Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization.
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ABSTRACT:
SUBMITTER: Wang B
PROVIDER: S-EPMC6520116 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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Project description:PurposeTo investigate the development of corneal neovascularization, the corneal expression of vascular endothelial growth factor (VEGF), and the antiangiogenic effects of a VEGF-inhibitory antibody during experimental keratomycosis.MethodsScarified corneas of BALB/c mice were topically inoculated with Candidaalbicans and monitored daily for corneal neovascularization. A murine gene microarray compared infected corneas to controls 1 day after inoculation. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) determined levels of genes encoding VEGF-A, VEGF-B, VEGF-C, and VEGF-D and placental growth factor in infected, mock-inoculated, and normal corneas. Immunostaining localized VEGF-A in corneal sections. An anti-VEGF-A antibody that binds to murine VEGF was evaluated for effects on corneal neovascularization and fungal recovery.ResultsEyes with C. albicans keratitis manifested limbal capillary budding on the second postinoculation day, and intrastromal neovascular tufts subsequently grew at a mean rate of 250+/-80 microm/day. One day after the onset of C. albicans keratitis, VEGF-A was upregulated 12.5 fold (p=0.01) by microarray and 8.8 fold (p=0.004) by real-time RT-PCR, followed by a measured decline toward baseline over one week. VEGF-A was present in the epithelium and stroma of infected corneas. Scarification alone did not alter VEGF expression compared to the normal cornea. Anti-VEGF-A antibody significantly (p<0.01) decreased the formation of new corneal blood vessels during experimental keratomycosis without adversely affecting the fungal load of C. albicans keratitis.ConclusionsUntreated C. albicans keratitis induces VEGF-A and leads to progressive corneal neovascularization that is preventable by a VEGF-blocking antibody.
| S-EPMC2756518 | biostudies-literature
Project description:Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro angiogenesis assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles potently inhibited VEGF-induced tube formation, scratch wounding migration, and proliferation of human endothelial cells. In a rat model of alkali burn injury-induced corneal neovascularization, a subconjunctival injection of Apa-HSA-PEG nanoparticles induced a significant decrease in neovascularization compared to that observed with an injection of free apatinib solution or phosphate-buffered saline. An in vivo distribution study using HSA-PEG nanoparticles loaded with fluorescent hydrophobic model drugs revealed the presence of a substantial number of nanoparticles in the corneal stroma within 24 h after injection. These in vitro and in vivo results demonstrate that apatinib-loaded nanoparticles may be promising for the prevention and treatment of corneal neovascularization-related ocular disorders.
| S-EPMC5503670 | biostudies-literature
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.
| S-EPMC6476551 | biostudies-literature
Project description:Corneal neovascularization (NV) predisposes patients to compromised corneal transparency and visional acuity. Sunitinib malate (Sunb-malate) targeting against multiple receptor tyrosine kinases, exerts potent antiangiogenesis. However, the rapid clearance of Sunb-malate eye drops administered through topical instillation limits its therapeutic efficacy and poses a challenge for potential patient compliance. Sunb-malate, the water-soluble form of sunitinib, was shown to have higher intraocular penetration through transscleral diffusion following subconjunctival (SCT) injection in comparison to its sunitinib free base formulation. However, it is difficult to load highly water-soluble drugs and achieve sustained drug release. We developed Sunb-malate loaded poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres (Sunb-malate MS) with a particle size of approximately 15 μm and a drug loading of 7 wt%. Sunb-malate MS sustained the drug release for 30 days under the in vitro infinite sink condition. Subconjunctival (SCT) injection of Sunb-malate MS provided a prolonged ocular drug retention and did not cause ocular toxicity at a dose of 150 μg of active agent. Sunb-malate MS following SCT injection more effectively suppressed the suture-induced corneal NV than either Sunb-malate free drug or the placebo MS. Local sustained release of Sunb-malate through the SCT injection of Sunb-malate MS mitigated the proliferation of vascular endothelial cells and the recruitment of mural cells into the cornea. Moreover, the gene upregulation of proangiogenic factors induced by the pathological process was greatly neutralized by SCT injection of Sunb-malate MS. Our findings provide a sustained release platform for local delivery of tyrosine kinase inhibitors to treat corneal NV.
| S-EPMC8105765 | biostudies-literature
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.
| S-EPMC2994359 | biostudies-literature
Project description:The present study aimed to investigate the effects of diabetes mellitus (DM) on the generation of experimental corneal neovascularization (CrNV) and choroidal neovascularization (ChNV). Diabetes was induced in mice by intraperitoneal injection of streptozotocin (STZ). Experimental CrNV and ChNV were induced by alkali injury and laser photocoagulation, respectively. CrNV and ChNV were compared between the STZ?induced diabetic mice and control mice two weeks after injury. Relative expression of angiogenic factors was quantified by reverse transcription?quantitative polymerase chain reaction, and progenitor cell or macrophage accumulation in the early phase following injury was examined by flow cytometric analysis. Compared with the alkali?injured normal mice, the alkali?injured diabetic mice (STZ?induced) exhibited no significant difference in CrNV occurrence, whereas the laser?injured diabetic mice exhibited significantly reduced levels of ChNV compared with those of the laser?injured control animals. The laser?induced intrachoroidal mRNA expression levels of angiogenic factors, including vascular endothelial growth factor, hypoxia?induced factor?1?, chemokine (C?C motif) ligand 3, and stromal cell?derived factor?1?, were reduced in the laser?injured diabetic mice when compared with laser?injured control mice. Furthermore, the laser?induced intrachoroidal infiltration of c?Kit+ progenitor cells was impaired in the laser?injured diabetic mice compared with the laser?injured control mice. Overall, diabetes did not exert a significant effect on the generation of experimental CrNV. However, diabetes reduced laser?induced ChNV through downregulation of intrachoroidal progenitor cell infiltration and angiogenic factor expression.
| S-EPMC6172380 | biostudies-other
Project description:The future of tissue engineering requires development of intelligent biomaterials using nanoparticles. Magnetic nanoparticles (MNPs) have several applications in biology and medicine; one example is Food and Drug Administration (FDA)-approved contrast agents in magnetic resonance imaging. Recently, MNPs have been encapsulated within cell-encapsulating hydrogels to create novel nanobiomaterials (i.e., M-gels), which can be manipulated and assembled in magnetic fields. The M-gels can be used as building blocks for bottom-up tissue engineering to create 3D tissue constructs. For tissue engineering applications of M-gels, it is essential to study the release of encapsulated MNPs from the hydrogel polymer network and the effect of MNPs on hydrogel properties, including mechanical characteristics, porosity, swelling behavior, and cellular response (e.g., viability, growth). Therefore, we evaluated the release of MNPs from photocrosslinkable gelatin methacrylate hydrogels as the polymer network undergoes biodegradation using inductively coupled plasma atomic emission spectroscopy. MNP release correlated linearly with hydrogel biodegradation rate with correlation factors (Pearson product moment correlation coefficient) of 0.96 ± 0.03 and 0.99 ± 0.01 for MNP concentrations of 1% and 5%, respectively. We also evaluated the effect of MNPs on hydrogel mechanical properties, porosity, and swelling behavior, as well as cell viability and growth in MNP-encapsulating hydrogels. Fibroblasts encapsulated with MNPs in hydrogels remained viable (>80% at t = 144 h) and formed microtissue constructs in culture (t = 144 h). These results indicated that MNP-encapsulating hydrogels show promise as intelligent nanobiomaterials, with great potential to impact broad areas of bioengineering, including tissue engineering, regenerative medicine, and pharmaceutical applications.
| S-EPMC3813440 | biostudies-literature
Project description:PurposeCorneal neovascularization (CrNV) arises from many causes including corneal inflammatory, infectious, or traumatic insult, and frequently leads to impaired vision. This study seeks to determine the role of B-cell leukemia/lymphoma 10 (BCL-10) in the development of experimental CrNV.MethodsCorneas from BCL-10 knockout (KO) mice and wild-type (WT) mice were burned by sodium hydroxide (NaOH) to create the CrNV model and neovascular formation in the corneas was assessed 2 weeks later. Intracorneal macrophage accumulation and the expression of angiogenic factors were quantified by flow cytometric analysis (FCM) and real-time PCR, respectively.ResultsThe amount of CrNV was determined 2 weeks after alkali burn. Compared to WT mice, the amount of CrNV in BCL-10 KO mice was significantly decreased. FCM revealed that F4/80-positive macrophages were markedly decreased in BCL-10 KO mice compared with WT mice. Reverse transcription PCR showed that the mRNA expression levels of intracorneal vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (bFGF) and monocyte chemotactic protein 1 were reduced in BCL-10 KO mice compared with WT mice.ConclusionBCL-10 KO mice exhibited reduced alkali-induced CrNV by suppressing intracorneal macrophage infiltration, which subsequently led to decreased VEGF-A and bFGF expression, suggesting that BCL-10 may become a potential clinical intervening target of CrNV.
| S-EPMC6043546 | biostudies-literature
Project description:PurposeTo elucidate the mechanism behind epigenetic alteration associated with dexamethasone (DEX) sodium phosphate treatment.MethodsWe performed enzyme-linked immunosorbent assay to quantify changes in global DNA methylation and hydroxymethylation, quantitative real-time PCR (qRT-PCR) of the DNA methylation- and hydroxymethylation-related gene, in vitro DNA methyltransferase (DNMT) enzymatic activity assays with purified DNMTs, and DNA hydroxymethylation pattern with super-resolution imaging.ResultsWe identified global DNA hypomethylation and hyper-hydroxymethylation upon DEX treatment, associated with aberrant mRNA expression levels of DNMT and ten-eleven translocation (TET) proteins. Additionally, DEX exposure could directly hinder DNMT activities.ConclusionsWe showed that DEX-induced epigenetic alterations are linked to aberrant DNMT and TET expression, potentially through an essential role of DNMT.
| S-EPMC8645185 | biostudies-literature
Project description:In order to find out the vital genes during the corneal neovascularization (CNV), we set up two CNV models, one being induced by suture placement and the other by alkali burn to the corneal center. Young adult Balb/c and C57BL/6 were used. The corneas were checked daily for CNV development and some of the corneas were removed at two pre-determined time points for RNA extraction. Preliminary experiment indicated slightly different dynamics in suture- or chemical burn-induced CNV. Vigorous growth appeared at day 5 and day 6 in S-CNV and CB-CNV, and reached maximum length around day 10 and day 14, respectively, in S-CNV and CB-CNV. To check whether genetic MHC background has any effect on development of CNV, we compared CB-CNV in Balb/c and C57BL/6 mice at day 6. Corneas from Balb/c mice were isolated 5 and 10 days after suture-induced CNV, and 6 and 14 days after chemical burn-induced CNV. Corneas from C57BL/6 mice were isolated 6 days after chemical burn-induced CNV. Each time point had two or three biological replications.
2011-02-08 | E-GEOD-23347 | biostudies-arrayexpress