Antiangiogenic Nanomicelles for the Topical Delivery of Aflibercept to Treat Retinal Neovascular Disease

Abstract

The traditional intravitreal injection delivery of antivascular endothelial growth factor (anti‐VEGF) to the posterior segment of the eye for treatment of retinal diseases is invasive and associated with sight‐threatening complications. To avoid such complications, there has been significant interest in developing polymers for topical drug delivery to the retina. This study reports a nanomicelle drug delivery system made of a copolymer EPC (nEPCs), which is capable of delivering aflibercept to the posterior segment topically through corneal–scleral routes. EPC is composed of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and polycaprolactone (PCL) segments. In this study, aflibercept‐loaded nEPCs (nEPCs + A) are capable of penetrating the cornea in ex vivo porcine eye models and deliver a clinically significant amount of aflibercept to the retina in laser‐induced choroidal neovascularization (CNV) murine models, causing CNV regression. nEPCs + A also demonstrate biocompatibility in vitro and in vivo. Interestingly, this study also suggests that nEPCs have intrinsic antiangiogenic properties. The ability to deliver anti‐VEGF drugs and the intrinsic antiangiogenic properties of nEPCs may result in synergistic effects, which can be harnessed for effective therapeutics. nEPCs may be a promising topical anti‐VEGF delivery platform for the treatment of retinal diseases.

Recent developments of temperature‐responsive polymers for ophthalmic applications

“…Taking into consideration the viscosity of hydrogels, which may cause ocular discomfort, and blurring of vision, we explored the use of EPC as nanomicelles for topical delivery of anti-VEGF (Aflibercept). 102 This is the first time the intrinsic anti-angiogenic effects of nEPC was reported (Figure 5A). More importantly, the nEPC could achieve a therapeutic Aflibercept concentration in murine vitreous due to its significantly high encapsulation efficiency and ability to deliver the protein across the corneal epithelial and sclera barriers.…”

“…Zhao et al reported that the pharmacokinetics of a murine eye might not mimic the human eye well because of the size difference. 102 Indeed, it is difficult to replicate human in vivo conditions. Thus, the results obtained from animal studies may not extend to humans.…”

Retinal Diseases: The Next Frontier in Pharmacodelivery

“…Research and development are still ongoing, with controversial outcomes that make them not yet mature enough for medical use [ 46 , 47 ]. A recent publication of a nanomicelles capable of delivering Aflibercept topically to the posterior segment demonstrated choroidal neovascularization regression [ 48 ]. In current clinical use, Difluprednate (Durezol ® ), for example, is a potent steroid emulsion for topical administration.…”

Biomaterials by design: Harnessing data for future development

“…Polymers are very useful as biomaterials due to their adaptability which is unparalleled by metals and ceramics [ 69 , 70 ]. The great range of physical and chemical characteristics of polymers have made numerous applications possible such as tissue engineering and delivery vehicles for drugs/genes [ [71] , [72] , [73] , [74] , [75] ]. It is predicted that medicinal polymers alone are around 1 billion dollars in market size.…”