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Microneedles: an innovative platform for gene delivery

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Abstract

The advent of microneedle (MN) technology has provided a revolutionary platform for the delivery of therapeutic agents, particularly in the field of gene therapy. For over 20 years, the area of gene therapy has undergone intense innovation and progression which has seen advancement of the technology from an experimental concept to a widely acknowledged strategy for the treatment and prevention of numerous disease states. However, the true potential of gene therapy has yet to be achieved due to limitations in formulation and delivery technologies beyond parenteral injection of the DNA. Microneedle-mediated delivery provides a unique platform for the delivery of DNA therapeutics clinically. It provides a means to overcome the skin barriers to gene delivery and deposit the DNA directly into the dermal layers, a key site for delivery of therapeutics to treat a wide range of skin and cutaneous diseases. Additionally, the skin is a tissue rich in immune sentinels, an ideal target for the delivery of a DNA vaccine directly to the desired target cell populations. This review details the advancement of MN-mediated DNA delivery from proof-of-concept to the delivery of DNA encoding clinically relevant proteins and antigens and examines the key considerations for the improvement of the technology and progress into a clinically applicable delivery system.

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References

  1. Mulligan RC. The basic science of gene therapy. Science. 1993;260:926–32.

    Article  CAS  PubMed  Google Scholar 

  2. Shedlock DJ, Weiner DB. DNA vaccination: antigen presentation and the induction of immunity. J Leukoc Biol. 2000;68:793–806.

    CAS  PubMed  Google Scholar 

  3. Ruponen M, Honkakoski P, Ronkko S, Pelkonen J, Tammi M, Urtti A. Extracellular and intracellular barriers in non-viral gene delivery. J Control Release. 2003;93(2):213–7.

    Article  CAS  PubMed  Google Scholar 

  4. Wang T, Upponi JR, Torchilin VP. Design of multifunctional non-viral gene vectors to overcome physiological barriers: dilemmas and strategies. Int J Pharm. 2012;427(1):3–20. doi:10.1016/j.ijpharm.2011.07.013.

    Article  CAS  PubMed  Google Scholar 

  5. McCarthy HO, Wang Y, Mangipudi SS, Hatefi A. Advances with the use of bio-inspired vectors towards creation of artificial viruses. Expert Opin Drug Deliv. 2010;7:497–512.

    Article  CAS  PubMed  Google Scholar 

  6. Larocca C, Schlom J. Viral vector-based therapeutic cancer vaccines. Cancer J. 2011;17(5):pp. 359–71. doi:10.1097/PPO.0b013e3182325e63.

    Article  Google Scholar 

  7. H. O. McCarthy, J. McCaffrey, C. M. McCrudden, A. Zholobenko, A. A. Ali, J. W. McBride, A. S. Massey, S. Pentlavali, K. Chen and G. Cole. Development and characterization of self-assembling nanoparticles using a bio-inspired amphipathic peptide for gene delivery. J. Controlled Release 2014.

  8. Zhang XX, McIntosh TJ, Grinstaff MW. Functional lipids and lipoplexes for improved gene delivery. Biochimie. 2012;94(1):42–58. doi:10.1016/j.biochi.2011.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005;4:581–93.

    Article  CAS  PubMed  Google Scholar 

  10. Bariya SH, Gohel MC, Mehta TA, Sharma OP. Microneedles: an emerging transdermal drug delivery system. J Pharm Pharmacol. 2012;64:11–29.

    Article  CAS  PubMed  Google Scholar 

  11. Menon GK. New insights into skin structure: scratching the surface. Adv Drug Deliv Rev. 2002;54(1):S3–17.

    Article  CAS  PubMed  Google Scholar 

  12. Prausnitz MR. Microneedles for transdermal drug delivery. Adv Drug Deliv Rev. 2004;56:581–7.

    Article  CAS  PubMed  Google Scholar 

  13. Kaushik S, Hord AH, Denson DD, McAllister DV, Smitra S, Allen MG, et al. Lack of pain associated with microfabricated microneedles. Anesth Analg. 2001;92:502–4.

    Article  CAS  PubMed  Google Scholar 

  14. Hengge UR, Walker PS, Vogel JC. Expression of naked DNA in human, pig, and mouse skin. J Clin Invest. 1996;97(12):2911–6. doi:10.1172/JCI118750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Heller R, Cruz Y, Heller LC, Gilbert RA, Jaroszeski MJ. Electrically mediated delivery of plasmid DNA to the skin, using a multielectrode array. Hum Gene Ther. 2010;21(3):357–62. doi:10.1089/hum.2009.065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gorres JP, Lager KM, Kong WP, Royals M, Todd JP, Vincent AL, et al. DNA vaccination elicits protective immune responses against pandemic and classic swine influenza viruses in pigs. Clin Vaccine Immunol. 2011;18(11):1987–95. doi:10.1128/CVI.05171-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Verstrepen BE, Bins AD, Rollier CS, Mooij P, Koopman G, Sheppard NC, et al. Improved HIV-1 specific T-cell responses by short-interval DNA tattooing as compared to intramuscular immunization in non-human primates. Vaccine. 2008;26(26):3346–51. doi:10.1016/j.vaccine.2008.03.091.

    Article  CAS  PubMed  Google Scholar 

  18. Low L, Mander A, McCann K, Dearnaley D, Tjelle T, Mathiesen I, et al. DNA vaccination with electroporation induces increased antibody responses in patients with prostate cancer. Hum Gene Ther. 2009;20(11):1269–78. doi:10.1089/hum.2009.067.

    Article  CAS  PubMed  Google Scholar 

  19. Al-Zahrani S, Zaric M, McCrudden C, Scott C, Kissenpfennig A, Donnelly RF. Microneedle-mediated vaccine delivery: harnessing cutaneous immunobiology to improve efficacy. Expert Opin Drug Deliv. 2012;9(5):541–50. doi:10.1517/17425247.2012.676038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kupper TS, Fuhlbrigge RC. Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol. 2004;4(3):211–22. doi:10.1038/nri1310.

    Article  CAS  PubMed  Google Scholar 

  21. Henry S, McAllister DV, Allen MG, Prausnitz MR. Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci. 1998;87:922–5.

    Article  CAS  PubMed  Google Scholar 

  22. McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG, et al. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc Natl Acad Sci U S A. 2003;100:13755–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xie Y, Xu B, Gao Y. Controlled transdermal delivery of model drug compounds by MEMS microneedle array. Nanomedicine. 2005;1:184–90.

    Article  CAS  PubMed  Google Scholar 

  24. Doddaballapur S. Microneedling with dermaroller. J Cutan Aesthet Surg. 2009;2(2):110–1. doi:10.4103/0974-2077.58529.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Rev: Adv. Drug Deliv; 2012. doi:10.1016/j.addr.2012.04.005.

    Google Scholar 

  26. Mikszta JA, Alarcon JB, Brittingham JM, Sutter DE, Pettis RJ, Harvey NG. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat Med. 2002;8(4):415–9. doi:10.1038/nm0402-415.

    Article  CAS  PubMed  Google Scholar 

  27. Pearton M, Allender C, Brain K, Anstey A, Gateley C, Wilke N, et al. Gene delivery to the epidermal cells of human skin explants using microfabricated microneedles and hydrogel formulations. Pharm Res. 2008;25(2):407–16. doi:10.1007/s11095-007-9360-y.

    Article  CAS  PubMed  Google Scholar 

  28. Birchall J, Coulman S, Pearton M, Allender C, Brain K, Anstey A, et al. Cutaneous DNA delivery and gene expression in ex vivo human skin explants via wet-etch micro-fabricated micro-needles. J Drug Target. 2005;13(7):415–21.

    Article  CAS  PubMed  Google Scholar 

  29. Chabri F, Bouris K, Jones T, Barrow D, Hann A, Allender C, et al. Microfabricated silicon microneedles for nonviral cutaneous gene delivery. Br J Dermatol. 2004;150(5):869–77. doi:10.1111/j.1365-2133.2004.05921.x.

    Article  CAS  PubMed  Google Scholar 

  30. Coulman SA, Barrow D, Anstey A, Gateley C, Morrissey A, Wilke N, et al. Minimally invasive cutaneous delivery of macromolecules and plasmid DNA via microneedles. Curr Drug Deliv. 2006;3(1):65–75.

    Article  CAS  PubMed  Google Scholar 

  31. Yin D, Liang W, Xing S, Gao Z, Zhang W, Guo Z, et al. Hepatitis B DNA vaccine-polycation nano-complexes enhancing immune response by percutaneous administration with microneedle. Biol Pharm Bull. 2013;36(8):1283–91.

    Article  CAS  PubMed  Google Scholar 

  32. Hu Y, Xu B, Ji Q, Shou D, Sun X, Xu J, et al. A mannosylated cell-penetrating peptide-graft-polyethylenimine as a gene delivery vector. Biomaterials. 2014;35(13):4236–46. doi:10.1016/j.biomaterials.2014.01.065.

    Article  CAS  PubMed  Google Scholar 

  33. Hu Y, Xu B, Xu J, Shou D, Liu E, Gao J, et al. Microneedle-assisted dendritic cell-targeted nanoparticles for transcutaneous DNA immunization. Polym Chem. 2015;6:373–9.

    Article  CAS  Google Scholar 

  34. Park KY, Jang WS, Lim YY, Ahn JH, Lee SJ, Kim CW, et al. Safety evaluation of stamp type digital microneedle devices in hairless mice. Ann Dermatol. 2013;25(1):46–53. doi:10.5021/ad.2013.25.1.46.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yan G, Arelly N, Farhan N, Lobo S, Li H. Enhancing DNA delivery into the skin with a motorized microneedle device. Eur J Pharm Sci. 2014;52:215–22. doi:10.1016/j.ejps.2013.11.015.

    Article  CAS  PubMed  Google Scholar 

  36. Gill HS, Soderholm J, Prausnitz MR, Sallberg M. Cutaneous vaccination using microneedles coated with hepatitis C DNA vaccine. Gene Ther. 2010;17(6):811–4. doi:10.1038/gt.2010.22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pearton M, Saller V, Coulman SA, Gateley C, Anstey AV, Zarnitsyn V, et al. Microneedle delivery of plasmid DNA to living human skin: formulation coating, skin insertion and gene expression. J Control Release. 2012;160(3):561–9. doi:10.1016/j.jconrel.2012.04.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Song JM, Kim YC, Compans EORW, Prausnitz MR, Kang SM. DNA vaccination in the skin using microneedles improves protection against influenza. Mol Ther. 2012;20(7):1472–80. doi:10.1038/mt.2012.69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim YC, Song JM, Lipatov AS, Choi SO, Lee JW, Donis RO, et al. Increased immunogenicity of avian influenza DNA vaccine delivered to the skin using a microneedle patch. Eur J Pharm Biopharm. 2012;81(2):239–47. doi:10.1016/j.ejpb.2012.03.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim YC, Yoo DG, Compans RW, Kang SM, Prausnitz MR. Cross-protection by co-immunization with influenza hemagglutinin DNA and inactivated virus vaccine using coated microneedles. J Control Release. 2013;172(2):579–88. doi:10.1016/j.jconrel.2013.04.016.

    Article  CAS  PubMed  Google Scholar 

  41. DeMuth PC, Min Y, Huang B, Kramer JA, Miller AD, Barouch DH, et al. Polymer multilayer tattooing for enhanced DNA vaccination. Nat Mater. 2013;12(4):367–76. doi:10.1038/nmat3550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fernando GJ, Chen X, Prow TW, Crichton ML, Fairmaid EJ, Roberts MS, et al. Potent immunity to low doses of influenza vaccine by probabilistic guided micro-targeted skin delivery in a mouse model. PLoS One. 2010;5(4):e10266. doi:10.1371/journal.pone.0010266.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chen X, Kask AS, Crichton ML, McNeilly C, Yukiko S, Dong L, et al. Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays. J Control Release. 2010;148(3):327–33. doi:10.1016/j.jconrel.2010.09.001.

    Article  CAS  PubMed  Google Scholar 

  44. Kask AS, Chen X, Marshak JO, Dong L, Saracino M, Chen D, et al. DNA vaccine delivery by densely-packed and short microprojection arrays to skin protects against vaginal HSV-2 challenge. Vaccine. 2010;28(47):7483–91. doi:10.1016/j.vaccine.2010.09.014.

    Article  CAS  PubMed  Google Scholar 

  45. Pearson FE, McNeilly CL, Crichton ML, Primiero CA, Yukiko SR, Fernando GJ, et al. Dry-coated live viral vector vaccines delivered by nanopatch microprojections retain long-term thermostability and induce transgene-specific T cell responses in mice. PLoS One. 2013;8(7):e67888. doi:10.1371/journal.pone.0067888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kines RC, Zarnitsyn V, Johnson TR, Pang YY, Corbett KS, Nicewonger JD, et al. Vaccination with human papillomavirus pseudovirus-encapsidated plasmids targeted to skin using microneedles. PLoS One. 2015;10(3):e0120797. doi:10.1371/journal.pone.0120797.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hooper JW, Golden JW, Ferro AM, King AD. Smallpox DNA vaccine delivered by novel skin electroporation device protects mice against intranasal poxvirus challenge. Vaccine. 2007;25(10):1814–23. doi:10.1016/j.vaccine.2006.11.017.

    Article  CAS  PubMed  Google Scholar 

  48. Wei Z, Zheng S, Wang R, Bu X, Ma H, Wu Y, et al. A flexible microneedle array as low-voltage electroporation electrodes for in vivo DNA and siRNA delivery. Lab Chip. 2014;14(20):4093–102. doi:10.1039/c4lc00800f.

    Article  CAS  PubMed  Google Scholar 

  49. Daugimont L, Baron N, Vandermeulen G, Pavselj N, Miklavcic D, Jullien MC, et al. Hollow microneedle arrays for intradermal drug delivery and DNA electroporation. J Membr Biol. 2010;236(1):117–25. doi:10.1007/s00232-010-9283-0.

    Article  CAS  PubMed  Google Scholar 

  50. Burkoth TL, Bellhouse BJ, Hewson G, Longridge DJ, Muddle AG, Sarphie DF. Transdermal and transmucosal powdered drug delivery. Crit Rev Ther Drug Carrier Syst. 1999;16(4):331–84.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang D, Das DB, Rielly CD. Potential of microneedle-assisted micro-particle delivery by gene guns: a review. Drug Deliv. 2014;21(8):pp. 571–87. doi:10.3109/10717544.2013.864345.

    Article  Google Scholar 

  52. Zhang D, Das DB, Rielly CD. Microneedle assisted micro-particle delivery from gene guns: experiments using skin-mimicking agarose gel. J Pharm Sci. 2014;103(2):613–27. doi:10.1002/jps.23835.

    Article  CAS  PubMed  Google Scholar 

  53. Zhang D, Das DB, Rielly CD. An experimental study of microneedle-assisted microparticle delivery. J Pharm Sci. 2013;102(10):3632–44. doi:10.1002/jps.23665.

    Article  CAS  PubMed  Google Scholar 

  54. Gonzalez-Gonzalez E, Speaker TJ, Hickerson RP, Spitler R, Flores MA, Leake D, et al. Silencing of reporter gene expression in skin using siRNAs and expression of plasmid DNA delivered by a soluble protrusion array device (PAD). Mol Ther. 2010;18(9):1667–74. doi:10.1038/mt.2010.126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gonzalez-Gonzalez E, Kim YC, Speaker TJ, Hickerson RP, Spitler R, Birchall JC, et al. Visualization of plasmid delivery to keratinocytes in mouse and human epidermis. Sci Rep. 2011;1:158. doi:10.1038/srep00158.

    PubMed  PubMed Central  Google Scholar 

  56. Qiu Y, Guo L, Zhang S, Xu B, Gao Y, Hu Y, et al. DNA-based vaccination against hepatitis B virus using dissolving microneedle arrays adjuvanted by cationic liposomes and CpG ODN. Drug Deliv. 2015;30:pp. 1–8. doi:10.3109/10717544.2014.992497.

    Article  Google Scholar 

  57. Bachy V, Hervouet C, Becker PD, Chorro L, Carlin LM, Herath S, et al. Langerin negative dendritic cells promote potent CD8+ T-cell priming by skin delivery of live adenovirus vaccine microneedle arrays. Proc Natl Acad Sci U S A. 2013;110(8):3041–6. doi:10.1073/pnas.1214449110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Quinn HL, Kearney MC, Courtenay AJ, McCrudden MT, Donnelly RF. The role of microneedles for drug and vaccine delivery. Expert Opin Drug Deliv. 2014;11(11):1769–80. doi:10.1517/17425247.2014.938635.

    Article  CAS  PubMed  Google Scholar 

  59. Kim NW, Lee MS, Kim KR, Lee JE, Lee K, Park JS, et al. Polyplex-releasing microneedles for enhanced cutaneous delivery of DNA vaccine. J Control Release. 2014;179:11–7. doi:10.1016/j.jconrel.2014.01.016.

    Article  CAS  PubMed  Google Scholar 

  60. Donnelly RF, Moffatt K, Alkilani AZ, Vicente-Perez EM, Barry J, McCrudden MT, et al. Hydrogel-forming microneedle arrays can be effectively inserted in skin by self-application: a pilot study centred on pharmacist intervention and a patient information leaflet. Pharm Res. 2014;31(8):1989–99. doi:10.1007/s11095-014-1301-y.

    Article  CAS  PubMed  Google Scholar 

  61. McCrudden MT, Alkilani AZ, Courtenay AJ, McCrudden CM, McCloskey B, Walker C, et al. Considerations in the sterile manufacture of polymeric microneedle arrays. Drug Deliv Transl Res. 2015;5(1):3–14. doi:10.1007/s13346-014-0211-1.

    Article  CAS  PubMed  Google Scholar 

  62. Davidson AH, Traub-Dargatz JL, Rodeheaver RM, Ostlund EN, Pedersen DD, Moorhead RG, et al. Immunologic responses to West Nile virus in vaccinated and clinically affected horses. J Am Vet Med Assoc. 2005;226(2):240–5.

    Article  PubMed  Google Scholar 

  63. De Filette M, Ulbert S, Diamond M, Sanders NN. Recent progress in west nile virus diagnosis and vaccination. Vet Res. 2012;43:16-9716-43. doi:10.1186/1297-9716-43-16.

    Article  Google Scholar 

  64. Bergman PJ, Camps-Palau MA, McKnight JA, Leibman NF, Craft DM, Leung C, et al. Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the animal medical center. Vaccine. 2006;24(21):4582–5. doi:10.1016/j.vaccine.2005.08.027.

    Article  CAS  PubMed  Google Scholar 

  65. Garver KA, LaPatra SE, Kurath G. Efficacy of an infectious hematopoietic necrosis (IHN) virus DNA vaccine in Chinook Oncorhynchus tshawytscha and sockeye O. nerka salmon. Dis Aquat Organ. 2005;64(1):13–22. doi:10.3354/dao064013.

    Article  CAS  PubMed  Google Scholar 

  66. Thacker EL, Holtkamp DJ, Khan AS, Brown PA, Draghia-Akli R. Plasmid-mediated growth hormone-releasing hormone efficacy in reducing disease associated with mycoplasma hyopneumoniae and porcine reproductive and respiratory syndrome virus infection. J Anim Sci. 2006;84(3):733–42.

    CAS  PubMed  Google Scholar 

  67. Kutzler MA, Weiner DB. DNA vaccines: ready for prime time? Nat Rev Genet. 2008;9(10):776–88. doi:10.1038/nrg2432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast, UK, BT9 7BL

    Joanne McCaffrey, Ryan F. Donnelly & Helen O. McCarthy

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  1. Joanne McCaffrey
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McCaffrey, J., Donnelly, R.F. & McCarthy, H.O. Microneedles: an innovative platform for gene delivery. Drug Deliv. and Transl. Res. 5, 424–437 (2015). https://doi.org/10.1007/s13346-015-0243-1

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