Pigment Epithelium-Derived Factor-Loaded PEGylated Nanoparticles as a New Antiangiogenic Therapy for Neovascularization.

Background: Pathological neovascularization, which involves a disruption in the balance between angiogenic and antiangiogenic factors under pathological conditions, is the basis of many intraocular diseases. Pigment epithelium-derived factor (PEDF) is a potent natural, endogenous inhibitor of neovascularization because of its antiangiogenic and neuroprotective benefits. However, its application is restricted by its instability and short half-life. The present study is aimed at investigating the cytotoxicity and antiangiogenic effects of PEDF-loaded PEGylated nanoparticles (NP-PEG-PEDF) on high glucose-stimulated human umbilical vein endothelial cells (HUVECs). Methods: In this study, NP-PEG-PEDF were fabricated using the multiple emulsion method for the first time. HUVECs were cultured in a high concentration of glucose (30 mmol/L D-glucose), simulating diabetic conditions. The antiangiogenic effects of vascular endothelial growth factor (VEGF), pure PEDF, and NP-PEG-PEDF on proliferation, migration, and tube formation were evaluated. VEGF secretion in high glucose-stimulated HUVECs was further tested in vitro. Results: NP-PEG-PEDF exhibited low cytotoxicity in HUVECs. Our results indicated that in vitro, NP-PEG-PEDF attenuated diabetes-induced HUVEC proliferation, migration, and tube formation and suppressed VEGF secretion. The apoptosis of diabetes-induced HUVECs occurred in a dose-dependent manner, which showed a statistically significant difference compared with the PEDF treatment group. Conclusion: Our study is the first to demonstrate that NP-PEG-PEDF exert antiangiogenic effects on high glucose-stimulated HUVECs and have the potential to alleviate microvascular dysfunction. These data suggest that the NP-PEG-PEDF delivery system may offer an innovative therapeutic strategy for preventing neovascularization of the fundus.

Cytomegalovirus-related uncontrolled glaucoma in an immunocompetent patient: a case report and systematic review.

BACKGROUND: Cytomegalovirus can cause ocular anterior uveitis with ocular hypertension. Basis on the therapy, ocular pressure usually can be controlled. We report a case of a man who had unilateral cytomegalovirus anterior uveitis with refractory glaucoma during the process of treatment. CASE PRESENTATION: A 57-year-old man who was diagnosed Posner-Schlossman syndrome and was admitted for repeatly attacks of raised IOP in left eye for 4 months. We found the cytomegalovirus -DNA was high (1800 copies/ml) in his aqueous. After systemic used of antiviral drug accompany with topical used of anti-inflammation, anti-glaucoma agents and genciclovir gel, the ocular pressure was dropped to normal. While the pressure elevated again in a month after stopping systemic antiviral treatment. Furthermore, the second test showed cytomegalovirus in aqueous humor decreased to 526 copies/ml. Intravenous drugs to antiviral, anti-inflammatory and anti-glaucoma were applied, but the ocular pressure was still high. In the progression of glaucomatous damage in the eye, glaucoma surgery was operated with no cytomegalovirus was detected. At last, the postoperative ocular pressure has been controlled. CONCLUSIONS: CMV infection is not rare. Patients have unilateral mild anterior inflammation with relapsed attacks of elevated intraocular pressure should be considered for CMV infection. We found that concurrent use of systemic and topical ganciclovir in a short period could reduce ocular CMV significantly, while ocular hypertension recurred. The antiviral treatment should be individualized. Glaucoma surgery could be offered to protect CEC loss and glaucomatous damage.

Meibomian gland dropout in Sjögren's syndrome and non-Sjögren's dry eye patients.

PURPOSE: The purpose of this study is to explore the differences in ocular symptoms and signs between Sjögren's syndrome (SS) and non-SS aqueous-deficient dry eye (ADDE) patients. METHODS: Twenty-two eyes of 22 SS patients (Group 1) and 22 eyes of 22 non-SS ADDE patients (Group 2) were enrolled. The evaluated variables included the Standard Patient Evaluation of Eye Dryness (SPEED), the Ocular Surface Disease Index (OSDI), tear meniscus height, first and average non-invasive keratographic breakup time (fNIKBUT and avNIKBUT), Schirmer I test, lipid layer thickness (LLT), meibomian gland expressibility, Marx line, corneal staining, conjunctival congestion, incomplete blinking, and meibomian gland dropout using two novel, non-invasive instruments, the Keratograph and LipiView II. RESULTS: Ocular signs of the NIKBUT (fNIKBUT: 3.8 (2.7, 5.2)s and 6.3 (3.7, 8.9)s, P = 0.024; avNIKBUT: 5.4 (4.5, 8.9)s and 7.6 (5.8, 13.7)s, P = 0.041), meibomian gland dropout of the upper eyelid (35.5% (29.1%, 54.8%) and 21.9% (16.7%, 24.9%), P = 0.000), and corneal staining (P = 0.050) were more severe but were associated with less severe symptoms, i.e., a lower SPEED score (P = 0.001), in SS subjects than in non-SS subjects. CONCLUSION: SS patients exhibit more severe meibomian gland destruction of the upper eyelid than non-SS patients. Meibomian gland dysfunction is another key cause of SS-associated dry eye.

Preliminary study of the effect of FK506 nanospheric-suspension eye drops on rejection of penetrating keratoplasty.

OBJECTIVE: The aim of this study was to investigate the effect of a topical FK506 nanospheric suspension in a rat model of penetrating keratoplasty. METHODS: FK506 nanospheres were prepared by using a biodegradable poly (lactic-co-glycolic acid) copolymer (PLGA). Its distribution in the eye and blood after a single instillation was examined in rabbits. Sprague-Dawley (SD) rats received corneal heterografts and were topically treated with phosphate-buffered saline (PBS), PLGA, FK-506 0.01% (nanospheres), or dexamethasone 0.05% solutions twice a day for 28 days. Rejection index and graft-survival time were recorded and compared between the four groups. Three grafts were collected at different time points for immunohistochemical studies. RESULTS: In the cornea, the FK-506 concentration reached its peak within 1 h of a single eye-drop instillation and then decreased by half (1667.85 +/- 611.87 ng/g) at 8 h. FK-506 cannot be detected in rabbit blood. There were significant differences in the graft-survival time between the FK-506 nanosphere group (15.09 +/- 4.81 days) and the other three groups [PBS (7.90 +/- 1.20, t = -4.594, P < 0.001), PLGA (8.44 +/- 0.88, t = - 4.074, P = 0.001) and dexamethasone (10.44 +/- 1.42, t = -2.790, P = 0.012)]. The rejected corneas in the FK506 nanosphere group showed significantly fewer CD4, CD8, CD68, CD79, vascular endothelial growth factor, ICAM, and tumor growth factor-beta(1)-positive cells than those in the other groups. CONCLUSIONS: FK506 0.01% nanospheric-suspension eye drops delayed the occurrence of corneal allograft rejection and prolonged allograft survival time. The FK506 nanospheres may be valuable in suppressing corneal graft rejection.

[The pharmacokinetics of FK506 and its nanoparticles in aqueous humor of rabbits].

OBJECTIVE: To investigate the pharmacokinetics of FK506 and its nanoparticles in aqueous humor of rabbits applied with eye drops or subconjunctiva injections. METHODS: 42 New Zealand albino rabbits were divided into 2 groups. (1) Nanoparticle solution containing 10 microg FK506 was injected into subconjunctiva or dropped on conjunctival sac of rabbits (68 eyes in 34 cases). (2) Eye drops containing 20 or 40 microg FK506 without nanoparticles were dropped on conjunctival sac of rabbits (16 eyes in 8 cases). Aqueous humor was collected at different times after local administration and FK506 concentrations were measured by ELISA. Ocular pharmacokinetic parameters of FK506 were calculated by 3p87 software. RESULTS: In the solution containing nanoparticle, the effective FK506 concentration in aqueous humor could be kept up to 16 h in eye drops group. The range of FK506 concentration was between (15.50 +/- 3.39) - (2.59 +/- 0.83) ng/ml. FK506 in aqueous humor can be maintained for 96 h by injecting into subconjunctiva and FK506 concentration were between (9.62 +/- 2.19) - (2.60 +/- 0.21) ng/ml from 6 - 96 h. T(max) and C(max) in eye drops were (1.25 +/- 0.50) h and (15.52 +/- 2.37) ng/ml respectively; while T(max) and C(max) in subconjunctiva injection were (64.00 +/- 13.86) h and (10.16 +/- 1.37) ng/ml respectively. Each AUC(0-->t) was (152.44 +/- 16.74) ng.ml(-1).h(-1) and (612.48 +/- 54.39) ng.ml(-1).h(-1) respectively; each Ka was 3.790 +/- 0.730 and 0.040 +/- 0.004 respectively; and each MRT was (8.20 +/- 1.28) h and (58.53 +/- 5.42) h respectively. In the eye drops containing 20 microg or 40 microg FK506 but without nanoparticles applied in conjunctival sac of rabbits, all effective FK506 concentrations in aqueous humor could not be kept over 4 h. T(max) was 1 h and C(max) was (18.93 +/- 6.95) ng/ml in 20 microg FK506, while in 40 microg FK506 T(max) was 2h and C(max) was (28.33 +/- 1.31) ng/ml. CONCLUSION: Solution with FK506 nanoparticle dropping onto the eye or injecting into subconjunctiva could be sustained in rabbit aqueous humor for a longer time than non-nanoparticle FK506 solution, while with injecting of nanoparticle FK506 solution it could be detected with a relative low but longer effective concentration.

[Dry eye in graft-versus-host disease].

OBJECTIVE: To investigate patients who had ocular presentations after allogeneic hematopoietic stem cell transplantation. METHODS: The eyes of 20 patients of leukemia who had undergone allogeneic hematopoietic stem cell transplantation were examined. The ocular surface of these patients was examined by slit-lamp. The eye examination also included evaluation of tear break-up time, Schirmer tests with and without nasal stimulation, and fluorescein staining, rose bengal staining, etc. Conjunctival impression cytology and pathological examination of surgical specimens from 3 patients were performed. RESULTS: Fourteen of 20 patients developed chronic graft-versus-host disease (cGVHD). Eight patients suffered from dry eye accompanied by GVHD simultaneously. The incidence of dry eye in GVHD was 57%. Among them, 4 cases were severe dry eye associated with significant decrease of visual acuity and even development of corneal ulcer. Ophthalmic pathology findings were as follows: loss of conjunctival goblet cells or significant reduction in amount; conjunctival and corneal epithelial keratinization and squamous metaplasia; and dominance of T cell in conjunctival inflammatory infiltration cells. CONCLUSION: Dry eye is the major ocular complication after allogeneic hematopoietic stem cell transplantation. It affected the patients' life quality severely. The high incidence and potentially severe ocular problems in these patients suggest that close ophthalmic monitoring is important in allogeneic hematopoietic stem cell transplantation.