specific renal uptake of randomly 50% n-acetylated low molecular weight chitosan. Mol. Pharm. 6(1):305–314, 2009.
Zhang, Z., et al. The targeting of 14-succinate triptolide-lysozyme conjugate to proximal renal tubular epithelial cells. Biomaterials 30(7):1372–1381, 2009.
Zhou, P., X. Sun, and Z. Zhang. Kidney–targeted drug delivery systems. Acta Pharmaceutica Sin. B 4(1):37–42, 2014.
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.
Acknowledgments
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
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Michael R. King oversaw the review of this article.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
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). https://doi.org/10.1007/s12195-020-00622-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12195-020-00622-3