SUPPLEMENT
Noninvasive Ocular Drug Delivery: Potential Transcorneal and Other Alternative Delivery Routes for Therapeutic Molecules in Glaucoma Marianna Foldvari, DPharmSci, PhD
strategies influencing the above-mentioned pathways have been investigated in an effort to improve glaucoma treatment (reviews by Zhang and colleagues3,4). The complex anatomy of the eye and the changes caused by the pathology and physiology of the specific conditions demand the design of drug delivery systems that consider such complexities for the specific target sites and barrier layers through which the delivery system and drug must pass through to provide the desired effect. Recent progress in ocular drug discovery and delivery includes research and development of novel classes of drugs, such as antiangiogenic agents, new IOP-lowering drugs, neuroprotective agents (neurotrophic factors, all-trans retinoic acid), antioxidants, rhoA kinase inhibitors (ROCK), bsecretase inhibitors, proteases, antifibrotic agents (connective tissue growth factor inhibitors), and gene therapy. Figure 1 summarizes the 4 essential components of treatment strategy: target sites, barriers in the eye, potential treatment approaches, and delivery systems.
Abstract: Drug delivery to the eye is made difficult by multiple barriers (such as the tear film, cornea, and vitreous) between the surface of the eye and the treatment site. These barriers are difficult to surmount for the purposes of drug delivery without causing toxicity. Using nanotechnology tools to control, manipulate, and study delivery systems, new approaches to delivering drugs, genes, and antigens that are effective and safe can be developed. Topical administration to the ocular surface would be the safest method for delivery, as it is noninvasive and painless compared with other delivery methods. However, there is only limited success using topical delivery methods, especially for gene therapy. Current thinking on treatments of the future enabled by nanodelivery systems and the identification of target specificity parameters that require deeper understanding to develop successful topical delivery systems for glaucoma is highlighted. Key Words: exfoliation syndrome, needle-free delivery, nanotechnology, glaucoma gene therapy
(J Glaucoma 2014;23:S80–S82)
NANO-ENABLED DELIVERY SYSTEMS
G
laucoma is one of the most common causes of both preventable and irreversible blindness in the world.1 Although the underlying mechanisms associated with glaucoma progression are still under investigation, damage to retinal ganglion cells (RGCs) is typically the result of mechanical injury resulting from increased intraocular pressure (IOP) caused by disruption of aqueous outflow through the trabecular meshwork or Schlemm’s canal. In addition to dealing with high IOP to prevent further damage to RGCs and their axons, local vascular insufficiency at the optic nerve head, activation of oxidative stress–related pathways, accumulation of exfoliation material in exfoliation syndrome, neurotrophic factor deprivation, suppression of prosurvival pathways, glial cell activation, glutamate excitotoxicity, and abnormal immune responses also require attention. Microarray studies of gene expression in the rat glaucomatous optic nerve head with extensive injury to that of the fellow eye identified abnormal expression of approximately 225 genes related to cellular proliferation, immune response, and the production of the extracellular matrix and cytoskeletal components.2 Many
Nanotechnology offers significant advantages in ocular drug delivery system development.5 The advantages range from increased residence time within ocular tissues to improved permeability to the posterior segment of the eye.6 One highly promising approach in ocular nanomedicine is gene therapy, which has potential for the delivery of protective or anti-apoptotic, neuroprotective, and growth factor genes into cells of the retina, resulting in expression of therapeutic proteins for prolonged periods.7 However, a significant limitation in glaucoma is the lack of effective delivery systems to the retina and optic nerve. “Effective” encompasses several qualitative, quantitative, and safety requirements. These are: (1) efficiency of delivery to the back of the eye; (2) biocompatibility; (3) targeted function; (4) prolonged effect; and (5) potentially noninvasive, painfree, and low-risk administration. Current methods used to deliver medicines to the back of the eye include systemic, intravitreal, subretinal, subconjunctival, and periocular injections. Currently, intravitreal and subretinal injections are considered to be the most effective and common methods of gene delivery to RGCs. Although effective, these methods are invasive and repeated delivery using such methods can result in further complications, such as retinal detachment, hemorrhages, and subretinal or preretinal fibrosis. Despite the current lack of success, topical gene application to the ocular surface would be the safest method for gene delivery to the retina, as it is noninvasive and painless compared with other delivery methods. There are a few promising approaches toward developing feasible topical gene delivery systems. Tong et al8
Received for publication August 11, 2014; accepted August 11, 2014. From the School of Pharmacy and Waterloo Institute of Nanotechnology, University of Waterloo, Waterloo, ON, Canada. Disclosure: The author declares no conflict of interest. Reprints: Marianna Foldvari, DPharmSci, PhD, School of Pharmacy and Waterloo Institute of Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, ON, Canada N2L 3G1 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins DOI: 10.1097/IJG.0000000000000122
S80 | www.glaucomajournal.com
J Glaucoma
Volume 23, Number 8 Suppl 1, October/November 2014
J Glaucoma
Volume 23, Number 8 Suppl 1, October/November 2014
Target sites in glaucoma
Noninvasive Ocular Drug Delivery
Barriers to topical drug delivery Tear fluid Cornea Trabecular meshwork Conjuctiva
Lens Trabecular meshwork
Ciliary body
Lens Vitreous
Retina Optic nerve head and nerve Lamina cribrosa
Ocular permeation pathways Conjuctiva-orbital-optic nerve head Cornea-posterior chamber-vitreous-retina Conjuctiva-sclera-choroid-RPE-retina
Potential therapeutic interventions 1)
IOP lowering agents (multiple mechanisms)
Delivery systems 1) Liposomes
2)
Aqueous outflow modulators
2)
Polymeric systems (PEO-PPO-PEO)
3)
Antioxidants
3)
Chitosan-based systems
4)
RhoA kinase inhibitors
4)
Niosomes
5)
Neurotrophic factors
5)
Nanosuspensions
5)
Microfiber disintegrators
6)
Dendrimers
7)
Exfoliation material dissolvers
7)
Peptides (POD)
8)
Proteases
8)
Nanoparticles
9)
Nucleic acids (genes and gene silencing)
9)
Nanospheres
10)
β-secretase inhibitors
10)
Hybrid systems
FIGURE 1. The 4 essential components in the design of glaucoma treatment strategies: the target site, barriers in the eye, potential therapeutic agent, and delivery systems. In the topical administration strategy, permeation pathways having potential to reach the retina by various delivery systems designed for drugs and genes are also shown.
have reported gene expression around the iris, sclera, conjunctiva, and lateral rectus muscle of rabbit eyes and in intraocular tissue of nude mice, following topical administration of poly(ethylene oxide)-poly(propylene oxide)poly(ethylene oxide) (PEO-PPO-PEO) polymeric micelles. Another type of nanoparticle system built from the novel peptide sequence GGG(ARKKAAKA)4 and termed POD (peptide for ocular delivery) successfully transfected retinal cells after topical administration.9 Recently our group engineered nanoparticles based on a new class of surfactants, dicationic N,N-bis(dimethylalkyl)a,o-alkene-diammonium surfactants, known as gemini surfactants, which are promising building blocks for nonviral gene delivery to the retina.10 Gemini surfactants (2 interlinked monomeric surfactants) are amphiphilic molecules, composed of at least 2 hydrophobic tails and 2 hydrophilic head groups linked by a spacer group.11,12 Through variations in the hydrophobic chain length, hydrophilic head groups, and spacer groups, a wide range of tailored compounds with a wide range of structural flexibility can be designed with utility as multimodal and tunable carriers for the topical administration of nucleic acids.7,13 r
2014 Lippincott Williams & Wilkins
CONCLUSIONS There is a great demand for effective topically administered ocular medicines. Advancing the design of delivery systems will provide for replacements of intraocular injections that come with side effects and poor acceptance by patients and also provide alternatives to implants, microneedles, and electrically driven systems.
REFERENCES 1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–267. 2. Johnson EC, Jia L, Cepurna WO, et al. Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model. Invest Ophthalmol Vis Sci. 2007;48:3161–3177. 3. Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov. 2012;11:541–559. 4. Edelhauser HF, Rowe-Rendleman CL, Robinson MR, et al. Ophthalmic drug delivery systems for the treatment of retinal
www.glaucomajournal.com |
S81
Foldvari
5. 6. 7.
8. 9.
J Glaucoma
diseases: basic research to clinical applications. Invest Ophthalmol Vis Sci. 2010;51:5403–5420. Zarbin MA, Montemagno C, Leary JF, et al. Nanomedicine in ophthalmology: the new frontier. Am J Ophthalmol. 2010; 150:144.e142–162.e142. Diebold Y, Calonge M. Applications of nanoparticles in ophthalmology. Prog Retin Eye Res. 2010;29:596–609. Alqawlaq S, Huzil JT, Ivanova MV, et al. Challenges in neuroprotective nanomedicine development: progress towards noninvasive gene therapy of glaucoma. Nanomedicine (Lond). 2012;7:1067–1083. Tong YC, Chang SF, Liu CY, et al. Eye drop delivery of nanopolymeric micelle formulated genes with cornea-specific promoters. J Gene Med. 2007;9:956–966. Johnson LN, Cashman SM, Kumar-Singh R. Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to
S82 | www.glaucomajournal.com
10.
11. 12. 13.
Volume 23, Number 8 Suppl 1, October/November 2014
ocular tissues including retina and cornea. Mol Ther. 2008; 16:107–114. Alqawlaq S, Sivak JM, Huzil JT, et al. Preclinical development and ocular biodistribution of gemini-DNA nanoparticles after intravitreal and topical administration: towards non-invasive glaucoma gene therapy. Nanomedicine. 2014. doi: 10.1016/ j.nano.2014.05.010 [published online ahead of print June 4, 2014]. Donkuru M, Badea I, Wettig S, et al. Advancing nonviral gene delivery: lipid- and surfactant-based nanoparticle design strategies. Nanomedicine (Lond). 2010;5:1103–1127. Wettig SD, Verrall RE, Foldvari M. Gemini surfactants: a new family of building blocks for non-viral gene delivery systems. Curr Gene Ther. 2008;8:9–23. Elsabahy M, Nazarali A, Foldvari M. Non-viral nucleic acid delivery: key challenges and future directions. Curr Drug Deliv. 2011;8:235–244.
r
2014 Lippincott Williams & Wilkins
Noninvasive Ocular Drug Delivery: Potential Transcorneal and Other Alternative Delivery Routes for Therapeutic Molecules in Glaucoma Marianna Foldvari, DPharmSci, PhD
strategies influencing the above-mentioned pathways have been investigated in an effort to improve glaucoma treatment (reviews by Zhang and colleagues3,4). The complex anatomy of the eye and the changes caused by the pathology and physiology of the specific conditions demand the design of drug delivery systems that consider such complexities for the specific target sites and barrier layers through which the delivery system and drug must pass through to provide the desired effect. Recent progress in ocular drug discovery and delivery includes research and development of novel classes of drugs, such as antiangiogenic agents, new IOP-lowering drugs, neuroprotective agents (neurotrophic factors, all-trans retinoic acid), antioxidants, rhoA kinase inhibitors (ROCK), bsecretase inhibitors, proteases, antifibrotic agents (connective tissue growth factor inhibitors), and gene therapy. Figure 1 summarizes the 4 essential components of treatment strategy: target sites, barriers in the eye, potential treatment approaches, and delivery systems.
Abstract: Drug delivery to the eye is made difficult by multiple barriers (such as the tear film, cornea, and vitreous) between the surface of the eye and the treatment site. These barriers are difficult to surmount for the purposes of drug delivery without causing toxicity. Using nanotechnology tools to control, manipulate, and study delivery systems, new approaches to delivering drugs, genes, and antigens that are effective and safe can be developed. Topical administration to the ocular surface would be the safest method for delivery, as it is noninvasive and painless compared with other delivery methods. However, there is only limited success using topical delivery methods, especially for gene therapy. Current thinking on treatments of the future enabled by nanodelivery systems and the identification of target specificity parameters that require deeper understanding to develop successful topical delivery systems for glaucoma is highlighted. Key Words: exfoliation syndrome, needle-free delivery, nanotechnology, glaucoma gene therapy
(J Glaucoma 2014;23:S80–S82)
NANO-ENABLED DELIVERY SYSTEMS
G
laucoma is one of the most common causes of both preventable and irreversible blindness in the world.1 Although the underlying mechanisms associated with glaucoma progression are still under investigation, damage to retinal ganglion cells (RGCs) is typically the result of mechanical injury resulting from increased intraocular pressure (IOP) caused by disruption of aqueous outflow through the trabecular meshwork or Schlemm’s canal. In addition to dealing with high IOP to prevent further damage to RGCs and their axons, local vascular insufficiency at the optic nerve head, activation of oxidative stress–related pathways, accumulation of exfoliation material in exfoliation syndrome, neurotrophic factor deprivation, suppression of prosurvival pathways, glial cell activation, glutamate excitotoxicity, and abnormal immune responses also require attention. Microarray studies of gene expression in the rat glaucomatous optic nerve head with extensive injury to that of the fellow eye identified abnormal expression of approximately 225 genes related to cellular proliferation, immune response, and the production of the extracellular matrix and cytoskeletal components.2 Many
Nanotechnology offers significant advantages in ocular drug delivery system development.5 The advantages range from increased residence time within ocular tissues to improved permeability to the posterior segment of the eye.6 One highly promising approach in ocular nanomedicine is gene therapy, which has potential for the delivery of protective or anti-apoptotic, neuroprotective, and growth factor genes into cells of the retina, resulting in expression of therapeutic proteins for prolonged periods.7 However, a significant limitation in glaucoma is the lack of effective delivery systems to the retina and optic nerve. “Effective” encompasses several qualitative, quantitative, and safety requirements. These are: (1) efficiency of delivery to the back of the eye; (2) biocompatibility; (3) targeted function; (4) prolonged effect; and (5) potentially noninvasive, painfree, and low-risk administration. Current methods used to deliver medicines to the back of the eye include systemic, intravitreal, subretinal, subconjunctival, and periocular injections. Currently, intravitreal and subretinal injections are considered to be the most effective and common methods of gene delivery to RGCs. Although effective, these methods are invasive and repeated delivery using such methods can result in further complications, such as retinal detachment, hemorrhages, and subretinal or preretinal fibrosis. Despite the current lack of success, topical gene application to the ocular surface would be the safest method for gene delivery to the retina, as it is noninvasive and painless compared with other delivery methods. There are a few promising approaches toward developing feasible topical gene delivery systems. Tong et al8
Received for publication August 11, 2014; accepted August 11, 2014. From the School of Pharmacy and Waterloo Institute of Nanotechnology, University of Waterloo, Waterloo, ON, Canada. Disclosure: The author declares no conflict of interest. Reprints: Marianna Foldvari, DPharmSci, PhD, School of Pharmacy and Waterloo Institute of Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, ON, Canada N2L 3G1 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins DOI: 10.1097/IJG.0000000000000122
S80 | www.glaucomajournal.com
J Glaucoma
Volume 23, Number 8 Suppl 1, October/November 2014
J Glaucoma
Volume 23, Number 8 Suppl 1, October/November 2014
Target sites in glaucoma
Noninvasive Ocular Drug Delivery
Barriers to topical drug delivery Tear fluid Cornea Trabecular meshwork Conjuctiva
Lens Trabecular meshwork
Ciliary body
Lens Vitreous
Retina Optic nerve head and nerve Lamina cribrosa
Ocular permeation pathways Conjuctiva-orbital-optic nerve head Cornea-posterior chamber-vitreous-retina Conjuctiva-sclera-choroid-RPE-retina
Potential therapeutic interventions 1)
IOP lowering agents (multiple mechanisms)
Delivery systems 1) Liposomes
2)
Aqueous outflow modulators
2)
Polymeric systems (PEO-PPO-PEO)
3)
Antioxidants
3)
Chitosan-based systems
4)
RhoA kinase inhibitors
4)
Niosomes
5)
Neurotrophic factors
5)
Nanosuspensions
5)
Microfiber disintegrators
6)
Dendrimers
7)
Exfoliation material dissolvers
7)
Peptides (POD)
8)
Proteases
8)
Nanoparticles
9)
Nucleic acids (genes and gene silencing)
9)
Nanospheres
10)
β-secretase inhibitors
10)
Hybrid systems
FIGURE 1. The 4 essential components in the design of glaucoma treatment strategies: the target site, barriers in the eye, potential therapeutic agent, and delivery systems. In the topical administration strategy, permeation pathways having potential to reach the retina by various delivery systems designed for drugs and genes are also shown.
have reported gene expression around the iris, sclera, conjunctiva, and lateral rectus muscle of rabbit eyes and in intraocular tissue of nude mice, following topical administration of poly(ethylene oxide)-poly(propylene oxide)poly(ethylene oxide) (PEO-PPO-PEO) polymeric micelles. Another type of nanoparticle system built from the novel peptide sequence GGG(ARKKAAKA)4 and termed POD (peptide for ocular delivery) successfully transfected retinal cells after topical administration.9 Recently our group engineered nanoparticles based on a new class of surfactants, dicationic N,N-bis(dimethylalkyl)a,o-alkene-diammonium surfactants, known as gemini surfactants, which are promising building blocks for nonviral gene delivery to the retina.10 Gemini surfactants (2 interlinked monomeric surfactants) are amphiphilic molecules, composed of at least 2 hydrophobic tails and 2 hydrophilic head groups linked by a spacer group.11,12 Through variations in the hydrophobic chain length, hydrophilic head groups, and spacer groups, a wide range of tailored compounds with a wide range of structural flexibility can be designed with utility as multimodal and tunable carriers for the topical administration of nucleic acids.7,13 r
2014 Lippincott Williams & Wilkins
CONCLUSIONS There is a great demand for effective topically administered ocular medicines. Advancing the design of delivery systems will provide for replacements of intraocular injections that come with side effects and poor acceptance by patients and also provide alternatives to implants, microneedles, and electrically driven systems.
REFERENCES 1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–267. 2. Johnson EC, Jia L, Cepurna WO, et al. Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model. Invest Ophthalmol Vis Sci. 2007;48:3161–3177. 3. Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov. 2012;11:541–559. 4. Edelhauser HF, Rowe-Rendleman CL, Robinson MR, et al. Ophthalmic drug delivery systems for the treatment of retinal
www.glaucomajournal.com |
S81
Foldvari
5. 6. 7.
8. 9.
J Glaucoma
diseases: basic research to clinical applications. Invest Ophthalmol Vis Sci. 2010;51:5403–5420. Zarbin MA, Montemagno C, Leary JF, et al. Nanomedicine in ophthalmology: the new frontier. Am J Ophthalmol. 2010; 150:144.e142–162.e142. Diebold Y, Calonge M. Applications of nanoparticles in ophthalmology. Prog Retin Eye Res. 2010;29:596–609. Alqawlaq S, Huzil JT, Ivanova MV, et al. Challenges in neuroprotective nanomedicine development: progress towards noninvasive gene therapy of glaucoma. Nanomedicine (Lond). 2012;7:1067–1083. Tong YC, Chang SF, Liu CY, et al. Eye drop delivery of nanopolymeric micelle formulated genes with cornea-specific promoters. J Gene Med. 2007;9:956–966. Johnson LN, Cashman SM, Kumar-Singh R. Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to
S82 | www.glaucomajournal.com
10.
11. 12. 13.
Volume 23, Number 8 Suppl 1, October/November 2014
ocular tissues including retina and cornea. Mol Ther. 2008; 16:107–114. Alqawlaq S, Sivak JM, Huzil JT, et al. Preclinical development and ocular biodistribution of gemini-DNA nanoparticles after intravitreal and topical administration: towards non-invasive glaucoma gene therapy. Nanomedicine. 2014. doi: 10.1016/ j.nano.2014.05.010 [published online ahead of print June 4, 2014]. Donkuru M, Badea I, Wettig S, et al. Advancing nonviral gene delivery: lipid- and surfactant-based nanoparticle design strategies. Nanomedicine (Lond). 2010;5:1103–1127. Wettig SD, Verrall RE, Foldvari M. Gemini surfactants: a new family of building blocks for non-viral gene delivery systems. Curr Gene Ther. 2008;8:9–23. Elsabahy M, Nazarali A, Foldvari M. Non-viral nucleic acid delivery: key challenges and future directions. Curr Drug Deliv. 2011;8:235–244.
r
2014 Lippincott Williams & Wilkins
