Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye

Abstract

To describe a novel microporous drug delivery system (DDS) for sustained antivascular endothelial growth factor (VEGF) delivery to the eye and to evaluate its efficacy in a corneal injury model. Methods: A macro-porous DDS (1.5 × 1.5 × 4 mm) loaded with 2 mg of bevacizumab was implanted subconjunctivally in three Dutch-belted pigmented rabbits after corneal alkali injury (2N NaOH). Three rabbits received sham DDS. Animals were followed for three months and assessed in vivo and ex vivo for corneal neovascularization (NV), epithelial defect, stromal scarring, endothelial cell loss, and expression of angiogenic and inflammatory markers in the cornea and retina. Results: Anti-VEGF DDS treatment led to complete inhibition of superior cornea NV and complete corneal re-epithelialization by day 58 whereas sham DDS resulted in severe cornea NV and persistent epithelial defect (9%∼12% of total cornea area) through the end of the study. Histologically, anti-VEGF DDS significantly reduced CD45 + and F4/80 CD11b + cell accumulation (79%, P < 0.05) in the cornea, ameliorated tumor necrosis factor-α expression (90%, P < 0.05), reduced corneal stromal scarring and prevented corneal endothelial cell loss, as compared to sham DDS. Moreover, anti-VEGF DDS achieved retinal penetration and reduction in retinal VEGF levels at 3 months. Conclusions: Use of subconjunctival anti-VEGF DDS suppresses cornea NV, inflammation, stromal scarring, prevents endothelial cell loss, and abrogates retinal VEGF upregulation in a rabbit corneal alkali burn model. Moreover, it delivers anti-VEGF antibodies to the retina for three months. This delivery platform could enable antibody therapy of other corneal and retinal vascular pathologies. Translational Relevance: We describe a method for sustained anti-VEGF delivery to the eye for the treatment of ocular injuries.

Considerations for Polymers Used in Ocular Drug Delivery

“…One of the earliest options explored was to simply increase the concentration of drug delivered in the eyedrop solution, overcoming delivery barriers through essentially brute force. However, this option presents its own challenges, as such high drug doses and accompanying polymer and preservative exposure could cause local irritation or toxicity in patients (207)(208)(209)(210). In addition, the higher drug dose per eyedrop leads to higher doses draining to the bloodstream, potentially exacerbating systemic side effects (208).…”

“…Injection into the subconjunctival space specifically allows drugs to be released next to the sclera and avoid corneal barriers to entry (202). Drugs are able to easily penetrate the more permeable scleral layer, potentially enabling significantly more efficient delivery to the interior of the eye, particularly the posterior segment (197,201,209,213). While subconjunctival drug injections and implants necessitate a relatively more invasive procedure than eyedrops, they offer the potential of prolonged drug delivery compared to eyedrops, potentially lasting months between injections or implant replacements (19,199).…”

“…Alternatively, subconjunctival injections of drug-loaded hydrogels composed of polymers such as PEG, PLGA, and HA can create a reservoir capable of extended release over a course of weeks or months, offering a more easily prepared alternative to micro-and nanoparticle systems (197,208). Finally, polymeric subconjunctival implants offer a more stable platform for drug delivery through the subconjunctival space, with research publications describing devices made of PDMS, PLGA, and polyurethane among others (19,197,209). Animal studies into the use polymer-based subconjunctival drug delivery systems have found promising initial data, with favorable biocompatibility and safety results for polyimide and PLGA implants and evidence of extended-release efficacy for PLGA microspheres in the subconjunctival space (215,216).…”

“…Research into other polymer systems for subconjunctival delivery is an emerging area, with several research efforts investigating alternative implant polymer compositions, nanoparticle-based delivery systems, and injectable hydrogels for use as drug reservoirs in the subconjunctival space (197,199,209,(248)(249)(250). However, many of these are still in the early phases of development, and are likely to require further research showing safety and biocompatibility, as well as well-developed animal studies to show efficacy, before they can be put into clinical trials (197).…”

A Review of Ocular Drug Delivery Platforms and Drugs for Infectious and Noninfectious Uveitis: The Past, Present, and Future

“…Maybe the furthest along in development and currently in phase III clinical trials after promising results in phase II trials, the port delivery system is a novel, permanent refillable surgical implant that is filled with ranibizumab for neovascular age-related macular degeneration [ 107 ]. Similarly, a porous subconjunctival drug delivery system of microspheres has been shown to deliver bevacizumab and anti-inflammatory antibodies to the cornea and retina in rabbits [ 108 , 109 , 110 ]. As more anti-inflammatory agents are being developed/studied as intravitreal agents to combat intraocular inflammation and macular edema in uveitis patients as discussed earlier, it remains to be seen, if, and how these novel delivery systems can be adapted to treating uveitis.…”