Abstract
Transdermal drug delivery systems have been studied as an attractive alternative to conventional delivery routes. However, the outermost layer of the skin, the stratum corneum, acts as a primary barrier to drug delivery. A synergistic combination of microneedles (MNs) and low-frequency ultrasound (U) was used to enhance the penetration of siRNA and ovalbumin. The specific gene knockdown caused by siRNAs through the RNA interference pathway is more stable when delivered via the transdermal route. Ovalbumin, a representative adjuvant, causes a more efficient immune response in the skin because of the numerous immune cells in the skin. The synergistic transdermal delivery resulted in approximately 7 times and 15 times greater penetration of siRNA and ovalbumin respectively than in their respective negative controls, and histological analysis showed minimal invasion. Thus, as the synergistic transdermal delivery enhanced the penetration of biomacromolecules into the skin, this technique is expected to yield a promising technology for a transdermal drug delivery system.
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Prausnitz, M. R., S. Mitragotri, and R. Langer (2004) Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov. 3: 115–124.
Paudel, K. S., M. Milewski, C. L. Swadley, N. K. Brogden, P. Ghosh, and A. L. Stinchcomb (2010) Challenges and opportunities in dermal/transdermal delivery. Ther. Deliv. 1: 109–131.
Christie, R. J., Y. Matsumoto, K. Miyata, T. Nomoto, S. Fukushima, K. Osada, J. Halnaut, F. Pittella, H. J. Kim, N. Nishiyama, and K. Kataoka (2012) Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection. ACS Nano. 6: 5174–5189.
Seneschal, J., R. A. Clark, A. Gehad, C. M. Baecher-Allan, and T. S. Kupper (2012) Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36: 873–884.
Zakrewsky, M., S. Kumar, and S. Mitragotri (2015) Nucleic acid delivery into skin for the treatment of skin disease: Proofs-ofconcept, potential impact, and remaining challenges. J. Control. Release. 219: 445–456.
Hsu, T. and S. Mitragotri (2011) Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc. Natl. Acad. Sci USA. 108: 15816–15821.
Valencia-Sanchez, M. A., J. Liu, G. J. Hannon, and R. Parker (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20: 515–524.
Castanotto, D. and J. J. Rossi (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457: 426–433.
Bungener, L., A. Huckriede, J. Wilschut, and T. Daemen (2002) Delivery of protein antigens to the immune system by fusionactive virosomes: a comparison with liposomes and ISCOMs. Biosci. Rep. 22: 323–338.
Brown, M. B., G. P. Martin, S. A. Jones, and F. K. Akomeah (2006) Dermal and transdermal drug delivery systems: current and future prospects. Drug Deliv. 13: 175–187.
Mitragotri, S., P. A. Burke, and R. Langer (2014) Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13: 655–672.
Larraneta, E., M. T. McCrudden, A. J. Courtenay, and R. F. Donnelly (2016) Microneedles: A new frontier in nanomedicine delivery. Pharm. Res. 33: 1055–1073.
Prausnitz, M. R. (2004) Microneedles for transdermal drug delivery. Adv. Drug Deliv. Rev. 56: 581–587.
Mitragotri, S. (2005) Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat. Rev. Drug Discov. 4: 255–260.
Lee, W. R., S. C. Shen, R. Z. Zhuo, K. C. Wang, and J. Y. Fang (2009) Enhancement of topical small interfering RNA delivery and expression by low-fluence erbium:YAG laser pretreatment of skin. Hum. Gene Ther. 20: 580–588.
Paithankar, D., B. H. Hwang, G. Munavalli, A. Kauvar, J. Lloyd, R. Blomgren, L. Faupel, T. Meyer, and S. Mitragotri (2015) Ultrasonic delivery of silica-gold nanoshells for photothermolysis of sebaceous glands in humans: Nanotechnology from the bench to clinic. J. Control. Release 206: 30–36.
Matriano, J. A., M. Cormier, J. Johnson, W. A. Young, M. Buttery, K. Nyam, and P. E. Daddona (2002) Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm. Res. 19: 63–70.
Widera, G., J. Johnson, L. Kim, L. Libiran, K. Nyam, P. E. Daddona, and M. Cormier (2006) Effect of delivery parameters on immunization to ovalbumin following intracutaneous administration by a coated microneedle array patch system. Vaccine 24: 1653–1664.
Mitragotri, S., D. Blankschtein, and R. Langer (1996) Transdermal drug delivery using low-frequency sonophoresis. Pharm. Res. 13: 411–420.
Polat, B. E., D. Blankschtein, and R. Langer (2010) Lowfrequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs. Expert Opin. Drug Deliv. 7: 1415–1432.
Bal, S. M., J. Caussin, S. Pavel, and J. A. Bouwstra (2008) In vivo assessment of safety of microneedle arrays in human skin. Eur. J. Pharm. Sci. 35: 193–202.
Singer, A. J., C. S. Homan, A. L. Church, and S. A. McClain (1998) Low-frequency sonophoresis: pathologic and thermal effects in dogs. Acad. Emerg. Med. 5: 35–40.
Boucaud, A., J. Montharu, L. Machet, B. Arbeille, M. C. Machet, F. Patat, and L. Vaillant (2001) Clinical, histologic, and electron microscopy study of skin exposed to low-frequency ultrasound. Anat. Rec. 264: 114–119.
Paliwal, S., B. H. Hwang, K. Y. Tsai, and S. Mitragotri (2013) Diagnostic opportunities based on skin biomarkers. Eur. J. Pharm. Sci. 50: 546–556.
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Ryu, Y.C., Kim, D.I., Kim, S.H. et al. Synergistic Transdermal Delivery of Biomacromolecules Using Sonophoresis after Microneedle Treatment. Biotechnol Bioproc E 23, 286–292 (2018). https://doi.org/10.1007/s12257-018-0070-6
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DOI: https://doi.org/10.1007/s12257-018-0070-6