EDITORIAL
The Nanotechnology Revolution Marco A. Zarbin, MD, PhD n this issue of the Asia-Pacific Journal of Ophthalmology, Sharaf et al1 review the use of nanotechnology-based strategies to improve the pharmacological treatment of anterior and posterior segment ophthalmic diseases. In addition, Sharaf et al1 report on the use of nanofabrication technology to develop minimally invasive biometric sensors. Nanotechnology, initially described by Richard Feynman,2 offers an unparalleled opportunity to improve drug delivery to the eye. Nanoparticle biodistribution is affected by particle size, shape, and surface properties. As noted elsewhere,3 particle size influences whether the particle is internalized via phagocytosis, macropinocytosis, caveolar-mediated endocytosis, or clathrin-mediated endocytosis, which in turn results in exposure of the nanoparticle to different intracellular environments.4 Compacted polylysine DNA nanoparticles, for example, are taken into cells and transported directly to the nucleus by the cell surface receptor nucleolin.5 One can direct nanoparticles to specific cells by labeling them with ligands for receptors that are abundant on the surface of the target cell.6 In addition to targeting a particular cell type, one also can engineer the nanoparticle for a particular mode of intracellular entry depending on the choice of nanoparticle-targeting molecules (eg, cholesterol promotes caveolin-mediated endocytosis).7,8 One can even target nanoparticles to particular subcellular organelles, such as the mitochondria9 or the nucleus.10 Thus, by manipulating the physical features of nanoparticle delivery systems, one may be able to improve drug safety and effectiveness by reducing the needed dose of medication and increasing the half-life of the medication at the target tissue. As noted by Sharaf et al,1 nanoengineering will enable us to improve drug, growth factor, and virus-mediated treatment of chronic conditions such as glaucoma,11 uveitis,12 or retinal edema (due to venous occlusion or choroidal neovascularization) as well as treatment of intraocular tumors and other conditions associated with cell proliferation such as capsular fibrosis after cataract surgery, ocular neovascularization, and proliferative vitreoretinopathy.13 Microelectromechanical systemYbased or nanoelectromechanical systemYbased engineering allows one to construct small devices using computer-aided design. Application of different manufacturing procedures (eg, oxidation, photolithography, etching, diffusion, sputtering, chemical vapor deposition, ion implantation, and epitaxy) enables one to control features of these devices down to the submicron level, which permits production of mechanical structures at length scales ranging from 100 nm or less to greater than 1 cm.14 Because one can create complex microfabricated biomaterial substrates with designed microscale and nanoscale features using these techniques, individual cell responses can be controlled (eg, attachment and motility), which enables one to attenuate the foreign body response, simulate tissue organization, and promote cell differentiation.15Y22 In their review, Sharaf et al1 describe efforts to develop nanomachines that measure biological variables, focusing on intraocular pressure. Of course, one also can envision devices that measure oxygen tension, pH, glucose concentration, the redox state of a cell or subcellular organelle, temperature, or blood pressure. Finally, one might couple the measuring and therapeutic capacity of nanomachines to create devices that measure critical biological variables (eg, redox state) and provide treatment (eg, antioxidant therapy) at the appropriate time and place and in the appropriate quantity, a concept termed theragnostics. Nanotechnology will revolutionize our approach to problems such as drug delivery and postoperative scarring. Nanotechnologists may provide highly innovative solutions to regenerative ophthalmology, such as the use of optogenetics to treat blindness due to degenerative retinal disease.23 As noted elsewhere,14 the earliest impact of nanomedicine is likely to involve the areas of biopharmaceuticals (eg, drug delivery, drug discovery),24 implantable materials (eg, tissue regeneration scaffolds, bioresorbable materials), implantable devices (eg, intraocular pressure monitors,25 glaucoma
I
From the Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School, Rutgers University, Newark, NJ. Received for publication May 21, 2014; accepted May 22, 2014. Supported in part by the Foundation Fighting Blindness, Inc, and the New Jersey Lions Eye Research Foundation. The author has no funding or conflicts of interest to declare. Reprints: Marco A. Zarbin, MD, PhD, Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School, Rutgers University, 90 Bergen St, Newark, NJ 07103. E-mail: [email protected]. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000064
Asia-Pacific Journal of Ophthalmology
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Volume 3, Number 3, May/June 2014
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Copyright © 2014 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
131
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Editorial
drainage valves26), and diagnostic tools (eg, genetic testing, cellular imaging). Important obstacles to the incorporation of nanotechnology include the development of safe manufacturing techniques and unintended biological consequences of nanomaterial use.27 Nonetheless, it seems likely that nanotechnology will provide revolutionary treatments for ophthalmic diseases within the next decade. REFERENCES 1. Sharaf MG, Cetinel S, Heckler L, et al. Nanotechnology-based approaches for ophthalmology applications: Therapeutic and diagnostic strategies. Asia Pac J Ophthalmol. 2014. In press. 2. Feynman R. There’s plenty of room at the bottom. Eng Sci. 1960;23:22Y36. 3. Zarbin MA, Montemagno C, Leary JF, et al. Regenerative nanomedicine and the treatment of degenerative retinal diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4:113Y137. 4. Rejman J, Oberle V, Zuhorn IS, et al. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(Pt 1):159Y169. 5. Chen X, Kube DM, Cooper MJ, et al. Cell surface nucleolin serves as receptor for DNA nanoparticles composed of pegylated polylysine and DNA. Mol Ther. 2008;16:333Y342.
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Volume 3, Number 3, May/June 2014
13. Zarbin MA, Montemagno C, Leary JF, et al. Use of nanoparticles in the treatment of age-related macular degeneration, glaucoma, and other degenerative retinal diseases. In: Thassu D, Chader JC, eds. Ocular Drug Delivery: Barriers and Application of Nanoparticulate Systems: New York, NY: Taylor & Francis; 2012. In press. 14. Zarbin MA, Montemagno C, Leary JF, et al. Nanotechnology in ophthalmology. Can J Ophthalmol. 2010;45:457Y476. 15. Ainslie KM, Tao SL, Popat KC, et al. In vitro immunogenicity of silicon-based micro- and nanostructured surfaces. ACS Nano. 2008;2:1076Y1084. 16. Curtis AS, Gadegaard N, Dalby MJ, et al. Cells react to nanoscale order and symmetry in their surroundings. IEEE Trans Nanobioscience. 2004;3:61Y65. 17. Dalby MJ, Riehle MO, Sutherland DS, et al. Changes in fibroblast morphology in response to nano-columns produced by colloidal lithography. Biomaterials. 2004;25:5415Y5422. 18. Gallagher JO, McGhee KF, Wilkinson CD, et al. Interaction of animal cells with ordered nanotopography. IEEE Trans Nanobioscience. 2002;1:24Y28. 19. Huang NF, Patel S, Thakar RG, et al. Myotube assembly on nanofibrous and micropatterned polymers. Nano Lett. 2006;6:537Y542.
6. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9:615Y627.
20. Kim DH, Kim P, Suh KY, et al. Modulation of Adhesion and Growth of Cardiac Myocytes by Surface Nanotopography. 27th Annual International. Conference of the Engineering in Medicine and Biology Society 2005:4091Y94.
7. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev. 2007;59:748Y758.
21. Popat KC, Leoni L, Grimes CA, et al. Influence of engineered titania nanotubular surfaces on bone cells. Biomaterials. 2007;28:3188Y3197.
8. Torchilin VP. Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers. 2008;90:604Y610.
22. Yim EK, Reano RM, Pang SW, et al. Nanopattern-induced changes in morphology and motility of smooth muscle cells. Biomaterials. 2005;26:5405Y5413.
9. Boddapati SV, D’Souza GG, Erdogan S, et al. Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 2008;8:2559Y2563.
23. Zarbin M, Montemagno C, Leary J, et al. Artificial vision. Panminerva Med. 2011;53:167Y177.
10. Wagstaff KM, Jans DA. Importins and beyond: non-conventional nuclear transport mechanisms. Traffic. 2009;10:1188Y1198. 11. Chu TC, He Q, Potter DE. Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent. J Ocul Pharmacol Ther. 2002;18:507Y514. 12. Kassem MA, Abdel Rahman AA, Ghorab MM, et al. Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs. Int J Pharm. 2007;340:126Y133.
24. Wei C, Wei W, Morris M, et al. Nanomedicine and drug delivery. Med Clin North Am. 2007;91:863Y870. 25. Dresher RP, Irazoqui PP. A compact nanopower low output impedance CMOS operational amplifier for wireless intraocular pressure recordings. Conf Proc IEEE Eng Med Biol Soc. 2007;2007:6056Y6059. 26. Pan T, Brown JD, Ziaie B. An artificial nano-drainage implant (ANDI) for glaucoma treatment. Conf Proc IEEE Eng Med Biol Soc. 2006;1:3174Y3177. 27. Zarbin MA, Montemagno C, Leary JF, et al. Nanomedicine in ophthalmology: the new frontier. Am J Ophthalmol. 2010;150:144Y162.
"It is what you read when you don’t have to that determines what you will be when you can’t help it." V Oscar Wilde
132
www.apjo.org
* 2014 Asia Pacific Academy of Ophthalmology
Copyright © 2014 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
The Nanotechnology Revolution Marco A. Zarbin, MD, PhD n this issue of the Asia-Pacific Journal of Ophthalmology, Sharaf et al1 review the use of nanotechnology-based strategies to improve the pharmacological treatment of anterior and posterior segment ophthalmic diseases. In addition, Sharaf et al1 report on the use of nanofabrication technology to develop minimally invasive biometric sensors. Nanotechnology, initially described by Richard Feynman,2 offers an unparalleled opportunity to improve drug delivery to the eye. Nanoparticle biodistribution is affected by particle size, shape, and surface properties. As noted elsewhere,3 particle size influences whether the particle is internalized via phagocytosis, macropinocytosis, caveolar-mediated endocytosis, or clathrin-mediated endocytosis, which in turn results in exposure of the nanoparticle to different intracellular environments.4 Compacted polylysine DNA nanoparticles, for example, are taken into cells and transported directly to the nucleus by the cell surface receptor nucleolin.5 One can direct nanoparticles to specific cells by labeling them with ligands for receptors that are abundant on the surface of the target cell.6 In addition to targeting a particular cell type, one also can engineer the nanoparticle for a particular mode of intracellular entry depending on the choice of nanoparticle-targeting molecules (eg, cholesterol promotes caveolin-mediated endocytosis).7,8 One can even target nanoparticles to particular subcellular organelles, such as the mitochondria9 or the nucleus.10 Thus, by manipulating the physical features of nanoparticle delivery systems, one may be able to improve drug safety and effectiveness by reducing the needed dose of medication and increasing the half-life of the medication at the target tissue. As noted by Sharaf et al,1 nanoengineering will enable us to improve drug, growth factor, and virus-mediated treatment of chronic conditions such as glaucoma,11 uveitis,12 or retinal edema (due to venous occlusion or choroidal neovascularization) as well as treatment of intraocular tumors and other conditions associated with cell proliferation such as capsular fibrosis after cataract surgery, ocular neovascularization, and proliferative vitreoretinopathy.13 Microelectromechanical systemYbased or nanoelectromechanical systemYbased engineering allows one to construct small devices using computer-aided design. Application of different manufacturing procedures (eg, oxidation, photolithography, etching, diffusion, sputtering, chemical vapor deposition, ion implantation, and epitaxy) enables one to control features of these devices down to the submicron level, which permits production of mechanical structures at length scales ranging from 100 nm or less to greater than 1 cm.14 Because one can create complex microfabricated biomaterial substrates with designed microscale and nanoscale features using these techniques, individual cell responses can be controlled (eg, attachment and motility), which enables one to attenuate the foreign body response, simulate tissue organization, and promote cell differentiation.15Y22 In their review, Sharaf et al1 describe efforts to develop nanomachines that measure biological variables, focusing on intraocular pressure. Of course, one also can envision devices that measure oxygen tension, pH, glucose concentration, the redox state of a cell or subcellular organelle, temperature, or blood pressure. Finally, one might couple the measuring and therapeutic capacity of nanomachines to create devices that measure critical biological variables (eg, redox state) and provide treatment (eg, antioxidant therapy) at the appropriate time and place and in the appropriate quantity, a concept termed theragnostics. Nanotechnology will revolutionize our approach to problems such as drug delivery and postoperative scarring. Nanotechnologists may provide highly innovative solutions to regenerative ophthalmology, such as the use of optogenetics to treat blindness due to degenerative retinal disease.23 As noted elsewhere,14 the earliest impact of nanomedicine is likely to involve the areas of biopharmaceuticals (eg, drug delivery, drug discovery),24 implantable materials (eg, tissue regeneration scaffolds, bioresorbable materials), implantable devices (eg, intraocular pressure monitors,25 glaucoma
I
From the Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School, Rutgers University, Newark, NJ. Received for publication May 21, 2014; accepted May 22, 2014. Supported in part by the Foundation Fighting Blindness, Inc, and the New Jersey Lions Eye Research Foundation. The author has no funding or conflicts of interest to declare. Reprints: Marco A. Zarbin, MD, PhD, Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School, Rutgers University, 90 Bergen St, Newark, NJ 07103. E-mail: [email protected]. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000064
Asia-Pacific Journal of Ophthalmology
&
Volume 3, Number 3, May/June 2014
www.apjo.org
Copyright © 2014 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
131
Asia-Pacific Journal of Ophthalmology
Editorial
drainage valves26), and diagnostic tools (eg, genetic testing, cellular imaging). Important obstacles to the incorporation of nanotechnology include the development of safe manufacturing techniques and unintended biological consequences of nanomaterial use.27 Nonetheless, it seems likely that nanotechnology will provide revolutionary treatments for ophthalmic diseases within the next decade. REFERENCES 1. Sharaf MG, Cetinel S, Heckler L, et al. Nanotechnology-based approaches for ophthalmology applications: Therapeutic and diagnostic strategies. Asia Pac J Ophthalmol. 2014. In press. 2. Feynman R. There’s plenty of room at the bottom. Eng Sci. 1960;23:22Y36. 3. Zarbin MA, Montemagno C, Leary JF, et al. Regenerative nanomedicine and the treatment of degenerative retinal diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4:113Y137. 4. Rejman J, Oberle V, Zuhorn IS, et al. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(Pt 1):159Y169. 5. Chen X, Kube DM, Cooper MJ, et al. Cell surface nucleolin serves as receptor for DNA nanoparticles composed of pegylated polylysine and DNA. Mol Ther. 2008;16:333Y342.
&
Volume 3, Number 3, May/June 2014
13. Zarbin MA, Montemagno C, Leary JF, et al. Use of nanoparticles in the treatment of age-related macular degeneration, glaucoma, and other degenerative retinal diseases. In: Thassu D, Chader JC, eds. Ocular Drug Delivery: Barriers and Application of Nanoparticulate Systems: New York, NY: Taylor & Francis; 2012. In press. 14. Zarbin MA, Montemagno C, Leary JF, et al. Nanotechnology in ophthalmology. Can J Ophthalmol. 2010;45:457Y476. 15. Ainslie KM, Tao SL, Popat KC, et al. In vitro immunogenicity of silicon-based micro- and nanostructured surfaces. ACS Nano. 2008;2:1076Y1084. 16. Curtis AS, Gadegaard N, Dalby MJ, et al. Cells react to nanoscale order and symmetry in their surroundings. IEEE Trans Nanobioscience. 2004;3:61Y65. 17. Dalby MJ, Riehle MO, Sutherland DS, et al. Changes in fibroblast morphology in response to nano-columns produced by colloidal lithography. Biomaterials. 2004;25:5415Y5422. 18. Gallagher JO, McGhee KF, Wilkinson CD, et al. Interaction of animal cells with ordered nanotopography. IEEE Trans Nanobioscience. 2002;1:24Y28. 19. Huang NF, Patel S, Thakar RG, et al. Myotube assembly on nanofibrous and micropatterned polymers. Nano Lett. 2006;6:537Y542.
6. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9:615Y627.
20. Kim DH, Kim P, Suh KY, et al. Modulation of Adhesion and Growth of Cardiac Myocytes by Surface Nanotopography. 27th Annual International. Conference of the Engineering in Medicine and Biology Society 2005:4091Y94.
7. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev. 2007;59:748Y758.
21. Popat KC, Leoni L, Grimes CA, et al. Influence of engineered titania nanotubular surfaces on bone cells. Biomaterials. 2007;28:3188Y3197.
8. Torchilin VP. Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers. 2008;90:604Y610.
22. Yim EK, Reano RM, Pang SW, et al. Nanopattern-induced changes in morphology and motility of smooth muscle cells. Biomaterials. 2005;26:5405Y5413.
9. Boddapati SV, D’Souza GG, Erdogan S, et al. Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 2008;8:2559Y2563.
23. Zarbin M, Montemagno C, Leary J, et al. Artificial vision. Panminerva Med. 2011;53:167Y177.
10. Wagstaff KM, Jans DA. Importins and beyond: non-conventional nuclear transport mechanisms. Traffic. 2009;10:1188Y1198. 11. Chu TC, He Q, Potter DE. Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent. J Ocul Pharmacol Ther. 2002;18:507Y514. 12. Kassem MA, Abdel Rahman AA, Ghorab MM, et al. Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs. Int J Pharm. 2007;340:126Y133.
24. Wei C, Wei W, Morris M, et al. Nanomedicine and drug delivery. Med Clin North Am. 2007;91:863Y870. 25. Dresher RP, Irazoqui PP. A compact nanopower low output impedance CMOS operational amplifier for wireless intraocular pressure recordings. Conf Proc IEEE Eng Med Biol Soc. 2007;2007:6056Y6059. 26. Pan T, Brown JD, Ziaie B. An artificial nano-drainage implant (ANDI) for glaucoma treatment. Conf Proc IEEE Eng Med Biol Soc. 2006;1:3174Y3177. 27. Zarbin MA, Montemagno C, Leary JF, et al. Nanomedicine in ophthalmology: the new frontier. Am J Ophthalmol. 2010;150:144Y162.
"It is what you read when you don’t have to that determines what you will be when you can’t help it." V Oscar Wilde
132
www.apjo.org
* 2014 Asia Pacific Academy of Ophthalmology
Copyright © 2014 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
