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Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization.

ABSTRACT: Corneal neovascularization (CNV) leads to the loss of corneal transparency and vision impairment, and can ultimately cause blindness. Topical corticosteroids are the first line treatment for suppressing CNV, but poor ocular bioavailability and rapid clearance of eye drops makes frequent administration necessary. Patient compliance with frequent eye drop application regimens is poor. We developed biodegradable nanoparticles (NP) loaded with dexamethasone sodium phosphate (DSP) using zinc ion bridging, DSP-Zn-NP, with dense coatings of poly(ethylene glycol) (PEG). DSP-Zn-NP were safe and capable of providing sustained delivery of DSP to the front of the eye following subconjunctival (SCT) administration in rats. We reported that a single SCT administration of DSP-Zn-NP prevented suture-induced CNV in rats for two weeks. In contrast, the eyes receiving SCT administration of either saline or DSP solution developed extensive CNV in less than 1 week. SCT administration of DSP-Zn-NP could be an effective strategy in preventing and treating CNV.

SUBMITTER: Wang B

PROVIDER: S-EPMC6520116 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization.

Wang Bing B Tang Yating Y Oh Yumin Y Lamb Nicholas W NW Xia Shiyu S Ding Zheng Z Chen Baiwei B Suarez María J MJ Meng Tuo T Kulkarni Vineet V Eberhart Charles G CG Ensign Laura M LM Stark Walter J WJ Hanes Justin J Xu Qingguo Q

Nanomedicine : nanotechnology, biology, and medicine 20190121

Corneal neovascularization (CNV) leads to the loss of corneal transparency and vision impairment, and can ultimately cause blindness. Topical corticosteroids are the first line treatment for suppressing CNV, but poor ocular bioavailability and rapid clearance of eye drops makes frequent administration necessary. Patient compliance with frequent eye drop application regimens is poor. We developed biodegradable nanoparticles (NP) loaded with dexamethasone sodium phosphate (DSP) using zinc ion brid ...[more]

PMID: 30677499

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Project description: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.

Project description:PurposeThe S100A protein family is involved in various inflammatory processes. Two of its members, S100A4 and A13, are thought to be pro-angiogenic in tumor development. This study examines whether S100A proteins are involved in the pathogenesis of inflammation-associated corneal neovascularization (CorNV).MethodsWe used 10-0 nylon suture--(S) or chemical burn (CB)--induced CorNV models for a microarray analysis of the genome-wide expression pattern. At different time points after suturing, we conducted histopathological examinations to detect the infiltration of inflammatory cells into the corneal stroma. Representative members of the S100A family (S100A4, S100A6, S100A8, S100A9, and S100A13), pro-inflammatory cytokines (IL-1β, IL-6, transforming growth factor β1, and MIP-2), and pro-angiogenic factors (fibroblast growth factor and vascular endothelial growth factor) were detected with reverse-transcription quantitative PCR (RT-QPCR). We used immunofluorescence to monitor neutrophil or macrophage infiltration and S100A8 or S100A9 protein deposition in neovascularized corneas. Antibody-mediated neutrophil depletion or S100A8 depletion in mice was performed to evaluate the role of neutrophils and S100A proteins in suture-induced corneal neovascularization (S-CorNV).ResultsMicroarray profiling revealed that S100A4, S100A6, S100A8, S100A9, and S100A13 were upregulated in both CorNV models, with S100A8 and S100A9 manifesting the most significant changes compared to the normal animals. An RT-QPCR assay of these S100A genes and cytokine genes in the S-CorNV corneas showed that the changes were time-dependent, reaching the apex at day 5. Immunofluorescence analysis demonstrated that neutrophils and macrophages produce S100A8 and S100A9. The depletion of neutrophils beginning one day before S-CorNV induction decreased disease severity and S100A8/S100A9 deposition in the neovascularized corneas. The extent of upregulation of other detected S100A genes and pro-inflammatory or pro-angiogenic genes was also decreased by neutrophil depletion. Subconjunctival administration of S100A8 antibodies also significantly inhibited the growth of vessels and inflammation in the S-CorNV model.ConclusionsWe determined that S100A proteins are involved in the inflammatory CorNV model and that S100A8 or S100A9 in particular might be employed as targets in managing diseases involving this pathological process.

Dataset Information

Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization.

Publications

Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization.

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