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Mun, Ellina A.; Morrison, Peter W. J.; Williams, Adrian C.; Khutoryanskiy, Vitaliy V. (2014)
Publisher: American Chemical Society
Languages: English
Types: Article
Subjects: RM

Classified by OpenAIRE into

mesheuropmc: eye diseases, sense organs
Overcoming the natural defensive barrier functions of the eye remains one of the greatest challenges of ocular drug delivery. Cornea is a chemical and mechanical barrier preventing the passage of any foreign bodies including drugs into the eye, but the factors limiting penetration of permeants and nanoparticulate drug delivery systems through the cornea are still not fully understood. In this study, we investigate these barrier properties of the cornea using thiolated and PEGylated (750 and 5000 Da) nanoparticles, sodium fluorescein, and two linear polymers (dextran and polyethylene glycol). Experiments used intact bovine cornea in addition to bovine cornea de-epithelialized or tissues pretreated with cyclodextrin. It was shown that corneal epithelium is the major barrier for permeation; pretreatment of the cornea with β-cyclodextrin provides higher permeation of low molecular weight compounds, such as sodium fluorescein, but does not enhance penetration of nanoparticles and larger molecules. Studying penetration of thiolated and PEGylated (750 and 5000 Da) nanoparticles into the de-epithelialized ocular tissue revealed that interactions between corneal surface and thiol groups of nanoparticles were more significant determinants of penetration than particle size (for the sizes used here). PEGylation with polyethylene glycol of a higher molecular weight (5000 Da) allows penetration of nanoparticles into the stroma, which proceeds gradually, after an initial 1 h lag phase.
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    • (1) Yorio, T.; Clark, A. F.; Wax, M. B. Ocular Therapeutics; Eye on New Discoveries; Elsevier: 2008; pp 3−30.
    • (2) World Health Organization [http://www.who.int/blindness/ history/en/].
    • (3) Hornof, M.; Toropainen, E.; Uttri, A. Cell culture models of the ocular barriers. Eur. J. Pharm. Biopharm. 2005, 60, 207−225.
    • (4) Ranta, V. P.; Urtti, A. Transscleral drug delivery to the posterior eye: Prospects of pharmacokinetic modeling. Adv. Drug Delivery Rev.
    • (5) (a) Laude, A.; Tan, L. E.; Wilson, C. G.; Lascaratos, G.; Elashry, M.; Aslam, T.; Patton, N.; Dhillon, B. Intravitreal therapy for neovascular age-related macular degeneration and inter-individual variations in vitreous pharmacokinetics. Prog. Retinal Eye Res. 2010, 29, 466−475. (b) Wilson, C. G. Topical drug delivery in the eye. Exp. Eye Res. 2004, 78, 737−743. (c) Hughes, P. M.; Olejnik, O.; Chang-Lin, J.- E.; Wilson, C. G. Topical and systemic drug delivery to the posterior segments. Adv. Drug Delivery Rev. 2005, 57, 2010−2032.
    • (6) Bochot, A.; Fattal, E. Liposomes for intravitreal drug delivery: A state of the art. J. Controlled Release 2012, 161, 628−634.
    • (7) Thrimawithana, T. R.; Young, S.; Bunt, C. R.; Green, C.; Alany, R. G. Drug delivery to the posterior segment of the eye. Drug Discovery Today 2011, 16, 270−277.
    • (8) Geroski, D. H.; Edelhauser, H. F. Drug delivery for posterior segment eye disease. Invest. Ophthalmol. Visual Sci. 2000, 41, 961−964.
    • (9) Urtti, A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv. Drug Delivery Rev. 2006, 58, 1131−1135.
    • (10) Jarvinen, K.; Jarvinen, T.; Urtti, A. Ocular absorption following topical delivery. Adv. Drug Delivery Rev. 1995, 16, 3−19.
    • (11) Washington, N.; Washington, C. and Wilson, C. G.
    • Physiological Pharmaceutics. Barriers to drug absorption, 2nd ed.; Taylor and Francis: 2001; pp 249−270.
    • (12) Hillery, A. M.; Lloyd, A. W.; Swarbick, J. Drug delivery and targeting for pharmacists and pharmaceutical scientists; CRC Press: 2001; pp 329−353.
    • (13) Huang, H. S.; Schoenwald, R. D.; Lach, J. L. Corneal penetration behavior of beta-blocking agents II: assessment of barrier contributions. J. Pharm. Sci. 1983, 72, 1272−1279.
    • (14) Huang, A. J. W.; Tseng, S. C. G.; Kenyont, K. R. Paracellular permeability of corneal and conjunctival epithelia. Invest. Ophthalmol.
    • Visual Sci. 1989, 30, 684−689.
    • (15) Sahoo, S. K.; Dilnawaz, F.; Krishnakumar, S. Nanotechnology in ocular drug delivery. Drug Discovery Today 2008, 13, 144−151.
    • (16) Eljarrat-Binstock, E.; Orucov, F.; Aldouby, Y.; Frucht-Pery, J.; Domb, A. J. Charged nanoparticles delivery to the eye using hydrogel iontophoresis. J. Controlled Release 2008, 126, 156−161.
    • (17) Baba, K.; Tanaka, Y.; Kubota, A.; Kasai, H.; Yokokura, S.; Nakanishi, H.; Nishida, K. A method for enhancing the ocular penetration of eye drops using nanoparticles of hydrolyzable dye. J.
    • Controlled Release 2011, 153, 278−287.
    • (18) Campos, A. M.; Sanchez, A.; Alonso, M. J. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporine A. Int. J.
    • Pharm. 2001, 224, 159−168.
    • (19) Qu, X.; Khutoryanskiy, V. V.; Stewart, A.; Rahman, S.; Papahadjopoulos-Sternberg, B.; Dufes, C.; McCarthy, D.; Wilson, C.
    • Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude. Biomacromolecules 2006, 7, 3452−3459.
    • (20) Calvo, P.; Vila-Jato, J. L.; Alonso, M. J. Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers. Int. J. Pharm.
    • (21) Irmukhametova, G. S.; Mun, G. A.; Khutoryanskiy, V. V.
    • Thiolated mucoadhesive and PEGylated non-mucoadhesive organosilica nanoparticles from 3-mercaptopropyltrimethoxysilane. Langmuir 2011, 27, 9551−9556.
    • (22) Irmukhametova, G. S.; Fraser, B. J.; Keddie, J. L.; Mun, G. A.; Khutoryanskiy, V. V. Hydrogen-Bonding-Driven Self-Assembly of PEGylated Organosilica Nanoparticles with Poly(acrylic acid) in Aqueous Solutions and in Layer-by-Layer Deposition at Solid Surfaces.
    • Langmuir 2012, 28, 299−306.
    • (23) Mun, E. A.; Hannell, C.; Rogers, S. E.; Hole, P.; Williams, A. C.; Khutoryanskiy, V. V. On the Role of Specific Interactions in the Diffusion of Nanoparticles in Aqueous Polymer Solutions. Langmuir 2014, 30, 308−317.
    • (24) Suhonen, P.; Jarvinen, T.; Koivisto, S.; Urtti, A. Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea. Eur. J. Pharm. Sci. 1998, 6, 169−176.
    • (25) Tegtmeyer, S.; Papantoniou, I.; Muller-Goymann, C. C.
    • Reconstruction of an in vitro cornea and its use for drug permeation studies from different formulations containing pilocarpine hydrochloride. Eur. J. Pharm. Biopharm. 2001, 51, 119−125.
    • (26) Baydoun, L.; Muller-Goymann, C. C. Influence of noctenylsuccinate starch on in vitro permeation of sodium diclofenac across excised porcine cornea in comparison to Voltaren ophtha. Eur.
    • J. Pharm. Biopharm. 2003, 56, 73−79.
    • (27) Reichl, S.; Dohring, S.; Bednarz, J.; Muller-Goymann, C. C.
    • Biopharm. 2005, 60, 305−308.
    • (28) Friedrich, I.; Reichl, S.; Muller-Goymann, C. C. Drug release and permeation studies of nanosuspensions based on solidified reverse micellar solutions (SRMS). Int. J. Pharm. 2005, 305, 167−175.
    • (29) Morrison, P. W. J.; Connon, C. J.; Khutoryanskiy, V. V.
    • Cyclodextrin-Mediated Enhancement of Riboflavin Solubility and Corneal Permeability. Mol. Pharmaceutics 2013, 10, 756−762.
    • (30) Qi, H. P.; Gao, X. C.; Zhang, L. Q.; Wei, S. Q.; Bi, S.; Yang, Z.
    • C.; Cui, H. In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. Eur. J. Pharmacol. 2013, 705, 20−25.
    • (31) Jingjing, L.; Shaoying, F.; Nan, W.; Yongsheng, H.; Xiaoning, Z.; Hao, C. The effects of combined menthol and borneol on fluconazole permeation through the cornea ex vivo. Eur. J. Pharmacol. 2012, 688, 1−5.
    • (32) Diebold, Y.; Calonge, M. Applications of nanoparticles in ophthalmology. Prog. Retinal Eye Res. 2010, 29, 596−609.
    • (33) Loftsson, T.; Masson, M. Cyclodextrins in topical drug formulations: theory and Practice. Int. J. Pharm. 2001, 225, 15−30.
    • (34) Bary, A. R.; Tucker, I. G.; Davies, N. M. Considerations in the use of hydroxypropyl-b-cyclodextrin in the formulation of aqueous ophthalmic solutions of hydrocortisone. Eur. J. Pharm. Biopharm.
    • (35) Hao, J.; Li, S. K.; Liu, C.-Y.; Kao, W. W. Y. Electrically assisted delivery of macromolecules into the corneal epithelium. Exp. Eye Res.
    • (36) Kaur, H.; Ahuja, M.; Kumar, S.; Dilbaghi, N. Carboxymethyl tamarind kernel polysaccharide nanoparticles for ophthalmic drug delivery. Int. J. Biol. Macromol. 2012, 50, 833−839.
    • (37) Sharma, R.; Ahuja, M.; Kaur, H. Thiolated pectin nanoparticles: Preparation, characterization and ex vivo corneal permeation study.
    • Carbohydr. Polym. 2012, 87, 1606−1610.
    • (38) (a) Muchtar, S.; Abdulrazik, M.; Frucht-Pery, J.; Benita, S. Exvivo permeation study of indomethacin from a submicron emulsion through albino rabbit cornea. J. Controlled Release 1997, 44, 55−64.
    • Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration. Mol. Vision 2008, 14, 150−160.
    • (39) Khutoryanskiy, V. V. Advances in Mucoadhesion and Mucoadhesive Polymers. Macromol. Biosci. 2011, 11, 748−764.
    • (40) Prydal, J. I.; Kerr-Muir, M. G.; Dilly, P. N. Comparison of tear film thickness in three species determined by the glass fibre method and confocal microscopy. Eye 1993, 7, 472−475.
    • (41) Bernkop-Schnurch, A. Thiomers: A new generation of mucoadhesive polymers. Adv. Drug Delivery Rev. 2005, 57, 1569−1582.
    • (42) Deutel, B.; Greindl, M.; Thaurer, M.; Bernkop-Schnürch, A.
    • Novel Insulin Thiomer Nanoparticles: In Vivo Evaluation of an Oral Drug Delivery System. Biomacromolecules 2008, 9, 278−285.
    • (43) Wollensak, G.; Spoerl, E.; Seiler, T. Riboflavin/Ultraviolet-Ainduced Collagen Crosslinking for the Treatment of Keratoconus. Am.
    • J. Ophthalmol. 2003, 135, 620−627.
    • (44) Newsome, D. A.; Gross, J.; Hassell, J. R. Human corneal stroma contains three distinct collagens. Invest. Ophthalmol. Visual Sci. 1982, 22, 376−381.
    • (45) Meek, K. M.; Fullwood, N. J. Corneal and scleral collagensa microscopist's perspective. Micron 2001, 32, 261−272.
    • (46) Meek, K. M.; Boote, C. The organization of collagen in the corneal stroma. Exp. Eye Res. 2004, 78, 503−512.
    • (47) Saika, S.; Ooshima, A.; Shima, K.; Tanaka, S.; Ohnishi, Y.
    • J. Ophthalmol. 1996, 40, 303−309.
    • (48) Lai, S. K.; Wang, Y.-Y.; Hanes, J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv.
    • Drug Delivery Rev. 2009, 61, 58−171.
    • (49) Xu, Q.; Boylan, N. J.; Cai, S.; Miao, B.; Patel, H.; Hanes, J.
    • Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus. J. Controlled Release 2013, 170, 279−286.
    • (50) Suh, J.; Choy, K.-L.; Lai, S. K.; Suk, J. S.; Tang, B. C.; Prabhu, S.; Hanes, J. PEGylation of nanoparticles improves their cytoplasmic transport. Int. J. Nanomed. 2007, 2, 735−741.
    • (51) Xu, Q.; Boylan, N. J.; Suk, J. S.; Wang, Y.-Y.; Nance, E. A.; Yang, J.-C.; McDonnell, P. J.; Cone, R. A.; Duh, E. J.; Hanes, J. Nanoparticle diffusion in, and microrheology of, the bovine vitreous ex vivo. J.
    • Controlled Release 2013, 167, 76−84.
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