Nano Research

, Volume 8, Issue 2, pp 621–635 | Cite as

Phenylboronic acid modified mucoadhesive nanoparticle drug carriers facilitate weekly treatment of experimentallyinduced dry eye syndrome

  • Shengyan Liu
  • Chu Ning Chang
  • Mohit S. Verma
  • Denise Hileeto
  • Alex Muntz
  • Ulrike Stahl
  • Jill Woods
  • Lyndon W. Jones
  • Frank X. Gu
Research Article


Topical formulations, commonly applied for treatment of anterior eye diseases, require frequent administration due to rapid clearance from the ocular surface, typically through the lacrimal drainage system or through over-spillage onto the lids. We report on a mucoadhesive nanoparticle drug delivery system that may be used to prolong the precorneal residence time of encapsulated drugs. The nanoparticles were formed from self-assembly of block copolymers composed of poly(d, l-lactide) and Dextran. The enhanced mucoadhesion properties were achieved by surface functionalizing the nanoparticles with phenylboronic acid. The nanoparticles encapsulated up to 12 wt.% of Cyclosporine A (CycA) and sustained the release for up to five days at a clinically relevant dose, which led us to explore the therapeutic efficacy of the formulation with reduced administration frequency. By administering CycA-loaded nanoparticles to dry eye-induced mice once a week, inflammatory infiltrates were eliminated and the ocular surface completely recovered. The same once a week dosage of the nanoparticles also showed no signs of physical irritation or inflammatory responses in acute (1 week) and chronic (12 weeks) studies in healthy rabbit eyes. These findings indicate that the nanoparticles may significantly reduce the frequency of administration for effective treatment of anterior eye diseases without causing ocular irritation.


biocompatibility copolymer mucoadhesion nanoparticle drug delivery ophthalmology 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

12274_2014_547_MOESM1_ESM.pdf (1.1 mb)
Supplementary material, approximately 1.05 MB.


  1. [1]
    Gaudana, R.; Jwala, J.; Boddu, S. H. S.; Mitra, A. K. Recent perspectives in ocular drug delivery. Pharm. Res. 2009, 26, 1197–1216.CrossRefGoogle Scholar
  2. [2]
    Diebold, Y.; Calonge, M. Applications of nanoparticles in ophthalmology. Prog. Retin. Eye Res. 2010, 29, 596–609.CrossRefGoogle Scholar
  3. [3]
    Liu, S.; Jones, L.; Gu, F. X. Nanomaterials for ocular drug delivery. Macromol. Biosci. 2012, 12, 608–620.CrossRefGoogle Scholar
  4. [4]
    Cho, H. K.; Cheong, I. W.; Lee, J. M.; Kim, J. H. Polymeric nanoparticles, micelles and polymersomes from amphiphilic block copolymer. Korean. J. Chem. Eng. 2010, 27, 731–740.CrossRefGoogle Scholar
  5. [5]
    Subbiah, R.; Veerapandian, M.; Yun, K. S. Nanoparticles: Functionalization and multifunctional applications in biomedical sciences. Curr. Med. Chem. 2010, 17, 4559–4577.CrossRefGoogle Scholar
  6. [6]
    Gavini, E.; Chetoni, P.; Cossu, M.; Alvarez, M. G.; Saettone, M. F.; Giunchedi, P. PLGA microspheres for the ocular delivery of a peptide drug, vancomycin using emulsification/spray-drying as the preparation method: In vitro/in vivo studies. Eur. J. Pharm. Biopharm. 2004, 57, 207–212.CrossRefGoogle Scholar
  7. [7]
    Yoncheva, K.; Vandervoort, J.; Ludwig, A. Development of mucoadhesive poly(lactide-co-glycolide) nanoparticles for ocular application. Pharm. Dev. Technol. 2011, 16, 29–35.CrossRefGoogle Scholar
  8. [8]
    Gupta, H.; Aqil, M.; Khar, R. K.; Ali, A.; Bhatnagar, A.; Mittal, G. Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery. Nanomed-nanotechnol. 2010, 6, 324–333.CrossRefGoogle Scholar
  9. [9]
    Lee, V. H. L. Review: New directions in the optimization of ocular drug delivery. J. Ocul. Pharmacol. 1990, 6, 157–164.CrossRefGoogle Scholar
  10. [10]
    Zimmer, A.; Kreuter, J. Microspheres and nanoparticles used in ocular delivery systems. Adv. Drug Deliv. Rev. 1995, 16, 61–73.CrossRefGoogle Scholar
  11. [11]
    Bazile, D.; Prud□homme, C.; Bassoullet, M. T.; Marlard, M.; Spenlehauer, G.; Veillard, M. Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system. J. Pharm. Sci. 1995, 84, 493–498.CrossRefGoogle Scholar
  12. [12]
    Dhar, S.; Gu, F. X.; Langer, R.; Farokhzad, O. C.; Lippard, S. J. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17356–17361.CrossRefGoogle Scholar
  13. [13]
    Dong, Y. and Feng, S.-S. In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherapy. Biomaterials 2007, 28, 4154–4160.CrossRefGoogle Scholar
  14. [14]
    Esmaeili, F.; Ghahremani, M. H.; Ostad, S. N.; Atyabi, F.; Seyedabadi, M.; Malekshahi, M. R.; Amini, M.; Dinarvand, R. Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA-PEG-folate conjugate. J. Drug Target. 2008, 16, 415–423.CrossRefGoogle Scholar
  15. [15]
    Gao, Y.; Sun, Y.; Ren, F.; Gao, S. PLGA-PEG-PLGA hydrogel for ocular drug delivery of dexamethasone acetate. Drug Dev. Ind. Pharm. 2010, 36, 1131–1138.CrossRefGoogle Scholar
  16. [16]
    Vega, E.; Egea, M. A.; Calpena, A. C.; Espina, M.; Garcia, M. L. Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA-PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery. Int. J. Nanomedicine 2012, 7, 1357–1371.CrossRefGoogle Scholar
  17. [17]
    Yang, J.; Yan, J.; Zhou, Z.; Amsden, B. G. Dithiol-PEG-PDLLA micelles: Preparation and evaluation as potential topical ocular delivery vehicle. Biomacromolecules 2014, 15, 1346–1354CrossRefGoogle Scholar
  18. [18]
    Verma, M. S.; Liu, S.; Chen, Y. Y.; Meerasa, A.; Gu, F. X. Size-tunable nanoparticles composed of Dextran-b-poly(d,l-lactide) for drug delivery applications. Nano. Res. 2012, 5, 49–61.CrossRefGoogle Scholar
  19. [19]
    Goodwin, A. P.; Tabakman, S. M.; Welsher, K.; Sherlock, S. P.; Prencipe, G.; Dai, H. Phospholipid-Dextran with a single coupling point: A useful amphiphile for functionalization of nanomaterials. J. Am. Chem. Soc. 2009, 131, 289–296.CrossRefGoogle Scholar
  20. [20]
    Ludwig, A. The use of mucoadhesive polymers in ocular drug delivery. Adv. Drug Deliv. Rev. 2005, 57, 1595–1639.CrossRefGoogle Scholar
  21. [21]
    Shaikh, R.; Raj Singh, T. R.; Garland, M. J.; Woolfson, A. D.; Donnelly, R. F. Mucoadhesive drug delivery systems. J. Pharm. Bioall. 2011, 3, 89–100.CrossRefGoogle Scholar
  22. [22]
    Khutoryanskiy, V. V. Advances in mucoadhesion and mucoadhesive polymers. Macromol. Biosci. 2011, 11, 748–764.CrossRefGoogle Scholar
  23. [23]
    du Toit, L. C.; Pillay, V.; Choonara, Y. E.; Govender, T.; Carmichael, T. Ocular drug delivery-A look towards nanobioadhesives. Expert Opin. Drug Deliv. 2011, 8, 71–94.CrossRefGoogle Scholar
  24. [24]
    Li, N.; Zhuang, C.; Wang, M.; Sui, C.; Pan, W. Low molecular weight chitosan-coated liposomes for ocular drug delivery: In vitro and in vivo studies. Drug Deliv. 2012, 19, 28–35.CrossRefGoogle Scholar
  25. [25]
    Mahmoud, A. A.; El-Feky, G. S.; Kamel, R.; Awad, G. E. A. Chitosan/sulfobutylether-beta-cyclodextrin nanoparticles as a potential approach for ocular drug delivery. Int. J. Pharm. 2011, 413, 229–236.CrossRefGoogle Scholar
  26. [26]
    Abdelbary, G. Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes. Pharm. Dev. Technol. 2011, 8, 44–56.CrossRefGoogle Scholar
  27. [27]
    Li, N.; Zhuang, C.; Wang, M.; Sun, X.; Nie, S.; Pan, W. Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery. Int. J. Pharm. 2009, 379, 131–138.CrossRefGoogle Scholar
  28. [28]
    De 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 cyclosporin A. Int. J. Pharm. 2001, 224, 159–168.CrossRefGoogle Scholar
  29. [29]
    Matsumoto, A.; Cabral, H.; Sato, N.; Kataoka, K.; Miyahara, Y. Assessment of tumor metastasis by the direct determination of cell-membrane sialic acid expression. Angew. Chem. Int. Edit. 2010, 49, 5494–5497.CrossRefGoogle Scholar
  30. [30]
    Matsumoto, A.; Sato, N.; Cabral, H.; Kataoka, K.; Miyahara, Y. Self-assembled molecular gate field effect transistor for label free sialic acid detection at cell membrane. Eurosensor XXIV Conference 2010, 5, 926–929.Google Scholar
  31. [31]
    Matsumoto, A.; Sato, N.; Kataoka, K.; Miyahara, Y. Noninvasive sialic acid detection at cell membrane by using phenylboronic acid modified self-assembled monolayer gold electrode. J. Am. Chem. Soc. 2009, 131, 12022–12023.CrossRefGoogle Scholar
  32. [32]
    Ivanov, A. E.; Eccles, J.; Panahi, H. A.; Kumar, A.; Kuzimenkova, M. V.; Nilsson, L.; Bergenstahl, B.; Long, N.; Phillips, G. J.; Mikhalovsky, S. V.; et al. Boronate-containing polymer brushes: Characterization, interaction with saccharides and mammalian cancer cells. J. Biomed. Mater. Res. A. 2009, 88A, 213–225.CrossRefGoogle Scholar
  33. [33]
    Liu, A.; Peng, S.; Soo, J. C.; Kuang, M.; Chen, P.; Duan, H. Quantum dots with phenylboronic acid tags for specific labeling of sialic acids on living cells. Anal. Chem. 2011, 83, 1124–1130.CrossRefGoogle Scholar
  34. [34]
    Otsuka, H.; Uchimura, E.; Koshino, H.; Okano, T.; Kataoka, K. Anomalous binding profile of phenylboronic acid with N-acetylneuraminic acid (Neu5Ac) in aqueous solution with varying pH. J. Am. Chem. Soc. 2003, 125, 3493–3502.CrossRefGoogle Scholar
  35. [35]
    Cheng, C.; Zhang, X.; Wang, Y.; Sun, L.; Li, C. Phenylboronic acid-containing block copolymers: Synthesis, self-assembly, and application for intracellular delivery of proteins. New J. Chem. 2012, 36, 1413–1421.CrossRefGoogle Scholar
  36. [36]
    Deshayes, S.; Cabral, H.; Ishii, T.; Miura, Y.; Kobayashi, S.; Yamashita, T.; Matsumoto, A.; Miyahara, Y.; Nishiyama, N.; Kataoka, K. Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J. Am. Chem. Soc. 2013, 135, 15501–15507.CrossRefGoogle Scholar
  37. [37]
    Liu, S.; Jones, L.; Gu, F. X. Development of mucoadhesive drug delivery system using phenylboronic acid functionalized poly(d,l-lactide)-b-Dextran nanoparticles. Macromol. Biosci. 2012, 12, 1622–1626.CrossRefGoogle Scholar
  38. [38]
    Shen, J.; Wang, Y.; Ping, Q.; Xiao, Y.; Huang, X. Mucoadhesive effect of thiolated PEG stearate and its modified NLC for ocular drug delivery. J. Controlled Release 2009, 137, 217–223.CrossRefGoogle Scholar
  39. [39]
    Vijay, A. K.; Sankaridurg, P.; Zhu, H.; Willcox, M. D. P. Guinea pig models of acute keratitis responses. Cornea 2009, 28, 1153–1159.CrossRefGoogle Scholar
  40. [40]
    Cole, N.; Hume, E. B. H.; Vijay, A. K.; Sankaridurg, P.; Kumar, N.; Willcox, M. D. P. In vivo performance of melimine as an antimicrobial coating for contact lenses in models of CLARE and CLPU. Invest. Ophthalmol. Vis. Sci. 2010, 5, 390–395.CrossRefGoogle Scholar
  41. [41]
    Diebold, Y.; Jarrin, M.; Saez, V.; Carvalho, E. L. S.; Orea, M.; Calonge, M.; Seijo, B.; Alonso, M. J. Ocular drug delivery by liposome-chitosan nanoparticle complexes (LCS-NP). Biomaterials 2007, 28, 1553–1564.CrossRefGoogle Scholar
  42. [42]
    Dursun, D.; Wang, M.; Monroy, D.; Li, D. Q.; Lokeshwar, B. L.; Stern, M. E.; Pflugfelder, S. C. A mouse model of keratoconjunctivitis sicca. Invest. Ophthalmol. Vis. Sci. 2002, 43, 632–638.Google Scholar
  43. [43]
    Bromba, C.; Carrie, P.; Chui, J. K. W.; Fyles, T. M. Phenyl boronic acid complexes of diols and hydroxyacids. Supramol. Chem. 2009, 21, 81–88.CrossRefGoogle Scholar
  44. [44]
    Shiomori, K.; Ivanov, A. E.; Galaev, I. Y.; Kawano, Y.; Mattiasson, B. Thermoresponsive properties of sugar sensitive copolymer of N-isopropylacrylamide and 3-(acrylamido)phenylboronic acid. Macromol. Chem. Physic. 2004, 205, 27–34.CrossRefGoogle Scholar
  45. [45]
    Kitano, S.; Kataoka, K.; Koyama, Y.; Okano, T.; Sakurai, Y. Glucose-responsive complex-formation between poly(vinyl alcohol) and poly(n-vinyl-2-pyrrolidone) with pendent phenylboronic acid moieties. Makromol. Chem-Rapid. 1991, 12, 227–233.CrossRefGoogle Scholar
  46. [46]
    Wang, Y.; Zhang, X.; Han, Y.; Cheng, C.; Li, C. pH- and glucose-sensitive glycopolymer nanoparticles based on phenylboronic acid for triggered release of insulin. Carbohydr. Polym. 2012, 89, 124–131.CrossRefGoogle Scholar
  47. [47]
    Lee, D.; Shirley, S. A.; Lockey, R. F.; Mohapatra, S. S. Thiolated chitosan nanoparticles enhance anti-inflammatory effects of intranasally delivered theophylline. Resp. Res. 2006, 7, 112.CrossRefGoogle Scholar
  48. [48]
    Yuan, X.-B.; Li, H.; Yuan, Y. Preparation of cholesterol-modified chitosan self-aggregated nanoparticles for delivery of drugs to ocular surface. Carbohydr. Polym. 2006, 65, 337–345.CrossRefGoogle Scholar
  49. [49]
    Hermans, K.; Van Den Plas, D.; Schreurs, E.; Weyenberg, W.; Ludwig, A. Cytotoxicity and anti-inflammatory activity of Cyclosporine A loaded PLGA nanoparticles for ocular use. Pharmazie 2014, 69, 32–37.Google Scholar
  50. [50]
    Shen, J.; Deng, Y.; Jin, X.; Ping, Q.; Su, Z.; Li, L. Thiolated nanostructured lipid carriers as a potential ocular drug delivery system for Cyclosporine A: Improving in vivo ocular distribution. Int. J. Pharm. 2010, 402, 248–253.CrossRefGoogle Scholar
  51. [51]
    Aksungur, P.; Demirbilek, M.; Denkbas, E. B.; Vandervoort, J.; Ludwig, A.; Unlu, N. Development and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies. J. Controlled Release 2011, 151, 286–294.CrossRefGoogle Scholar
  52. [52]
    Basaran, E.; Yenilmez, E.; Berkman, M. S.; Buyukkoroglu, G.; Yazan, Y. Chitosan nanoparticles for ocular delivery of Cyclosporine A. J. Microencapsul. 2014, 31, 49–57.CrossRefGoogle Scholar
  53. [53]
    Dong, Y. C.; Feng, S. S. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials 2004, 25, 2843–2849.CrossRefGoogle Scholar
  54. [54]
    Musumeci, T.; Ventura, C. A.; Giannone, I.; Ruozi, B.; Montenegro, L.; Pignatello, R.; Puglisi, G. PLA/PLGA nanoparticles for sustained release of docetaxel. Int. J. Pharm. 2006, 325, 172–179.CrossRefGoogle Scholar
  55. [55]
    Francis, M. F.; Lavoie, L.; Winnik, F. M.; Leroux, J.-C. Solubilization of cyclosporin A in Dextran-g-polyethyleneglycolalkyl ether polymeric micelles. Eur. J. Pharm. Biopharm. 2003, 56, 337–346.CrossRefGoogle Scholar
  56. [56]
    Aliabadi, H. M.; Mahmud, A.; Sharifabadi, A. D.; Lavasanifar, A. Micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) as vehicles for the solubilization and controlled delivery of Cyclosporine A. J. Controlled Release 2005, 104, 301–311.CrossRefGoogle Scholar
  57. [57]
    Velluto, D.; Demurtas, D.; Hubbell, J. A. PEG-b-PPS diblock copolymer aggregates for hydrophobic drug solubilization and release: Cyclosporin A as an example. Mol. Pharm. 2008, 5, 632–642.CrossRefGoogle Scholar
  58. [58]
    Mondon, K.; Zeisser-Labouebe, M.; Gurny, R.; Moeller, M. Novel cyclosporin A formulations using MPEG-hexyl-substituted polylactide micelles: A suitability study. Eur. J. Pharm. Biopharm. 2011, 77, 56–65.CrossRefGoogle Scholar
  59. [59]
    Yang, W. Q.; Gao, X. M.; Wang, B. H. Boronic acid compounds as potential pharmaceutical agents. Med. Res. Rev. 2003, 23, 346–368.CrossRefGoogle Scholar
  60. [60]
    Toshida, H.; Nakayasu, K.; Kanai, A. Effect of cyclosporin A eyedrops on tear secretion in rabbit. Jpn. J. Ophthalmol. 1998, 42, 168–173.CrossRefGoogle Scholar
  61. [61]
    Stern, M. E.; Gao, J. P.; Siemasko, K. F.; Beuerman, R. W.; Pflugfelder, S. C. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp. Eye Res. 2004, 78, 409–416.CrossRefGoogle Scholar
  62. [62]
    Keklikci, U.; Soker, S. I.; Sakalar, Y. B.; Unlu, K.; Ozekinci, S.; Tunik, S. Efficacy of topical cyclosporin A 0.05% in conjunctival impression cytology specimens and clinical findings of severe vernal keratoconjunctivitis in children. Jpn. J. Ophthalmol. 2008, 52, 357–362.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Shengyan Liu
    • 1
    • 2
  • Chu Ning Chang
    • 1
  • Mohit S. Verma
    • 1
    • 2
  • Denise Hileeto
    • 3
  • Alex Muntz
    • 3
  • Ulrike Stahl
    • 3
  • Jill Woods
    • 3
  • Lyndon W. Jones
    • 2
    • 3
  • Frank X. Gu
    • 1
    • 2
  1. 1.Department of Chemical EngineeringUniversity of WaterlooWaterlooCanada
  2. 2.Waterloo Institute for NanotechnologyUniversity of WaterlooWaterlooCanada
  3. 3.Centre for Contact Lens ResearchUniversity of WaterlooWaterlooCanada

Personalised recommendations