Abstract
PURPOSE. Intravitreal injection of antiangiogenic agents is becoming a standard treatment for neovascular retinal diseases. Sustained release of therapeutics by injecting colloidal carriers is a promising approach to reduce the injection frequency, which reduces treatment burdens and the risk of complications on patients. Such sustained release often requires carriers to have micrometer-scale dimension that, however, can potentially promote glaucoma and inflammation. Small, polycationic particles can be immobilized in vitreous through multiple cooperative ionic interactions with hyaluronic acid of the vitreous interior, but such particles are generally toxic. Here, we synthesized and examined a biocompatible dextran-based nanocarrier (<50 nm in diameter) conjugated with cationic peptides containing L-arginine with minimal toxicity, aiming to provide sustained release of therapeutic drugs in vitreous. METHODS. We synthesized the nanocarriers with condensed cholesteryl dextran (CDEX) as core material. Cationic peptides containing 1 to 4 arginine groups, along with fluorescence tags, were conjugated to the CDEX surface. We monitored the carrier diffusion rate ex vivo and half-lives in vivo in rodent vitreous using fluorescence imaging. We evaluated the toxicity by histological examinations at the second, third, eighth, and thirty-sixth week. RESULTS. The diffusion rate of nanocarriers was inversely related to zeta potential values in freshly isolated vitreous humor. We observed increased half-lives in vivo with increasing zeta potential (up to 240 days). Histological examinations confirmed no adverse effects on ocular morphology and organization. CONCLUSIONS. We demonstrated the potential of L-arginine peptide-conjugated nanocarriers toward safe and sustained therapeutic release system for posterior eye diseases.
Original language | English (US) |
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Pages (from-to) | 5142-5150 |
Number of pages | 9 |
Journal | Investigative Ophthalmology and Visual Science |
Volume | 58 |
Issue number | 12 |
DOIs | |
State | Published - Oct 2017 |
Funding
The authors thank Mark Johnson and Yang Zhang for fruitful discussions. Supported in part by National Institutes of Health grants R24EY022883, DP3DK108248, R01EY026078, P30 EY016665, and EPA 83573701; an unrestricted award from Research to Prevent Blindness (RPB) to the Department of Ophthalmology and Visual Sciences (University of Wisconsin-Madison); Retina Research Foundation (RRF); Illinois Society for the Prevention of Blindness; RRF/Daniel M. Albert Chair (CMS); and the RPB Stein Innovation Award (NS). Disclosure: H. Li, None; W. Liu, Opticent, Inc. (I); C.M. Sorenson, None; N. Sheibani, None; D.M. Albert, None; T. Senanayake, None; S. Vinogradov, None; J. Henkin, None; H.F. Zhang, Opticent, Inc. (I)
Keywords
- Fluorescence imaging
- Intravitreal drug delivery
- Nanoparticle
ASJC Scopus subject areas
- Ophthalmology
- Sensory Systems
- Cellular and Molecular Neuroscience