Evolving Drug Delivery Techniques for Treating AMD
Standard treatment of neovascular age-related macular degeneration (AMD) consists of repeated intravitreal injections of drugs that inhibit vascular endothelial growth factor (VEGF).1 Although this strategy is effective for many patients, the cumulative risks of endophthalmitis2 and other vision-threatening complications, and the financial burdens on patients, family members, and the health care system increase with repeated injections. Alternate treatment strategies such as treat-and-extend3 and as-needed4 regimens reduce but do not eliminate re-injections.
Sustained-release intravitreal delivery systems might be preferable to repeated injections if the duration of drug release exceeds inter-injection intervals and if the safety profile is favorable.5 Three extended release intravitreal therapy strategies are being evaluated: noninvasive techniques, intravitreal implants, and colloidal carriers.6
Noninvasive techniques do not require intravitreal injections. Studied approaches include iontophoresis (the use of low-intensity electrical current to facilitate diffusion)7 and hydrogel contact lenses.8 Other “noninvasive” techniques that require scleral perforation without violating the vitreous include submacular suprachoroidal effusion9 and microneedle injections into the suprachoroidal space.10
Intravitreal implants may be either bioerodable or nonbioerodable. In general, nonbioerodable implants offer more precise drug release over a longer duration, but the implant is permanently retained in the eye.11 A bioerodable dexamethasone delivery system (DDS, Ozurdex, Allergan, Irvine, CA)12 and a nonbioerodable fluocinolone implant (Retisert, Bausch & Lomb, Rochester, NY)13 have received FDA approval for retinal vein occlusions and posterior uveitis. A smaller nonbioerodable fluocinolone insert (Iluvien, Alimera, Alpharetta, GA) has been approved in Europe for the treatment of diabetic macular edema.14 Other implants, including encapsulated cell synthesis of ciliary neurotrophic factor,15 a nonbioerodable intracapsular ring implant containing bevacizumab, and a refillable trans-scleral reservoir containing ranibizumab, have been investigated.16 Variations on this strategy include a nonbioerodable implant with mechanical puncture or laser induced drug release17 and a programmable, refillable mini drug pump.18
Colloidal carriers are liquid suspensions of liposomes (0.01-10 µm), microparticles
(> 1 µm) or nanoparticles (< 1 µm) that reduce drug degradation and toxicity, and extend duration of action. Liposomes are synthetic bioerodable spheres of lipid bilayers surrounding a drug-containing aqueous compartment19 that are utilized in many FDA-approved (e.g. verteporfin) and investigational (e.g. bevacizumab20 and SU5416 [an anti-angiogenic agent]21) medications. Microparticles and nanoparticles are made of either natural or synthetic materials including bioerodable substances such as polylactic-co-glycolic acid (PLGA), used in the casing of the DDS, and polyethylene-glycol (PEG), used to extend the duration of action and prevent the catabolism of pegaptanib.22 Particles containing various anti-angiogenic compounds have been reported, including bevacizumab,23 TG-0054,24 gold,25 and a serpin-derived peptide.26 Dendrimers, globular structures containing branch-like structures surrounding a drug-containing core, have delivered an anti-VEGF oligonucleotide27 and fluocinolone.28 Thermoresponsive hydrogels also have been studied for drug delivery29 and have been reported to release bevacizumab.30
In theory, a sustained-release anti-VEGF intravitreal delivery system would benefit patients, and embedding these drugs inside FDA-approved carriers such as liposomes, PEG, or PLGA is easy to envision. In practice, however, an extended-release system would not become widely adopted unless it offered improvement in efficacy, safety, convenience, or cost. Because the as-needed and treat-and-extend injection regimens are successful for many patients, an extended-release system would have to provide several months of drug delivery to represent a worthwhile advance. As the duration of drug delivery increases, patients and ophthalmologists would likely be more willing to accept higher costs or decreased convenience, such as surgical implantation as opposed to in-office injections. However, treatments that offer extended durations of action may require longer clinical trials to achieve FDA approval. As we continue to collect investigational data, the future role of extended-release therapy for neovascular AMD will become clearer.
1. Kovach JL, Schwartz SG, Flynn HW Jr, Scott IU. Anti-VEGF treatment strategies for wet AMD. J Ophthalmol 2012;doi:10.155/2012/786870.
2. Schwartz SG, Flynn HW, Scott IU. Endophthalmitis after intravitreal injections. Expert Opin Pharmacother 2009;10:2119-26.
3. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina 2009;29:1424-31.
4. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol
5. Schwartz SG, Scott IU, Flynn Jr, Stewart MW. Drug delivery techniques for treating age-related macular degeneration. Expert Opin Drug Deliv 2013 Nov 13 [Epub ahead of print].
6. del Pozo-Rodriguez A, Delgado D, Gascon AR, Solinis MA. Lipid nanoparticles as drug/gene delivery systems to the retina. J Ocul Pharmacol Ther 2013;29:173-88.
7. Pescina S, Ferrari G, Govoni P, et al. In-vitro permeation of bevacizumab through human sclera: effect of iontophoresis application. J Pharm Pharmacol 2010;62:1189-94.
8. Schultz C, Breaux J, Schentag J, Morck D. Drug delivery to the posterior segment of the eye through hydrogel contact lenses. Clin Exp Optom 2011;94:212-8.
9. Tetz M, Rizzo S, Augustin AJ. Safety of submacular suprachoroidal drug administration via a microcatheter: retrospective analysis of European treatment results. Ophthalmologica 2012;227:183-9.
10. Patel SR, Berezosky DE, McCarey BE, et al. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci 2012;53:4433-41.
11. Kompella UB, Kadam RS, Lee VH. Recent advances in ophthalmic drug delivery. Ther Deliv
12. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results. Ophthalmology 2011;118:2453-60.
13. Callanan DG, Jaffe GJ, Martin DA, et al. Treatment of posterior uveitis with a fluocinolone implant: three-year clinical trial results. Arch Ophthalmol 2008;126:1191-201.
14. Schwartz SG, Flynn HW Jr. Fluocinolone acetonide implantable device for diabetic retinopathy. Curr Pharm Biotechnol 2011;12:347-51.
15. Kauper K, McGovern C, Sherman S. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest Ophthalmol Vis Sci 2012;53:7894-901.
16. Gooch N, Burr RM, Holt DJ, et al. Design and in vitro biocompatibility of a novel ocular drug delivery device. J Funct Biomater 2013;4:14-26.
17. Zaman RT, Gopal A, Starr K, et al. Micro-patterned drug delivery device for light-activated drug release. Laser Surg Med 2012;44:30-48.
18. Saati S, Lo R, Li PY, et al. Mini drug pump for ophthalmic use. Trans Am Ophthalmol Soc 2009;107:60-70.
19. Honda M, Asai T, Oku N, et al. Liposomes and nanotechnology in drug development: focus on ocular targets. Int J Nanomedicine 2013;8:495-503.
20. Abrishami M, Zarei-Ghanavati S, Souroush D, et al. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (Avastin) for intravitreal administration. Retina 2009;29:699-703.
21. Honda M, Asai T, Umemoto T, et al. Suppression of choroidal neovascularization by intravitreal injection of liposomal SU5416. Arch Ophthalmol 2011;129:317-21.
22. Kompella UB, Amrite AC, Pacha Ravi R, Durazo SA. Nanomedicines for the back of the eye drug delivery, gene delivery, and imaging. Prog Retin Eye Res 2013;172-98.
23. Pan CK, Durairaj C, Kompella UB, et al. Comparison of long-acting bevacizumab formulations in the treatment of choroidal neovascularization in a rat model. J Ocul Pharmacol Ther 2011;27:219-24.
24. Shelke NB, Kadam R, Tyagi P, et al. Intravitreal poly(L-lactide) microparticles sustain retinal and choroidal delivery of TG-0054, a hydrophyilic drug intended for neovascular diseases. Drug Deliv Transl Res
25. Kim JH, Kim MH, Jo DH, et al. The inhibition of retinal neovascularization by gold nanoparticles via suppression of VEGFR-2 activation. Biomaterials 2011;32:1865-71.
26. Shmueli RB, Ohnaka M, Miki A, et al. Long-term suppression of ocular neovascularization by intraocular injection of biodegradable polymeric particles containing a serpin-derived peptide. Biomaterials
27. Marano RJ, Toth I, Wimmer N, et al. Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity. Gene Ther 2005;12:1544-50.
28. Iezzi R, Guru BR, Glybina IV, et al. Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. Biomaterials 2012;33:979-88.
29. Kang Derwent JJ, Mieler WF. Thermoresponsive hydrogels as a new ocular delivery platform to the posterior segment of the eye. Trans Am Ophthalmol Soc 2008;106:206-13.
30. Wang CH, Hwang YS, Chiang PR, et al. Extended release of bevacizumab by thermosensitive biodegradable biocompatible hydrogel. Biomacromolecules 2012;13:40-8.
About our author(s):
Stephen G. Schwartz, MD, MBA
Bascom Palmer Eye Institute
University of Miami Miller
School of Medicine
Harry W. Flynn, Jr., MD
Bascom Palmer Eye Institute
University of Miami Miller
School of Medicine
Michael W. Stewart, MD
Department of Ophthalmology
Mayo Clinic School of Medicine