Drug Delivery to the Posterior Segment
DARYL E. KURZ, MD · THOMAS A. CIULLA, MD
Intravitreal pegaptanib sodium (Macugen, OSI/Pfizer) and intravitreal ranibizumab (Lucentis, Genentech) received Food and Drug Administration (FDA) approval for the treatment of neovascular age-related macular degeneration (AMD) in 2004 and 2006, respectively. Pegaptanib is an RNA aptamer designed to target vascular endothelial growth factor (VEGF)165 and larger isoforms, and ranibizumab is a monoclonal antibody antigen-binding fragment that targets all isoforms of VEGF and their smaller bioactive cleavage products. Bevacizumab (Avastin, Genentech), a full-length humanized monoclonal antibody that targets all isoforms and active cleavage products of VEGF-A, is FDA-approved in combination with chemotherapy for the systemic treatment of metastatic colorectal cancer and lung cancer. Intravitreal bevacizumab has also recently been used off-label for the treatment of neovascular AMD. The successful treatment of wet AMD with these 3 anti-VEGF agents — pegaptanib, ranibizumab, and bevacizumab — has begun to replace thermal laser photocoagulation and photodynamic therapy as primary treatments. In addition, these agents have ushered in a new paradigm for ocular drug delivery, in which intraocular injection has become a commonplace yet less-than-desired means of delivering high doses of drug locally.
This article will explore newer methods of retinal drug delivery that hold further promise to reduce the number and invasiveness of future treatments. A number of products utilizing new methods of drug delivery are currently undergoing clinical evaluation, including encapsulated cell technology (ciliary neurotrophic factor [CNTF] delivery, Neurotech USA, Lincoln, RI), I-vation (SurModics, Irvine), Medidur (Alimera Sciences, Alpharetta, GA ), and Posurdex (Dexamethasone Posterior Segment Drug Delivery System [DDS], Allergan, Irvine, CA). Additional techniques are currently undergoing preclinical evaluation, including liposomes, microparticulates, iontophoresis, electroporation, and viral vectors. This article will briefly discuss each of these exciting modalities, with articles immediately following that describe each the 4 aforementioned technologies in greater detail.
|Daryl E. Kurz, MD, is clinical associate professor of ophthalmology at the Ohio State University, an associate with Midwest Macula in Indianapolis, and on the staff at retina/vitreous service at the Indianapolis Veterans Administration Hospital. Thomas A. Ciulla, MD, practices on the retina service at Midwest Eye Institute and serves as attending physician and surgeon at Methodist Hospital in Indianapolis. Neither author has any financial interest in any product mentioned in this article.|
ENCAPSULATED CELL TECHNOLOGY
NT-501 delivers CNTF to the posterior segment of the eye where it can protect photoreceptors from dying. Genetically modified human cells have been encapsulated and are capable of residing in the eye with the function of secreting CNTF for relatively long periods. Phase 2/3 studies looking at treatment of early- and late-stage retinitis pigmentosa are recruiting patients; a phase 2 study for patients with AMD and geographic atrophy is under way.
SurModics specializes in polymer coatings that allow for sustained release of drugs. I-vation is now in early testing in the United States for delivery of triamcinolone acetonide. I-vation TA is a helical coil coated with triamcinolone and polymer. It resembles a tiny corkscrew with a plastic coating. This design allows for a small wound with a comparatively large amount of deliverable drug. The same polymer used to slow the release of triamcinolone in the eye is currently in use in Johnson and Johnson's (New Brunswick, NJ) Cypher drug-eluting coronary stent. In vitro its platform has been used for delivery of active proteins for an extended period of time. If this works out in vivo, I-Vation could be a major contribution to the field of AMD treatment.
Medidur is an insert containing fluocinolone acetonide injected through the pars plana with a 25-g transconjunctival injector system in the office. It measures 3.5 mm in length and 0.37 mm in diameter and will require no sutures. Alimera has created 2 delivery rates: 0.2 μg/day and 0/5 μg/day. In September 2005, recruitment started for the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) study. The trial will use the 0.2 μg delivery system and follow 900 patients for 36 months.
Investigations into prolonging the half-life of dexamethasone in the eye are being done by Allergan with the dexamethasone DDS implant. Dexamethasone DDS releases either 350 μg or 700 μg of dexamethasone and is inserted through a 22-g puncture of the pars plana. Allergan essentially reduces the surface area of the dexamethasone by combining it with a biodegradable copolymer of lactic and glycolic acid (the same material as in dissolving suture) that slows its release in the vitreous cavity. Phase 2 results recently appeared in Archives of Ophthalmology and show effectiveness in treating macular edema.1
The history of liposomes began 40 years ago and their use in medicine continues to undergo refinement.2 They consist of a lipid bilayer that surrounds an aqueous compartment. Lipid-soluble materials can be dissolved in the lipid bilayer, and water-soluble materials can be dissolved in the central aqueous portion. Their use in posterior-segment drug delivery focuses on their ability to reduce toxicity of drugs, prolong the half-life of drugs, and deliver drugs specifically to the retinal pigment epithelium (RPE). Their use in treatment of the posterior segment is currently limited by clouding of the vitreous cavity for 14 to 21 days after injection, inability of unilamellar liposomes to cross the internal limiting membrane, and potential for cataract with high doses.3
Liposomes have some advantage over viral vectors in delivering genetic therapy to target cells in that they avoid the potential for inflammation and other potential side effects associated with viruses. Liposomes tend to aggregate in the vitreous, limiting their ability to reach the retina or RPE after injection into the vitreous cavity. It has been found that attaching polyethylene glycol to the liposome decreases its aggregating properties. However, conventional peglylation seems to reduce the liposome's ability to transfect the target cells. Recently, a process called postpegylation allows efficient transfection. Although intravitreal liposomes are still highly investigational, progress is being made toward use in the clinic.4,5
We can divide microparticulates into 2 basic categories: microscapsules and microspheres. Microcapsules, as one might imagine, have the drug encapsulated inside a polymeric film. Microspheres have the drug dispersed throughout the polymeric matrix. Polylactic acid (PLA) and polyglycolic acid (PLGA) are the 2 most commonly used matrix materials since they degrade to lactic and glycolic acids via the Krebs cycle and can be eliminated from the body.6,7
Investigation into the delivery of pegaptanib with microspheres was published in 2003. This in vitro study showed that pegaptanib could be released from microspheres in a biologically active state and could pass through rabbit sclera after being released. If this can be worked out in vivo it would allow for an anti-VEGF compound to be delivered periocularly with less frequent dosing than currently available.8,9
Microspheres have also been used to deliver protein kinase C (PKC)412 to the retina and choroid. PKC412 is a kinase inhibitor that blocks several isoforms of PKC and receptors for VEGF. Periocular injection of microspheres containing PKC412 in pigs was able to significantly suppress choroidal neovascularization (CNV) at Bruch's membrane laser rupture sites.10
Iontophoresis is the use of low-voltage continuous electricity to drive charged drug particles into a tissue. Varying the intensity of the electric field allows precise amounts of drug to be delivered. Most of the work on iontophoresis has been done with skin and delivery of local anesthetics.8,11,12
Since DNA and RNA are highly charged at neutral pH, they are ideal molecules for iontophoresis. This may be another method of delivering ocular gene therapy. Iontophoresis reduces the risks of delivery by making drugs less invasive, but at this point it does not address decreasing the frequency of the dosing regimen.
Electroporation, also referred to as electropermeabilization or electrotransfer, uses high-voltage electrical pulses of microsecond duration to induce pore formation in cell membranes. The porated state remains for minutes after the pulses are applied.13 Through these pores molecules, drugs can be delivered to the cytoplasm by passive diffusion. Once the pores are formed, iontophoresis can also be used to enhance the delivery of charged molecules such as DNA.
There are predominantly 3 categories of viruses used for gene therapy: (1) adenoviruses; (2) adeno-associated viruses (AAVs); and (3) retroviruses (includes oncoretroviruses and lentiviruses).
Adenoviruses do not integrate into the genome, so they can only offer robust short-term transgene expression. Adenoviruses can also be associated with strong humoral immune responses that limit their use in the eye. Adeno-associated viruses (AAVs) can integrate into the genome and are capable of long-term transgene expression. Unfortunately, the carrying capacity of this vector is small, limiting the genes that can be delivered.
Oncoretroviruses have a large carrying capacity but cannot infect the nondividing cells that make up most of the eye. Lentiviral vectors have been extensively investigated for gene transfer. Lentiviral vectors are the preferred virus type in the work of Stout and colleagues14 because they can transduce dividing and nondividing cells and integrate into the genome, and they have a decent carrying capacity.
Viruses have drawbacks. Transferred genes must integrate into genomes for long-term expression to occur. Control of the integration site is not possible, so disrupting normal cellular functions is a risk. If the gene were to insert in the middle of a tumor-suppressor gene or the gene inserted too close to an oncogene and caused upregulation, then unchecked cell growth and division could occur.14
Phase 1 study results with adenoviral vector expressing human pigment epithelium-derived factor (Ad PEDF) came out in 2006. This adenoviral vector has been modified to cause less collateral damage, and only 25% showed signs of inflammation. These were managed without difficulty. PEDF is thought to decrease the growth of CNV and protect photoreceptors. Delivery of the gene that produces PEDF will hopefully have this effect in future studies.15
Phase 1 results with another adenoviral vector containing herpes simplex thymidine kinase (AdV-TK) appeared in 2005. Patients with bilateral retinoblastoma, extensive vitreous seeds, and other therapies were considered, and eight patients were enrolled and underwent intravitreous injection of AdV-TK adjacent to the tumor sites (since AdV-TK does not diffuse through vitreous). Intravenous gancicyclovir was then given every 12 hours for 7 days. All patients showed regression of vitreous seeds by fundoscopy. Mild inflammation occurred at a dose of 1010 viral particles, and moderate inflammation, corneal edema, and increased intraocular pressure occurred at 1011 viral particles. All patients eventually underwent enucleation because of continued growth of the primary tumor not treated with gene therapy. This phase 1 study shows promising results, and with more hard work results will likely only improve.16
Remarkable progress has been made over the last5 years in drugs available for macular degeneration. Over the next 5 years we can expect safer and less frequent ways to deliver these and other drugs. RP
- Kuppermann BD, Blumenkranz MS, Haller JA, et al. Dexamethasone DDS Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309-317.
- Ebrahim S, Peyman GA, Lee PJ. Applications of liposomes in ophthalmology. Surv Ophthalmol. 2005;50:167-182.
- Yasukawa T, Ogura Y, Tabata Y, Kimura H, Wiedemann P, Honda Y. Drug delivery systems for vitreoretinal diseases. Prog Retin Eye Res. 2004;23:253-281.
- Peeters L, Sanders NN, Braeckmans K, et al. Vitreous: a barrier to nonviral ocular gene therapy. Invest Ophthalmol Vis Sci. 2005;46:3553-3561.
- Peeters L, Sanders NN, Jones A, Demeester J, De Smedt SC. Post-pegylated lipoplexes are promising vehicles for gene delivery in RPE cells. J Control Release. 2007 Aug 28;121(3):208-17. Epub 2007 Jun 5.
- Kurz D, Ciulla TA. Novel approaches for retinal drug delivery. Ophthalmol Clin North Am. 2002;15:405-410.
- Moshfeghi AA, Peyman GA. Micro- and nanoparticulates. Adv Drug Deliv Rev. 2005;57:2047-2052.
- Booth BA, Vidal Denham L, Bouhanik S, Jacob JT, Hill JM. Sustained-release ophthalmic drug delivery systems for treatment of macular disorders: present and future applications. Drugs Aging. 2007;24:581-602.
- Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with polylactic-co-glycolic acid microspheres. Invest Ophthalmol Vis Sci. 2003;44:290-299.
- Saishin Y, Silva RL, Saishin Y, et al. Periocular injection of microspheres containing PKC412 inhibits choroidal neovascularization in a porcine model. Invest Ophthalmol Vis Sci. 2003;44:4989-4993.
- Hsu J. Drug delivery methods for posterior segment disease. Curr Opin Ophthalmol. 2007;18:235-239.
- Myles ME, Neumann DM, Hill JM. Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis. Adv Drug Deliv Rev. 2005;57:2063-2079.
- Bejjani RA, Andrieu C, Bloquel C, Berdugo M, BenEzra D, Behar-Cohen F. Electrically assisted ocular gene therapy. Surv Ophthalmol. 2007;52:196-208.
- Stout JT. Gene transfer for the treatment of neovascular ocular disease (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2006;104:530-560.
- Campochiaro PA, Nguyen QD, Shah SM, et al. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther. 2006;17:167-176.
- Chevez-Barrios P, Chintagumpala M, Mieler W, et al. Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by gancicyclovir. J Clin Oncol. 2005;23:7927-7935.