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Jacques Alexander Bertrand, Joseph Michael Sherwood, Guorong Li, W Daniel Stamer, Darryl R Overby; Sustained local delivery of dexamethasone using nanoparticles for steroid-induced ocular hypertension in mice. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4706.
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© ARVO (1962-2015); The Authors (2016-present)
Systemic glucocorticoid (GC) treatment in mice, utilizing implantable osmotic mini-pumps, recapitulates some hallmarks of steroid induced ocular hypertension (OHT) in humans. Induction of OHT via systemic delivery requires a high dosage of GC, resulting in systemic adverse events, such as marked weight loss. Alternative methods, such as topical delivery, require 3-times daily application, which is technically demanding. We propose a refined method of steroid induced-OHT via biodegradable GC-loaded nanoparticles (NP) injected subconjunctivally for sustained local delivery of GC to the eye.
A custom synthesized pentablock copolymer (PDLLA-PCL-PEG-PCL-PDLLA 22kDa) was loaded with dexamethasone (DEX, 10 mg/ml) dissolved in dichloromethane and sonicated in 2% polyvinyl alcohol, to produce NP that were collected by centrifugation. 9 male mice (C57BL/6J, 10-12 wks) were injected subconjunctivally with 10µl of NP suspension (0.14 mg DEX) while the contralateral eyes received 10µl of unloaded NP. Intraocular pressure (IOP) was measured twice weekly (9-10AM) under isoflurane anaesthesia in both eyes using a rebound tonometer (TonoLab, Icare, Finland). 30 days after injection, mice were euthanized and both eyes were enucleated for outflow facility (C) measurements using iPerfusion. Paired t-tests were used to determine statistical significance. Experiments were conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Visual Research.
Baseline IOP of DEX-treated eyes increased by 3.6 ± 0.2 mmHg (mean, 95% CI, P <10-6) from 12.1 ± 4.6 to 15.9 ± 4.0 mmHg (mean ± 2SD) 5 days post injection, which was sustained for 28 days. In contrast, the control eyes with baseline IOP of 12.4 ± 3.6 mmHg, showed a transient IOP spike 2 days post injection, which settled to 13.5 ± 6.2 mmHg (mean ± 2SD) 5 days post injection; an increase of 0.8 ± 0.4 mmHg (mean, 95% CI). The mean weight increased from 26.7 ± 3.8 to 27.1 ± 3.8 grams over the study. C decreased by 44% relative to sham-treated control eyes, (P= 0.013, n= 5).
A single subconjunctival injection of DEX loaded NP induced sustained OHT equivalent to that observed using systemic delivery (2.6 ± 1.6 mmHg (mean ± SD), Overby et al. IOVS 2014). However there were no apparent adverse systemic side effects, thereby offering a refined method which reduces animal numbers and preserves animal welfare.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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