Application of direct electric current to the corneal and conjunctival epithelia regulates the tight junctional assembly for ocular iontophoretic drug delivery

Authors

  • Hidehisa Sekijima Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan, https://orcid.org/0000-0001-6927-5625
  • Yutaro Hazama Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan, https://orcid.org/0000-0001-9444-0311
  • Soichiro Kimura Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan, https://orcid.org/0000-0003-1744-7397
  • Yasunori Morimoto Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan, https://orcid.org/0000-0001-8708-6908
  • Hideo Ueda Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan, https://orcid.org/0000-0002-0795-6262

Abstract

Objectives: In this study, we determined how iontophoresis (IP) affects tight junctions (TJs) in isolated rabbit corneas and conjunctiva.

Methods: Direct electric current in the range of 0.5–2.0 and 0.5–10 mA/cm2 were applied to the cornea and conjunctiva, respectively, for 30 min. The localization and expression levels of TJ-associated proteins were assessed before and after the application of the electric currents using immunostaining and western blotting.

Results: In both corneal and conjunctival epithelia, the localization of proteins, such as claudin-1, claudin-4, occludin, and ZO-1, was temporarily altered by anodal and cathodal IP; however, the protein relocalization was slower at higher currents. Additionally, in both anodal and cathodal IP, the expression levels of claudin-1 and occludin in the cornea and conjunctiva remained unchanged after the application of the electric currents compared with those before.

Conclusion: Our results indicated that the application of a direct electric current temporarily regulated TJ assemblies without altering the levels of TJ-associated proteins in both the cornea and conjunctiva. This temporary weakening of the paracellular barrier by the current may be responsible for the enhanced drug transport across the cornea and conjunctiva induced by ocular IP.

Keywords: ocular drug delivery, iontophoresis, electric current, cornea, conjunctiva, tight junction

Keywords:

ocular drug delivery, iontophoresis, electric current, cornea, conjunctiva, tight junction

DOI

https://doi.org/10.22270/jddt.v14i3.6455

Author Biographies

Hidehisa Sekijima, Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Department of Forensic Medicine and Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

Yutaro Hazama, Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Soichiro Kimura, Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Yasunori Morimoto, Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Hideo Ueda, Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

Department of Hospital Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan,

References

Ahamed I, Patton TF, “Importance Of The Noncorneal Absorption Route In Topical Ophthalmic Drug Delivery” Invest Ophthalmol Vis Sci, 1985; 26(4):584–587.

Maurice DM, Mishima S. Ocular pharmacokinetics. In: Sears ML, editor. Handbook of experimental pharmacology. Berlin: Springer; 1984. p. 19–116.

Kalia YN, Naik A, Garrison J, Guy RH, “Iontophoretic Drug Delivery” Adv Drug Deliv Rev, 2004; 56 (5):619–658. DOI: https://doi.org/10.1016/j.addr.2003.10.026

Eljarrat-Binstock E, Domb AJ, “Iontophoresis: A Non-Invasive Ocular Drug Delivery” J Control Release, 2006; 110(3):479–489. DOI: https://doi.org/10.1016/j.jconrel.2005.09.049

Barza M, Peckman C, Baumf J, “Transscleral Iontophoresis Of Gentamicin In Monkeys” Invest Ophthalmol Vis Sci, 1987; 28:1033–1036. DOI: https://doi.org/10.1001/archopht.1987.01060100120040

Grossman RE, Chu DF, Lee DA, “Regional Ocular Gentamicin Levels After Transcorneal And Transscleral Iontophoresis” Invest Ophthalmol Vis Sci, 1990; 31:909–916.

Frucht-Pery J, Mechoulam H, Siganos CS, Ever-Hadani P, Shapiro M, Domb A, “Iontophoresis-Gentamicin Delivery Into The Rabbit Cornea, Using A Hydrogel Delivery Probe” Exp Eye Res, 2004; 78(3):745–749. DOI: https://doi.org/10.1016/s0014-4835(03)00215-x

Choi TB, Lee DA, “Transscleral And Transcorneal Iontophoresis Of Vancomycin In Rabbit Eyes” J Ocul Pharmacol, 1988; 4(2):153–164. DOI: https://doi.org/10.1089/jop.1988.4.153

Rootman DS, Hobden JA, Jantzen JA, Gonzalez JR, O’callaghan RJ, Hill JM, “Iontophoresis Of Tobramycin For The Treatment Of Experimental Pseudomonas Keratitis In The Rabbit” Arch Ophthalmol, 1988; 106(2):262–265. DOI: https://doi.org/10.1001/archopht.1988.01060130276043

Hobden JA, Rootman DS, O’Callaghan RJ, Hill JM, “Iontophoretic application of tobramycin to uninfected and Pseudomonas aeruginosa-infected rabbit corneas” Antimicrob Agents Chemother, 1988; 32:978–981. DOI: https://doi.org/10.1128/aac.32.7.978

Hayden BC, Jockovich ME, Murray TG, Voigt M, Milne P, Kralinger M, Feuer WJ, Hernandez E, Parel JM, “Pharmacokinetics of systemic versus forcal carboplatin chemotherapy in the rabbit eye: possible implication in the treatment of retinoblastoma” Invest Ophthalmol Vis Sci, 2004; 45(10):3644–3649. DOI: https://doi.org/10.1167/iovs.04-0228

Behar-Cohen FF, El Aouni A, Gautier S, David G, Davis J, Chapon P, Parel JM, “Transscleral Coulomb-Controlled Iontophoresis Of Methylprednisolone Into The Rabbit Eye: Influence Of Duration Of Treatment, Current Intensity And Drug Concentration On Ocular Tissue And Fluid Levels” Exp Eye Res, 2002; 74(1):51–59. DOI: https://doi.org/10.1006/exer.2001.1098

Eljarrat-Binstock E, Raiskup F, Frucht-Pery J, Domb AJ, “Transcorneal And Transscleral Iontophoresis Of Dexamethasone Phosphate Using Drug Loaded Hydrogel” J Control Release, 2005; 106(3):386–390. DOI: https://doi.org/10.1016/j.jconrel.2005.05.020

Sekijima H, Ehara J, Hanabata Y, Suzuki T, Kimura S, Lee VHL, Morimoto Y, Ueda H, “Characterization Of Ocular Iontophoretic Drug Transport Of Ionic And Non-Ionic Compounds In Isolated Rabbit Cornea And Conjunctiva” Biol Pharm Bull, 2016; 39(6):1–10. DOI: https://doi.org/10.1248/bpb.b15-00932

Nemoto E, Takahashi H, Kobayashi D, Ueda H, Morimoto Y, “Effects Of Poly-L-Arginine On The Permeation Of Hydrophilic Compounds Through Surface Ocular Tissues” Biol Pharm Bull, 2006; 29(1):155–160. DOI: https://doi.org/10.1248/bpb.29.155

Ohtake K, Maeno T, Ueda H, Natsume H, Morimoto Y, “Poly-L-Arginine Predominantly Increases The Paracellular Permeability Of Hydrophilic Macromolecules Across Rabbit Nasal Epithelium In Vitro” Pharm Res, 2003; 20:153–160. DOI: https://doi.org/10.1023/a:1022485816755

Yamaki T, Ohtake K, Ichikawa K, Uchida M, Uchida H, Ohshima S, Juni K, Kobayashi J, Morimoto Y, Natsume H, “Poly-L-Arginine-Induced Internalization Of Tight Junction Proteins Increases The Paracellular Permeability Of The Caco-2 Cell Monolayer To Hydrophilic Macromolecules” Biol Pharm Bull, 2013; 36(36):432–441. DOI: https://doi.org/10.1248/bpb.b12-00878

De Campos AM, Diebold Y, Carvalho EL, Sánchez A, Alonso MJ, “Chitosan Nanoparticles As New Ocular Drug Delivery Systems: In Vitro Stability, In Vivo Fate, And Cellular Toxicity” Pharm Res, 2004; 21:803–810. DOI: https://doi.org/10.1023/b:pham.0000026432.75781.cb

Suzuki Y, Iga K, Yanai S, Matsumoto Y, Kawase M, Fukuda T, Adachi H, Higo N, Ogawa Y, “Iontophoretic Pulsatile Transdermal Delivery Of Human Parathyroid Hormone (1-34)” J Pharm Pharmacol, 2001; 53:1227–1234. DOI: https://doi.org/10.1211/0022357011776676

Furuse M, Sasaki H, Fujimoto K, Tsukita S, “A Single Gene Product, Claudin-1 Or -2, Reconstitutes Tight Junction Strands And Recruits Occludin In Fibroblasts” J Cell Biol, 1998; 143(2):391–401. DOI: https://doi.org/10.1083/jcb.143.2.391

Al-Sadi R, Khatib K, Guo S, Ye D, Youssef M, Ma T, “Occludin Regulates Macromolecule Flux Across The Intestinal Epithelium Tight Junction Barrier” Am J Physiol Gastrointest Liver Physiol, 2011; 300:1054–1064. DOI: https://doi.org/10.1152/ajpgi.00055.2011

Bhat M, Toledo-Velasquez D, Wang L, Malanga CJ, Ma JK, Rojanasakul Y, “Regulation of tight junction permeability by calcium mediators and cell cytoskeleton in rabbit tracheal epithelium” Pharm Res, 1993; 10: 991-997. DOI: https://doi.org/10.1023/a:1018906504944

Tokuda S, Miyazaki H, Nakajima K, Yamada T, Marunaka Y, “Hydrostatic Pressure Regulates Tight Junctions, Actin Cytoskeleton And Transcellular Ion Transport” Biochem Biophys Res Commun, 2009; 390(4):1315–1321. DOI: https://doi.org/10.1016/j.bbrc.2009.10.144

Tokuda S, Miyazaki H, Nakajima K, Yamada T, Marunaka Y, “NaCl Flux Between Apical And Basolateral Side Recruits Claudin-1 To Tight Junction Strands And Regulates Paracellular Transport” Biochem Biophys Res Commun, 2010; 393(13):390–396. DOI: https://doi.org/10.1016/j.bbrc.2010.02.002

Guy RH, Kalia YN, Delgado-Charroa MB, Merino V, López A, Marro D, “Iontophoresis: Electrorepulsion And Electroosmosis” J Control Release, 2000; 64(1–3):129–132. DOI: https://doi.org/10.1016/s0168-3659(99)00132-7

Published

2024-03-15
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How to Cite

1.
Sekijima H, Hazama Y, Kimura S, Morimoto Y, Ueda H. Application of direct electric current to the corneal and conjunctival epithelia regulates the tight junctional assembly for ocular iontophoretic drug delivery. J. Drug Delivery Ther. [Internet]. 2024 Mar. 15 [cited 2025 Oct. 25];14(3):27-38. Available from: https://www.jddtonline.info/index.php/jddt/article/view/6455

How to Cite

1.
Sekijima H, Hazama Y, Kimura S, Morimoto Y, Ueda H. Application of direct electric current to the corneal and conjunctival epithelia regulates the tight junctional assembly for ocular iontophoretic drug delivery. J. Drug Delivery Ther. [Internet]. 2024 Mar. 15 [cited 2025 Oct. 25];14(3):27-38. Available from: https://www.jddtonline.info/index.php/jddt/article/view/6455