OJOph  Vol.3 No.4 , November 2013
Nanobiotechnology in the Management of Glaucoma
Abstract: As the prevalence of glaucoma continues to rise, clinicians and researchers are confronted with an age-old problem: how to reduce risk factors and preserve vision in glaucoma. Current management options revolve around a validated paradigm—intraocular pressure reduction. Active investigations to improve drug delivery efficacy and surgical outcomes are flourishing. This article aims to provide the interested readers with a review of recent discoveries in nanobiotechnology for the management of glaucoma. Targeted drug-delivery systems using mesoscale vectors demonstrate promising delivery profiles. The utility of nanoparticulate therapies to support retinal ganglion cell survival is being investigated. Studies to modulate tissue regeneration and remodeling and improve post-trabeculectomy outcomes are underway. Though these modalities promise new avenues to manage glaucoma, immediate market availability is not anticipated soon.
Cite this paper: Nguyen, P. , Huang, A. and Yiu, S. (2013) Nanobiotechnology in the Management of Glaucoma. Open Journal of Ophthalmology, 3, 127-133. doi: 10.4236/ojoph.2013.34027.

[1]   S. J. Gedde, J. C. Schiffman, W. J. Feuer, et al., (Tube versus Trabeculectomy Study Group), “Three-Year Follow-Up of the Tube versus Trabeculectomy Study,” American Journal of Ophthalmology, Vol. 148, No. 5, 2009, pp. 670-684.

[2]   H. A. Quigley, “Glaucoma,” Lancet, Vol. 377, No. 9774, 2011, pp. 1367-1377.

[3]   M. G. Hattenhauer, D. H. Johnson, H. H. Ing, et al., “The Probability of Blindness from Open-Angle Glaucoma,” Ophthalmology, Vol. 105, No. 9, 1998, pp. 2099-2104.

[4]   M. A. Kass, D. K. Heuer, E. J. Higginbotham, et al., (For the Ocular Hypertension Treatment Study Group), “A Randomized Trial Determines That Topical Ocular Hypotensive Medication Delays or Prevents the Onset of Primary Open-Angle Glaucoma,” Archives of Ophthalmology, Vol. 120, No. 6, 2002, pp. 701-713.

[5]   S. Miglior, T. Zeyen, N. Pfeiffer, et al., “Results of the European Glaucoma Prevention Study,” Ophthalmology, Vol. 112, No. 9, 2005, pp. 366-375.

[6]   J. Burr, A. Azuara-Blanco and A. Avenell, “Medical versus Surgical Interventions for Open Angle Glaucoma,” Cochrane Database of Systematic Reviews, Vol. 18, 2005, Article ID: CD004399.

[7]   M. C. Leske, A. Heijl, L. Hyman, et al., “Predictors of Long-Term Progression in the Early Manifest Glaucoma Trial,” Ophthalmology, Vol. 114, No. 11, 2007, pp. 1965-1972.

[8]   M. A. Kass, M. O. Gordon, F. Gao, et al., (For the Ocular Hypertension Treatment Study Group), “Delaying Treatment of Ocular Hypertension,” Archives of Ophthalmology, Vol. 128, No. 3, 2010, pp. 276-287.

[9]   A. C. S. Crichton, P. Harasymowycz, C. M. L. Hutnik, et al., “Effectiveness of Dorzolamide-Timolol (Cosopt) in Patients Who Were Treatment Naive for Open-Angle Glaucoma or Ocular Hypertension: The COSOPT First-Line Study,” Journal of Ocular Pharmacology and Therapeutics, Vol. 26, No. 5, 2010, pp. 503-511.

[10]   D. C. Musch, B. W. Gillespie, P. R. Lichter, et al., “Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study: The Impact of Treatment and Other Baseline Factors,” Ophthalmology, Vol. 116, No. 2, 2009, pp. 200-207.

[11]   L. J. Katz, W. C. Steinmann, A. Kabir, et al., “Selective Laser Trabeculoplasty versus Medical Therapy as Initial Treatment of Glaucoma: A Prospective, Randomized Trial,” Journal of Glaucoma, Vol. 21, No. 7, 2011, pp. 460-468.

[12]   N. M. Davies, “Biopharmaceutical Considerations in Topical Ocular Drug Delivery,” Clinical and Experimental Pharmacology and Physiology, Vol. 27, No. 7, 2000, pp. 558-562.

[13]   T. Tsai, A. L. Robin and J. P. Smith III, “An Evaluation of How Glaucoma Patients Use Topical Medications: A Pilot Study,” Transactions of the American Ophthalmological Society, Vol. 105, 2007, pp. 29-33.

[14]   C. M. Olthoff, J. G. Hoevenaars, B. W. van den Borne, et al., “Prevalence and Determinants of Non-Adherence to Topical Hypotensive Treatment in Dutch Glaucoma Patients,” Graefe’s Archive for Clinical and Experimental Ophthalmology, Vol. 247, No. 2, 2009, pp. 235-243.

[15]   R. Gupta, B. Patil, B. M. Shah, et al., “Evaluating Eye Drop Instillation Technique in Glaucoma Patients,” Journal of Glaucoma, Vol. 21, No. 3, 2012, pp. 189-192.

[16]   F. C. Hugues and C. Le Jeunne, “Systemic and Local Tolerability of Ophthalmic Drug Formulations. An Update,” Drug Safety, Vol. 8, No. 5, 1993, pp. 365-380.

[17]   G. Walters and R. H. Taylor, “Severe Systemic Toxicity Caused by Brimonidine Drops in an Infant with Presumed Juvenile Xanthogranuloma,” Eye, Vol. 13, 1999, pp. 797-798.

[18]   J. O. Carlsen, N. A. Zabriskie, Y. H. Kwon, et al., “Apparent Central Nervous System Depression in Infants after the Use of Topical Brimonidine,” American Journal of Ophthalmology, Vol. 128, No. 2, 1999, pp. 255-256.

[19]   R. J. Bowman, J. Cope and K. K. Nischal, “Ocular and Systemic Side Effects of Brimonidine 0.2% Eye Drops (Alphagan) in Children,” Eye, Vol. 18, 2004, pp. 24-26.

[20]   A. P. Demayo and M. M. Reidenberg, “Grand Mal Seizure in a Child 30 Minutes after Cyclogyl (Cyclopentolate Hydrochloride) and 10% Neo-Synephrine (Phenylephrine Hydrochloride) Eye Drops Were Instilled,” Pediatrics, Vol. 113, No. 5, 2004, pp. e499-e500.

[21]   R. F. Wang, D. J. Gagliuso and S. M. Podos, “Effect of Flunarizine, a Calcium Channel Blocker, on Intraocular Pressure and Aqueous Humor Dynamics in Monkeys,” Journal of Glaucoma, Vol. 17, No. 1, 2008, pp. 73-78.

[22]   O. M. Koo, I. Rubinstein and H. Onyuksel, “Role of Nanotechnology in Targeted Drug Delivery and Imaging: A Concise Review,” Nanomedicine, Vol. 1, No. 3, 2005, pp. 193-212.

[23]   P. Nguyen, M. Meyyappan and S. C. Yiu, “Applications of Nanobiotechnology in Ophthalmology—Part I,” Ophthalmic Research, Vol. 44, 2010, pp. 1-16.

[24]   R. A. Petros and J. M. DeSimone, “Strategies in the Design of Nanoparticles for Therapeutic Applications,” Nature Reviews Drug Discovery, Vol. 9, 2010, pp. 615-627.

[25]   J. P. Adler-Moore and R. T. Proffitt, “Development, Characterization, Efficacy and Mode of Action of Ambisome, a Unilamellar Liposome Formulation of Amphotericin B,” Journal of Liposome Research, Vol. 3, No. 3, 1993, pp. 429-450.

[26]   K. Morand, A. C. Bartoletti, A. Bochot, et al., “Liposomal Amphotericin B Eye Drops to Treat Fungal Keratitis: Physico-Chemical and Formulation Stability,” International Journal of Pharmaceutics, Vol. 344, No. 1-2, 2007, pp. 150-153.

[27]   P. Chetoni, S. Rossi, S. Burgalassi, et al., “Comparison of Liposome-Encapsulated Acyclovir with Acyclovir Ointment: Ocular Pharmacokinetics in Rabbits,” Journal of Ocular Pharmacology and Therapeutics, Vol. 20, No. 2, 2004, pp. 169-177.

[28]   K. M. Hosny, “Optimization of Gatifloxacin Liposomal Hydrogel for Enhanced Transcorneal Permeation,” Journal of Liposome Research, Vol. 20, No. 1, 2010, pp. 31-37.

[29]   K. M. Hosny, “Ciprofloxacin as Ocular Liposomal Hydrogel,” AAPS PharmSciTech, Vol. 11, No. 1, 2010, pp. 241-246.

[30]   F. S. Habib, E. A. Fouad, M. S. Abdel-Rhaman, et al., “Liposomes as an Ocular Delivery System of Fluconazole: In-Vitro Studies,” Acta Ophthalmologica, Vol. 88, No. 8, 2010, pp. 901-904.

[31]   O. N. El-Gazayerly and A. H. Hikal, “Preparation and Evaluation of Acetazolamide Liposomes as an Ocular Delivery System,” International Journal of Pharmaceutics, Vol. 158, No. 2, 1997, pp. 121-127.

[32]   D. Aggarwal, A. Garg and I. P. Kaur, “Development of a Topical Niosomal Preparation of Acetazolamide: Preparation and Evaluation,” Journal of Pharmacy and Pharmacology, Vol. 56, No. 12, 2004, pp. 1509-1517.

[33]   A. S. Guinedi, N. D. Mortada, S. Mansour, et al., “Preparation and Evaluation of Reverse-Phase Evaporation and Multilamellar Niosomes as Ophthalmic Carriers of Acetazolamide,” International Journal of Pharmaceutics, Vol. 306, No. 1-2, 2005, pp. 71-82.

[34]   R. M. Hathout, S. Mansour, N. D. Mortada, et al., “Liposomes as an Ocular Delivery System for Acetazolamide: in Vitro and in Vivo Studies,” AAPS PharmSciTech, Vol. 8, No. 1, 2007, pp. E1-E12.

[35]   S. P. Vyas, N. Mysore, V. Jaitely, et al., “Discoidal Niosome Based Controlled Ocular Delivery of Timolol Maleate,” Pharmazie, Vol. 53, No. 7, 1998, pp. 466-469.

[36]   I. P. Kaur, D. Aggarwal, H. Singh and S. Kakkar, “Improved Ocular Absorption Kinetics of Timolol Maleate Loaded into a Bioadhesive Niosomal Delivery System,” Graefe’s Archive for Clinical and Experimental Ophthalmology, Vol. 248, No. 10, 2010, pp. 1467-1472.

[37]   P. Prabhu, K. R. Nitish, M. Koland, N. Harish, K. Vijayanarayan, G. Dhondge and R. Charyulu, “Preparation and Evaluation of Nano-Vesicles of Brimonidine Tartrate as an Ocular Drug Delivery System,” Journal of Young Pharmacists, Vol.2, No. 4, 2010, pp. 356-361.

[38]   S Maiti, S Paul, R Mondol, S. Ray and B. Sa, “Nanovesicular formulation of Brimonidine Tartrate for the Management of Glaucoma: In Vitro and in Vivo Evaluation,” AAPS PharmSciTech, Vol.12, No. 2, 2011, pp. 755-763.

[39]   M. Sabyasachi, P. Sayon, M. Ranjit, R. Somasree and S. Biawanath, “Nanovesicular Formulation of Brimonidine Tartrate for the Management of Glaucoma: In Vitro and in Vivo Evaluation,” AAPS PharmSciTech, Vol. 12, No. 2, 2011, pp. 755-763.

[40]   C. Sturesson, J. Carlfors, K. Edsman and M. Andersson, “Preparation of Biodegradable Poly(lactic-co-glycolic) Acid Microspheres and Their in Vitro Release of Timolol Maleate,” International Journal of Pharmaceutics, Vol. 89, No. 3, 1993, pp. 235-244.

[41]   J. P. Bertram, S.S. Saluja, J. McKain and E. B. Lavik, “Sustained Delivery of Timolol Maleate from Poly(lactic-co-glycolic acid)/Poly(lactic acid) Microspheres for over 3 Months,” Journal of Microencapsulation, Vol. 26, No. 1, 2009, pp. 18-26.

[42]   G. G. Giordano, P. Chevez-Barrios, M. F. Refojo and C. A. Garcia, “Biodegradation and Tissue Reaction to Intravitreous BiodeGradable Poly(D,L-lactic-co-glycolic)-Acid Microsphere,” Current Eye Research, Vol. 14, No. 9, 1995, pp. 761-768.

[43]   R. Chen, Y. Qian, R Li,Q. Zhang, D. F. Liu, M. Wang and Q. W. Xu, “Methazolamide Calcium Phosphate Nanoparticles in An Ocular Delivery System,” Yakugaku Zasshi, Vol. 130, No. 3, 2010, pp. 419-424.

[44]   R. Li, S. Jiang, D. Liu, X. Y. Bi, F. Z. Wang, Q. Zhang and Q. W. Xu, “A Potential New Therapeutic System for Glaucoma: Solid Lipid Nanoparticles Containing Methazolamide,” Journal of Microencapsulation, Vol. 28, No. 2, 2011, pp. 134-141.

[45]   S. K. Motwani, S. Chopra, S. Talegaonkar, K. Kohli, F. J. Ahmad and R. K. Khar, “Chitosan-Sodium Alginate Nanoparticles as Submicroscopic Reservoirs for Ocular Delivery: Formulation, Optimisation and in Vitro Characterization,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 68, No. 3, 2008, pp. 513-525.

[46]   X. B. Yuan, Y. B. Yuan, W. Jiang, et al., “Preparation of Rapamycin-Loaded Chitosan/PLA Nanoparticles for Immunosuppression in Corneal Transplantation,” International Journal of Pharmaceutics, Vol. 349, No. 1-2, 2008, pp. 241-248.

[47]   S. Wadhwa, R. Paliwal, S. R. Paliwal and S. P. Vyas, “Hyaluronic Acid Modified Chitosan Nanoparticles for Effective Management of Glaucoma: Development, Characterization, and Evaluation,” Journal of Drug Targeting, Vol. 18, No. 4, 2010, pp. 292-302.

[48]   R. J. Marano, N. Wimmer, P. S. Kearns, B. G. Thomas, I. Toth, M. Brankov and P. E. Rakoczy, “Inhibition of in Vitro VEGF Expression and Choroidal Neovascularization by Synthetic Dendrimer Peptide Mediated Delivery of a Sense Oligonucleotide,” Experimental Eye Research, Vol. 79, No. 4, 2004, pp. 525-535.

[49]   R. Ideta, F. Tasaka, W. D. Jang, et al., Nanotechnology-Based Photodynamic Therapy for Neovascular Disease using a Supramolecular Nanocarrier Loaded with a Den-Dritic Photosensitizer,” Nano Letters, Vol. 5, No. 12, 2005, pp. 2426-2431.

[50]   K. Sugisaki, T. Usui, N. Nishiyama, W. D. Jang, Y. S. Yanagi, S. Yamagami, S. Amano and K. Kataoka, “Photodynamic Therapy for Corneal Neovascularization Using Polymeric Micelles Encapsulating Dendrimer Porphyrins,” Investigative Ophthalmology & Visual Science, Vol. 49, No. 3, 2008, pp. 894-899.

[51]   Th. F. Vandamme and L. Brobeck, “Poly(amidoamine) Dendrimers as Ophthalmic Vehicles for Ocular Delivery of Pilocarpine Nitrate and Tropicamide,” Journal of Controlled Release, Vol. 102, No. 1, 2005, pp. 23-38.

[52]   C. A. Holden, P. Tyagi, A. Thakur, R. Kadam, G. Jadhav, U. B. Kompella and H. Yang, “Polyamidoamine Dendrimer Hydrogel for Enhanced Delivery of Antiglaucoma Drugs,” Nanomedicine, Vol. 8, No. 5, 2012, pp. 776-783.

[53]   H. A. Quigley, R. W. Nickells, L. A. Kerrigan, M. E. Pease, D. J. Thibault and D. J. Zack, “Retinal Ganglion Cell Death in Experimental Glaucoma and after Axotomy Occurs by Apoptosis,” Investigative Ophthalmology & Visual Science, Vol. 36, No. 5, 1995, pp. 774-786.

[54]   J. Weise, S. Isenmann, N. Klocker, S. Kugler, S. Hirsch, C. Gravel and M. Bahr, “Adenovirus-Mediated Expression of Ciliary Neurotrophic Factor (CNTF) Rescues Axotomized Rat Retinal Ganglion Cells but Does Not Support Axonal Regeneration in Vivo,” Neurobiology of Disease, Vol. 7, No. 3, 2000, pp. 212-223.

[55]   G. Parrilla-Reverter, M. Agudo, P. Sobrado-Calvo, et al., “Effects of Different Neurotrophic Factors on the Survival of Retinal Ganglion Cells after a Complete Intraorbital Nerve Crush Injury: A Quantitative in Vivo Study,” Experimental Eye Research, Vol. 89, No. 1, 2009, pp. 32-41.

[56]   M. D. Pease, D. J. Zack, C. Berlinicke, et al., “Effect of CNTF on Retinal Ganglion Cell Survival in Experimental Glaucoma,” Investigative Ophthalmology & Visual Science, Vol. 50, No. 5, 2009, pp. 2194-2200.

[57]   Y. Hu, S. G. Leaver, G. W. Plant, W. T. J. Hendriks, S. P. Niclou, J. Verhaagen, A. R. Harvey and Q. Cui, “Lentiviral-Mediated Transfer of CNTF to Schwann Cells within Reconstructed Peripheral Nerve Grafts Enhances Adult Retinal Ganglion Cell Survival and Axonal Regeneration,” Molecular Therapy, Vol. 11, No. 6, 2005, pp. 906-915.

[58]   M. K. Nkansah, S. Y. Tzeng, A. M. Holdt and E. B. Lavik, “Poly(lactic-co-glycolic acid) Nanospheres and Microspheres for Short and Long-Term Delivery of Bioactive Ciliary Neurotrophic Factor,” Biotechnology and Bioengineering, Vol. 100, No. 5, 2008, pp. 1010-1019.

[59]   S. Y. Tzeng and E. B. Lavik, “Photopolymerizable Nanoarray Hydrogels Deliver CNTF and Promote Differentiation of Neural Stem Cells,” Soft Matter, Vol. 6, No. 10, 2010, pp. 2208-2215.

[60]   M. Jeun, J. W. Jeoung, S. Moon, et al., “Engineered Superparamagnetic Mn0.5Zn0.5Fe2O4 Nanoparticles as a Heat Shock Protein Induction Agent for Ocular Neuroprotection in Glaucoma,” Biomaterials, Vol. 32, No. 2, 2011, pp. 387-394.

[61]   G. L. Skuta and R. K. Parrish 2nd, “Wound Healing in Glaucoma Filtering Surgery,” Survey of Ophthalmology, Vol. 32, No. 3, 1987, pp. 149-170.

[62]   M. M. Tahery and D. A. Lee, “Pharmacologic Control of Wound Healing in Glaucoma Filtration Surgery,” Journal of Ocular Pharmacology and Therapeutics, Vol. 5, No. 2, 1989, pp. 155-179.

[63]   D. A. Morris, M. O. Peracha, D. H. Shin, C. Kim, S. C. Cha and Y. Y. Kim, “Risk Factors for Early Filtration Failure Requiring Suture Release after Primary Glaucoma Triple Procedure with Adjunctive Mitomycin,” JAMA Ophthalmology, Vol. 117, No. 9, 1999, pp. 1149-1154.

[64]   P. W. DeBry, T. W. Perkins, G. Heatley, P. Kaufman, ; L. C. Brumback, “Incidence of Late-Onset Bleb-Related Complications Following Trabeculectomy with Mitomycin,” JAMA Ophthalmology, Vol. 120, No. 3, 2002, pp. 297-300.

[65]   A. M. Palanca-Capistrano, J. Hall, L. B. Cantor, L. Morqan, J. Hoop and D. Wudunn, “Long-Term Outcomes of Intraoperative 5-Fluorouracil versus Intraoperative Mitomycin C in Primary Trabeculectomy Surgery,” Ophthalmology, Vol. 116, No. 2, 2009, pp. 185-190.

[66]   L. J. Cui, N. X. Sun, X. H. Li, J. Huang and J. G.Yang, “Subconjunctival Sustained Release 5-Fluorouracil for Glaucoma Filtration Surgery,” Acta Pharmacologica Sinica, Vol. 29, No. 9, 2008, pp. 1021-1028.

[67]   Z. Hou, H. Wei, Q. Wang, et al., “New Method to Prepare Mitomycin C Loaded PLA-Nanoparticles with High Drug Entrapment Efficiency,” Nanoscale Research Letters, Vol. 4, No. 7, 2009, pp. 732-737.

[68]   A. E. Yassin, M. K. Anwer, H. A. Mowafy, I. M. El-Bagory, M. A. Bayomi and I. A. Alsarra, “Optimization of 5-Fluorouracil Solid-Lipid Nanoparticles: A Preliminary Study to Treat Colon Cancer,” International Journal of Medical Sciences, Vol.7, No. 6, 2010, pp. 398-408.

[69]   A. J. Shuhendler, R. Y. Cheung, J. Manias, A. Connor, A. M. Rauth and X. Y. Wu, “A Novel Doxorubicin-Mitopmycin C Co-Encapsulated Nano-Particle Formulation Exhibits Anti-Cancer Synergy in Multidrug Resistant Human Breast Cancer Cells,” Breast Cancer Research and Treatment, Vol. 119, No. 2, 2010, pp. 255-269.

[70]   S. Shaunak, S. Thomas, E. Gianasi, et al., “Polyvalent Dendrimer Glucosamine Conjugates Prevent Scar Tissue Formation,” Nature Biotechnology, Vol. 22, No. 8, 2004, pp. 977-984.

[71]   A. L. Gomes dos Santos, A Bochot, A Doyle, et al., “Sustained Release of Nanosized Complexes of Polyethylenimine and Anti-TGF-[beta]2 Oligonucleotide Improves the Outcome of Glaucoma Surgery,” Journal of Controlled Release, Vol. 112, No. 3, 2006, pp. 369-381.

[72]   C. Gómez-Gaete, N. Tsapis, M. Besnard, A. Bochot and E. Fattal, “Encapsulation of Dexamethasone into Biodegradable Polymeric Nanoparticles,” International Journal of Pharmaceutics, Vol. 331, No. 2, 2007, pp. 153-159.

[73]   T. W. Perkins, B. Faha, M. Ni, et al., “Adenovirus-Mediated Gene Therapy Using Human p21waf-1/cip-1 to prevent Wound Healing in a Rabbit Model of Glaucoma Filtration Surgery,” JAMA Ophthalmology, Vol. 120, No. 7, 2002, pp. 941-949.

[74]   J. G. Yang, N. X. Sun, L. J. Cui, X. H. Wang and Z. H. Feng, “Adenovirus-Mediated Delivery of p27KIP1 to Prevent Wound Healing after Experimental Glaucoma Filtration Surgery,” Acta Pharmacologica Sinica, Vol. 30, No. 4, 2009, pp. 413-423.

[75]   M. G. Spiga and T. Borrás, “Development of a Gene Therapy Virus with a Glucocorticoid-Inducible MMP1 for the Treatment of Steroid Glaucoma,” Investigative Ophthalmology & Visual Science, Vol. 51, No. 6, 2010, pp. 3029-3041.