期刊
JOURNAL OF CONTROLLED RELEASE
卷 329, 期 -, 页码 762-773出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.10.010
关键词
Antioxidant; Microparticle; Intraocular; Neurotrauma; Neuroprotection; Sustained delivery; Erythropoietin
资金
- DoD [W81XWH-15-1-0096, W81XWH-17-2-0055]
- NEI [R01 EY022349, U24 EY029893, P30EY008126, T32 EY021833]
- NIBIB [T32-EB021937]
- Potocsnak Discovery Grant in Regenerative Medicine
- Ayers Foundation Regenerative Visual Neuroscience Pilot Grant
- Ret. Maj. General Stephen L. Jones, MD Fund
- Vanderbilt University Medical Center Cell Imaging Shared Resource core facility (Clinical and Translational Science Award Grant from National Center for Research Resources) [UL1 RR024975]
- Research Prevent Blindness, Inc. (VEI)
- NIA [R01 NS094595]
The study compared two polymeric microparticle formulations for sustained release of EPO-R76E, demonstrating their potential therapeutic benefits in treating optic nerve injuries.
Wild-type erythropoietin (EPO) is promising for neuroprotection, but its therapeutic use is limited because it causes a systemic rise in hematocrit. We have developed an EPO-R76E derivative that maintains neuroprotective function without effects on hematocrit, but this protein has a short half-life in vivo. Here, we compare the efficacy and carrier-induced inflammatory response of two polymeric microparticle (MP) EPO-R76E sustained release formulations based on conventional hydrolytically degradable poly(lactic-co-glycolic acid) (PLGA) and reactive oxygen species (ROS)-degradable poly(propylene sulfide) (PPS). Both MP types effectively loaded EPO-R76E and achieved sustained release, providing detectable levels of EPO-R76E at the injection site in the eye in vivo for at least 28 days. Testing in an in vitro oxidative stress assay and a mouse model of blast-induced indirect traumatic optic neuropathy (bITON) showed that PPS and PLGA MP-mediated delivery of EPO-R76E provided therapeutic protection. While unloaded PLGA MPs inherently increase levels of pro-inflammatory cytokines in the bITON model, drug-free PPS MPs have innate antioxidant properties that provide therapeutic benefit both in vitro and in vivo. Both PLGA and PPS MPs enabled sustained release of EPO-R76E, providing therapeutic benefits including reduction in inflammation and axon degeneration, and preservation of visual function as measured by electroretinogram. The PPS-based MP platform is especially promising for further development, as the delivery system provides inherent antioxidant benefits that can be harnessed to work in complement with EPO-R76E or other drugs for neuroprotection in the setting of traumatic eye injury.
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