Controlled release of corticosteroid with biodegradable nanoparticles for treating experimental autoimmune uveitis

Lixia Luo, Jin Yang, Yumin Oh, Matthew J. Hartsock, Shiyu Xia, Yoo Chun Kim, Zheng Ding, Tuo Meng, Charles G Eberhart, Laura Ensign-Hodges, Jennifer Thorne, Walter J. Stark, Elia J Duh, Qingguo Xu, Justin S Hanes

Research output: Contribution to journalArticle

Abstract

Noninfectious uveitis is a potentially blinding ocular condition that often requires treatment with corticosteroids to prevent inflammation-related ocular complications. Severe forms of uveitis such as panuveitis that affects the whole eye often require a combination of topical and either regional or systemic corticosteroid. Regional corticosteroids are currently delivered inside the eye by intravitreal injection (e.g. Ozurdex®, an intravitreal dexamethasone implant). Intravitreal injection is associated with rare but potentially serious side effects, including endophthalmitis, retinal and vitreous hemorrhage, and retinal detachment. Subconjunctival (SCT) injection is a less invasive option that is a common route used for post-surgical drug administration and treatment of infection and severe inflammation. However, it is the water soluble form of dexamethasone, dexamethasone sodium phosphate (DSP), that has been demonstrated to achieve high intraocular penetration with subconjunctival injection. It is difficult to load highly water soluble drugs, such as DSP, and achieve sustained drug release using conventional encapsulation methods. We found that use of carboxyl-terminated poly(lactic-co-glycolic acid) (PLGA) allowed encapsulation of DSP into biodegradable nanoparticles (NP) with relatively high drug content (6% w/w) if divalent zinc ions were used as an ionic “bridge” between the PLGA and DSP. DSP-Zn-NP had an average diameter of 210 nm, narrow particle size distribution (polydispersity index ~0.1), and near neutral surface charge (−9 mV). DSP-Zn-NP administered by SCT injection provided detectable DSP levels in both the anterior chamber and vitreous chamber of the eye for at least 3 weeks. In a rat model of experimental autoimmune uveitis (EAU), inflammation was significantly reduced in both the front and back of the eye in animals that received a single SCT injection of DSP-Zn-NP as compared to animals that received either aqueous DSP solution or phosphate buffered saline (PBS). DSP-Zn-NP efficacy was evidenced by a reduced clinical disease score, decreased expression of various inflammatory cytokines, and preserved retinal structure and function. Furthermore, SCT DSP-Zn-NP significantly reduced microglia cell density in the retina, a hallmark of EAU in rats. DSP-Zn-NP hold promise as a new strategy to treat noninfectious uveitis and potentially other ocular inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)68-80
Number of pages13
JournalJournal of Controlled Release
Volume296
DOIs
StatePublished - Feb 28 2019

Fingerprint

dexamethasone 21-phosphate
Uveitis
Nanoparticles
Adrenal Cortex Hormones
Intravitreal Injections
Injections
Inflammation
Dexamethasone
Panuveitis
Vitreous Detachment
Pharmaceutical Preparations

Keywords

  • Animal model
  • Inflammation
  • Microglia
  • Ocular drug delivery
  • Polymers

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Controlled release of corticosteroid with biodegradable nanoparticles for treating experimental autoimmune uveitis. / Luo, Lixia; Yang, Jin; Oh, Yumin; Hartsock, Matthew J.; Xia, Shiyu; Kim, Yoo Chun; Ding, Zheng; Meng, Tuo; Eberhart, Charles G; Ensign-Hodges, Laura; Thorne, Jennifer; Stark, Walter J.; Duh, Elia J; Xu, Qingguo; Hanes, Justin S.

In: Journal of Controlled Release, Vol. 296, 28.02.2019, p. 68-80.

Research output: Contribution to journalArticle

Luo, Lixia ; Yang, Jin ; Oh, Yumin ; Hartsock, Matthew J. ; Xia, Shiyu ; Kim, Yoo Chun ; Ding, Zheng ; Meng, Tuo ; Eberhart, Charles G ; Ensign-Hodges, Laura ; Thorne, Jennifer ; Stark, Walter J. ; Duh, Elia J ; Xu, Qingguo ; Hanes, Justin S. / Controlled release of corticosteroid with biodegradable nanoparticles for treating experimental autoimmune uveitis. In: Journal of Controlled Release. 2019 ; Vol. 296. pp. 68-80.
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AU - Ding, Zheng

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N2 - Noninfectious uveitis is a potentially blinding ocular condition that often requires treatment with corticosteroids to prevent inflammation-related ocular complications. Severe forms of uveitis such as panuveitis that affects the whole eye often require a combination of topical and either regional or systemic corticosteroid. Regional corticosteroids are currently delivered inside the eye by intravitreal injection (e.g. Ozurdex®, an intravitreal dexamethasone implant). Intravitreal injection is associated with rare but potentially serious side effects, including endophthalmitis, retinal and vitreous hemorrhage, and retinal detachment. Subconjunctival (SCT) injection is a less invasive option that is a common route used for post-surgical drug administration and treatment of infection and severe inflammation. However, it is the water soluble form of dexamethasone, dexamethasone sodium phosphate (DSP), that has been demonstrated to achieve high intraocular penetration with subconjunctival injection. It is difficult to load highly water soluble drugs, such as DSP, and achieve sustained drug release using conventional encapsulation methods. We found that use of carboxyl-terminated poly(lactic-co-glycolic acid) (PLGA) allowed encapsulation of DSP into biodegradable nanoparticles (NP) with relatively high drug content (6% w/w) if divalent zinc ions were used as an ionic “bridge” between the PLGA and DSP. DSP-Zn-NP had an average diameter of 210 nm, narrow particle size distribution (polydispersity index ~0.1), and near neutral surface charge (−9 mV). DSP-Zn-NP administered by SCT injection provided detectable DSP levels in both the anterior chamber and vitreous chamber of the eye for at least 3 weeks. In a rat model of experimental autoimmune uveitis (EAU), inflammation was significantly reduced in both the front and back of the eye in animals that received a single SCT injection of DSP-Zn-NP as compared to animals that received either aqueous DSP solution or phosphate buffered saline (PBS). DSP-Zn-NP efficacy was evidenced by a reduced clinical disease score, decreased expression of various inflammatory cytokines, and preserved retinal structure and function. Furthermore, SCT DSP-Zn-NP significantly reduced microglia cell density in the retina, a hallmark of EAU in rats. DSP-Zn-NP hold promise as a new strategy to treat noninfectious uveitis and potentially other ocular inflammatory disorders.

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