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. 2015 Feb 28:200:71-7.
doi: 10.1016/j.jconrel.2015.01.001. Epub 2015 Jan 5.

Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye

Viet Anh Nguyen Huu  1 , Jing Luo  2 , Jie Zhu  2 , Jing Zhu  2 , Sherrina Patel  2 , Alexander Boone  3 , Enas Mahmoud  4 , Cathryn McFearin  4 , Jason Olejniczak  5 , Caroline de Gracia Lux  4 , Jacques Lux  4 , Nadezda Fomina  4 , Michelle Huynh  5 , Kang Zhang  6 , Adah Almutairi  7
Affiliations

Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye

Viet Anh Nguyen Huu et al. J Control Release. .

Erratum in

  • J Control Release. 2015 Apr 10;203:39

Abstract

Therapies for macular degeneration and diabetic retinopathy require intravitreal injections every 4-8 weeks. Injections are uncomfortable, time-consuming, and carry risks of infection and retinal damage. However, drug delivery via noninvasive methods to the posterior segment of the eye has been a major challenge due to the eye's unique anatomy and physiology. Here we present a novel nanoparticle depot platform for on-demand drug delivery using a far ultraviolet (UV) light-degradable polymer, which allows noninvasively triggered drug release using brief, low-power light exposure. Nanoparticles stably retain encapsulated molecules in the vitreous, and can release cargo in response to UV exposure up to 30 weeks post-injection. Light-triggered release of nintedanib (BIBF 1120), a small molecule angiogenesis inhibitor, 10 weeks post-injection suppresses choroidal neovascularization (CNV) in rats. Light-sensitive nanoparticles are biocompatible and cause no adverse effects on the eye as assessed by electroretinograms (ERG), corneal and retinal tomography, and histology.

Keywords: Anti-angiogenic; Light-triggered; Nanoparticle; Ocular; Polymer; Triggered release.

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Figures

Figure 1
Figure 1. UV light triggers release of encapsulated molecules in cultured macrophages
A, Raw264.7 macrophages incubated with fluorescein diacetate-containing nanoparticles (FDA NP) were irradiated with UV light (365 nm, 5 min, 10 mW/cm2). Scale bar = 100 μm. B, Quantification of fluorescence (n= 3 wells, p < 0.001). C. FDA release in phosphate buffer at 37 °C measured by fluorescence upon irradiation (Ex/Em = 490/514 nm).
Figure 2
Figure 2. Light-sensitive nanoparticles are biocompatible
A, Micrographs of H&E stained retinas 8 days after injections. Scale bar = 100 μm. B, Quantification of outer nuclear layer (ONL) thickness from histology sections (S2 – superior quadrant, I2 – inferior quadrant, ora – vicinity of ora serrata). C, Intraocular pressure measurements following the injection of nanoparticles. D, Electroretinograms (ERG) of rod scotopic response after injection of nanoparticles (n = 3).
Figure 3
Figure 3. Irradiation required for release does not damage the eye
A, Representative optical coherence tomography (OCT) scans through the retina (scale bar = 0.5 mm). B, Quantification of outer nuclear layer (ONL) thickness (ON – optical nerve, positive – towards temporal quadrant, negative – towards nasal quadrant; n = 3). C, Representative confocal tomographs of the corneal endothelium 2 weeks post-irradiation (scale bar = 50 μm). D, Quantification of stromal thickness from volume cornea tomographs (n = 4). E, Quantification of endothelial cell count ratio (n = 4).
Figure 4
Figure 4. Light-sensitive particles can release payload up to 30 weeks post-intravitreal injection
A-C, Fluorescent microscopy of retinal flat-mounts. Scale bar = 1 mm. D, Quantification of area of fluorescence coverage on retinal flat-mounts. Error bars represent SEM.
Figure 5
Figure 5. Light-triggered release of nintedanib (BIBF) post-injection inhibits CNV
A, Fluorescent microscope images of isolectin B4-Alexa Fluor 594 stained choroidal flat-mounts 2 weeks after CNV induction. Eyes were irradiated immediately post-injection (scale bar = 100 μm). B, Quantification of CNV spot size (n = 4-6). C, Choroidal flat-mounts from eyes irradiated 10 weeks post-injection, 2 weeks after CNV induction (scale bar = 100 μm). D, Quantification of CNV spot size (n = 4-6).
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