新型纳米载药系统对眼内血管新生抑制作用的研究

The vast majority of diseases that cause catastrophic loss of vision, such as age related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusions and ocular tumours, do so as a result of pathologic ocular neovascularization. Because neovascularization is the common pathway to blindness in these common conditions, the need to develop effective treatments for targeting ophthalmic angiogenesis-related disorders of the retina is very important. Clinically, an effective treatment is anti-VEGF antibody that has been proven to restore and preserve vision in patients that suffer from these blinding conditions. However, because of the large molecular size of anti-VEGF antibody, the unique anatomy and physiology of the ocular barriers has blocked the efficient delivery of drug to intraocular tissues, especially the choroid and the retina. The Current treatment requires frequent injections into the eye for life, with the considerable risks associated with that invasive intraocular procedure. There is therefore an immediate need to seek better, safer and non-invasive alternatives to prevent these conditions. The generation of shape-specific nanocarriers such as lyotropic liquid crystalline nanoparticles (cubosomes) and their potential for sustained-release show great promise in drug delivery. We have found that IgG conjugated in cubosome has enhanced cellular uptake compared to IgG itself. Moreover, the modified cubosome-conjugated IgG antibody can penetrate into mouse eyes when administrated subconjunctivally. Our hypothesis is that Cubosome conjugated anti-VEGF provides a potential drug delivery system to replace direct injections into the eye to block intraocular vascularisation, thus brings the non-invasive drug delivery method to the posterior segment of the eye. It is anticipated that this nanotechonoly-based drug delivery system will provide a non-invasive treatment for pathologic ocular neovascularization and thus potentially eliminate the risks of injection. If successful, it offers a practical revolution in the management of many eye diseases. This non-invasive ocular drug delivery method would open the way to translate these outcomes into clinical therapies...Specific Aims: .1..To formulate cubosomes conjugated FITC-labeled antibody with better cellular uptake and eye penetration both in vitro and in vivo. .2..To investigate the dosage and bioavailability of cubosome-conjugated anti-VEGF antibody through pharmacokinetic study in rabbits. .3..To determine the therapeutic potential of cubosome-conjugated anti-VEGF antibody on pathological ocular neovascularization in rats models: oxygen-induced retinopathy (OIR) model and laser induced choroidal neovascularization (CNV) model.

眼内新生血管性疾病如年龄相关性黄斑变性、糖尿病视网膜病变等是致盲的首要原因。目前临床对这类疾病的治疗主要依靠玻璃体腔内注射抗血管内皮生长因子（VEGF）抗体的方法，但这种创伤性治疗方式本身伴有感染、出血、视网膜脱离、视力丧失等风险。寻找一种微创、更安全有效的治疗方法是目前临床上亟需解决的难题。我们拟利用纳米立方液晶（cubosomes）作为药物载体的优点，建立一种新型立方液晶抗VEGF抗体结膜下给药系统，通过改良立方液晶的成分增强其被细胞摄取及透过眼组织屏障的能力；通过离体和在体实验，探讨该系统的安全性、有效性及对眼组织屏障的穿透能力；通过眼部血管新生动物模型验证此系统在结膜下给药的情况下对新生血管的治疗潜力。本课题的研究将避免直接眼内注射的风险，为大量眼部新生血管性疾病患者提供革命性的微创治疗方式，从而更好地提高患者的治疗效果，减少并发症的发生，其成果具有重要的科学意义和广阔的应用前景。

新生血管性眼病是眼科的难治性疾病和重要的致盲原因，很多致盲的眼病都是由于新生血管引起，如糖尿病性视网膜病变、年龄相关性黄斑病变、新生血管性青光眼、早产儿视网膜病变及各种眼部肿瘤等。因此眼部血管新生的治疗，成为患者、眼科医生和卫生系统的重要课题。血管内皮生长因子（VEGF）是直接作用于血管内皮细胞的多肽类生长因子，在生理性和病理性眼部新生血管的形成过程中都起着至关重要的作用。VEGF抑制剂可以抑制眼部新生血管形成。目前玻璃体腔内注射抗VEGF抗体的方法，是治疗眼内新生血管的首要方法。但这种创伤性治疗方式本身伴有感染、出血、视网膜脱离的风险，而且部分患者对抗VEGF抗体治疗产生耐药及不应性。如何减少眼内注射的次数及找到治疗的新靶点是目前临床迫切需要解决的难题。.本课题组利用立方液晶建立一种眼部缓释给药系统。我们利用不同的脂质及稳定剂制备了不同的立方液晶，并发现立方液晶的稳定性是受温度，盐分及酸碱度影响的。同时，我们发现利用F108 作为稳定剂比用F127作为稳定剂对细胞更安全（p<0.01）。应用立方液晶作为载药体系，载药效率为30%。立方液晶用于鼠眼玻璃体腔及结膜下注射后3个月视网膜各层厚度及功能都没有变化（p<0.05），证明立方液晶对视网膜组织没有毒副作用。立方液晶释药系统可以达到缓释药物的作用。.此外，我们还发现microRNA可以作为眼部新生血管的新靶点，并在分子、细胞和整体动物水平上证明此载药系统抗血管新生的作用及其机理。研究给予microRNA后对VEGF信号通路的影响，从分子水平探讨此给药系统的有效性；并通过荧光素眼底血管造影(FFA)，病理组织切片及脉络膜血管铺片检查等方法对microRNA用于治疗眼内新生血管的潜力进行检测。.本课题的研究将克服目前临床上对视网膜、脉络膜等眼后部组织的新生血管性疾病需要频繁玻璃体内注射的缺陷，避免眼内注射的风险；并为大量眼部血管新生性疾病患者提供革命性的微创治疗方式，从而更好地提高患者的治疗效果，减少并发症的发生

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