Tuning surface functionalities of sub-10 nm-sized nanocarriers to target outer retina in designing drug delivery agents for intravitreal administration

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Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness, generally affecting people over 50 years of age in industrialized countries. Despite the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in attenuating the growth of new blood vessels, substantial visual improvements are rare with this complex disease. Furthermore, the current regimen of repeated monthly intravitreal injections of drugs can result in serious side effects. Combination therapies-to complement antiVEGF alone-with a prolonged therapeutic effect and efficient delivery to the intended site are urgently needed, which could be realized through the use of carefully designed nanocarriers. To understand the physicochemical effects (e.g., size, charge, geometry) of intravitreally administered nanocarriers on their bioavailability, distribution, and targeting efficiency across multiple layers of the retina, here we prepared seven different types of surface-functionalized water-soluble dendritic nanocarriers with hydrodynamic sizes mostly under 5 nm. A similar stoichiometric amount of fluorophore was covalently attached to each of these biocompatible nanocarriers for quantitative analyses by confocal microscopy of cryosectioned healthy mouse eyes. Interestingly, at 24 h post-injection, the nanocarrier with multiple copies of glucosamine on the surface (D-NSG) accumulated predominantly in the photoreceptor layer and the retinal pigment epithelium (RPE), which are speculated to be associated with AMD pathogenesis (i.e., target sites). Furthermore, extended residence at these outer retinal layers was demonstrated by D-NSG, which appeared to gradually turn into micron-scale particles potentially through aggregation. Our systematic findings may provide useful guidelines for the rational design of intravitreal nanocarriers to treat vision-threatening retinal diseases, including AMD.
Publisher
ELSEVIER SCI LTD
Issue Date
2020-10
Language
English
Article Type
Article
Citation

BIOMATERIALS, v.255

ISSN
0142-9612
DOI
10.1016/j.biomaterials.2020.120188
URI
http://hdl.handle.net/10203/275993
Appears in Collection
BS-Journal Papers(저널논문)
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