Nanoengineering of therapeutics for retinal vascular disease

Abstract

Retinal vascular diseases, including diabetic retinopathy, neovascular age related macular degeneration, and retinal vein occlusion, are leading causes of blindness in the Western world. These diseases share several common disease mechanisms, including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation, which provide opportunities for common therapeutic strategies. Treatment of these diseases using laser therapy, anti-VEGF injections, and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying root causes of pathology, and may have deleterious side effects. Furthermore, many patients continue to progress toward legal blindness despite receiving regular therapy. Nanomedicine, the engineering of therapeutics at the 1-100 nm scale, is a promising approach for improving clinical management of retinal vascular diseases. Nanomedicine-based technologies have the potential to revolutionize the treatment of ophthalmology, through enabling sustained release of drugs over several months, reducing side effects due to specific targeting of dysfunctional cells, and interfacing with currently "undruggable" targets. We will discuss emerging nanomedicine-based applications for the treatment of complications associated with retinal vascular diseases, including angiogenesis and inflammation.

Keywords: AMD; Diabetic retinopathy; Nanomedicine; Nanoparticles; Nanotechnology; Retina; Retinal vascular disease.

Figure 1

Targeted therapy of CNV lesions using RGD-targeted nanoparticles. In a monkey model of laser induced CNV, RGD targeted nanoparticles loaded with Flt23k intraceptor plasmid suppressed CNV formation (perlecan staining) and fibrosis (collagen I staining) 4 weeks following a single intravenous injection of nanoparticles. Reproduced with permission from.

Figure 2

Detection of retinal hypoxia using fluorescein based molecular imaging probes HYPOX-1 and HYPOX-2. (A-C) Retinal flatmounts from mouse models of oxygen induced retinopathy (OIR, A) or mice reared in room air (B) intravenously injected with the hypoxia sensing probe HYPOX-1 (green) were stained with the endothelial cell marker ICAM-2 (red). (C) Retinal flatmount from OIR mouse intravitreally injected with HYPOX-2 (green) and stained with ICAM-2 (red). Accumulation of HYPOX-1 and HYPOX-2 is observed in the avascular retina. Scale bars = 100 μM. Reproduced with permission from.

Figure 3

Inhibition of pathologic vascular lesions in the Vldlr -/- mouse model using cerium oxide nanoparticles (nanoceria). This mouse model exhibits intraretinal (IRN) vascular lesions (B) and subretinal (SRN) vascular lesions (E) which are suppressed by a single injection of nanoceria (G,H). Reproduced with permission from.