载 VEGF-A 的 PLGA 微粒玻璃体腔内给药可减少早产儿视网膜病变动物模型中的视网膜血管闭塞。
Intravitreal Delivery of VEGF-A-loaded PLGA Microparticles Reduces Retinal Vaso-Obliteration in an In Vivo Mouse Model of Retinopathy of Prematurity.
机构信息
a Department of Pediatrics , University of Wisconsin-Madison , Madison , WI , USA.
b Department of Ophthalmology and Visual Sciences , University of Wisconsin-Madison , Madison , WI , USA.
出版信息
Curr Eye Res. 2019 Mar;44(3):275-286. doi: 10.1080/02713683.2018.1542736. Epub 2018 Nov 9.
PURPOSE
Retinopathy of prematurity (ROP) is a condition of abnormal retinal vascularization with reduced levels of vascular endothelial growth factor (VEGF) causing vaso-obliteration (Phase I), followed by abnormal neovascularization from increased VEGF (Phase II). We hypothesized that intravitreal pro-angiogenic VEGF-A in microparticle form would promote earlier retinal revascularization in an oxygen-induced ischemic retinopathy (OIR) mouse model.
MATERIALS AND METHODS
Wildtype mice (39) were exposed to 77% oxygen from postnatal day 7 (P7) to P12. VEGF-A-loaded poly(lactic-co-glycolic acid) (PLGA) (n = 15) or empty PLGA (n = 14) microparticles were fabricated using a water-in-oil-in-water double emulsion method, and injected intravitreally at P13 into mice right eyes (RE). Left eyes (LE) were untreated. At P20, after retinal fluorescein angiography, vascular parameters were quantified. Retinal VEGF levels at P13 and flatmounts at P20 were performed separately.
RESULTS
VEGF-A-loaded microparticles had a mean diameter of 4.2 μm. with a loading level of 8.6 weight.%. Retinal avascular area was reduced in VEGF-treated RE (39.5 ± 9.0%) compared to untreated LE (52.6 ± 6.1%, p < 0.0001) or empty microparticle-treated RE (p < 0.001) and untreated LEs (p = 0.001). Retinal arteries in VEGF-treated RE were less tortuous than untreated LE (1.08 ± 0.05 vs. 1.18 ± 0.08, p < 0.001) or empty-microparticles-treated RE (p = 0.02). Retinal arterial tortuosity was similar in the LE of VEGF and empty microparticle-treated mice (P > 0.05). Retinal vein width was similar in VEGF-treated and empty microparticle-treated RE (P > 0.9), which were each less dilated than their contralateral LE (p < 0.01). VEGF levels were higher in P13 OIR mice than RA mice (p < 0.0001). Retinal flatmounts showed vaso-obliteration and neovascularization.
CONCLUSIONS
Endogenous retinal VEGF is suppressed in OIR mice. Exogenous intravitreal VEGF-A-loaded microparticles in OIR mice reduced retinal vaso-obliteration and accelerated recovery from vein dilation and arterial tortuosity. This may be beneficial in preventing Phase II ROP without systemic effects.
目的
早产儿视网膜病变（ROP）是一种视网膜血管异常形成的疾病，血管内皮生长因子（VEGF）水平降低导致血管闭塞（I 期），随后 VEGF 增加导致异常新生血管形成（II 期）。我们假设玻璃体腔内以微粒形式存在的促血管生成 VEGF-A 会促进氧诱导缺血性视网膜病变（OIR）小鼠模型中视网膜更早的再血管化。
材料和方法
39 只野生型小鼠从出生后第 7 天（P7）到 P12 暴露于 77%的氧气中。使用水包油包水双乳液法制备负载 VEGF-A 的聚（乳酸-共-羟基乙酸）（PLGA）（n=15）或空 PLGA（n=14）微粒，并在 P13 时玻璃体腔内注射到小鼠右眼（RE）。左眼（LE）未治疗。在 P20 进行视网膜荧光素血管造影后，定量评估血管参数。分别在 P13 时进行视网膜 VEGF 水平检测，在 P20 时进行视网膜铺片。
结果
负载 VEGF-A 的微粒平均直径为 4.2μm，载药量为 8.6wt%。与未治疗的 LE（52.6±6.1%，p<0.0001）或空微粒治疗的 RE（p<0.001）和未治疗的 LE（p=0.001）相比，VEGF 治疗的 RE 中的视网膜无血管区面积减少。与未治疗的 LE（1.18±0.08）或空微粒治疗的 RE（p=0.02）相比，VEGF 治疗的 RE 中的视网膜动脉更直。在 VEGF 和空微粒治疗的小鼠中，LE 的视网膜静脉宽度相似（P>0.9），均小于其对侧 LE（p<0.01）。在 P13 OIR 小鼠中，VEGF 水平高于 RA 小鼠（p<0.0001）。视网膜铺片显示血管闭塞和新生血管形成。
结论
OIR 小鼠中内源性视网膜 VEGF 受到抑制。OIR 小鼠玻璃体腔内注射负载 VEGF-A 的外源性微粒可减少视网膜血管闭塞，并加速从静脉扩张和动脉扭曲中恢复。这可能有益于预防没有全身作用的 II 期 ROP。
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