4.8 Article

Microsphere antioxidant and sustained erythropoietin-R76E release functions cooperate to reduce traumatic optic neuropathy

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

  1. DoD [W81XWH-15-1-0096, W81XWH-17-2-0055]
  2. NEI [R01 EY022349, U24 EY029893, P30EY008126, T32 EY021833]
  3. NIBIB [T32-EB021937]
  4. Potocsnak Discovery Grant in Regenerative Medicine
  5. Ayers Foundation Regenerative Visual Neuroscience Pilot Grant
  6. Ret. Maj. General Stephen L. Jones, MD Fund
  7. Vanderbilt University Medical Center Cell Imaging Shared Resource core facility (Clinical and Translational Science Award Grant from National Center for Research Resources) [UL1 RR024975]
  8. Research Prevent Blindness, Inc. (VEI)
  9. NIA [R01 NS094595]

向作者/读者索取更多资源

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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