Nanoparticles for the Treatment of Neovascularizations in the Eye

用于治疗眼部新生血管的纳米颗粒

• 批准号: 269235691
• 负责人: Professor Dr. Achim Goepferich
• 金额: --
• 依托单位: Klinik und Poliklinik für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269235691?language=en
• 关键词: Nanoparticles; Treatment; Neovascularizations; Eye

Age-related macular degeneration (AMD) and diabetic retinopathy are among the leading causes of blindness and affect together worldwide more than 100 million people. The wet form of AMD and proliferative diabetic retinopathy (PDR) share pathogenic mechanisms of endothelial cell hyperproliferation and blood vessel hyperpermeability. Since vascular endothelial growth factor (VEGF) drives both processes, intraocular injections of VEGF antibodies evolved as a highly successful therapeutic strategy. However, since VEGF is a pivotal factor for retinal tissue maintenance its unspecific elimination triggers severe adverse effects. The goal of this project will be to develop nanoparticles for more selective therapeutic strategies. A first approach is a retinal and choroidal endothelium-specific anti-VEGF strategy and based on our discovery that integrin receptor-targeted nanoparticles accumulate in retinal blood vessels upon intravenous injection. We will design lipid nanoparticles that are able to transport cyclosporin A and itraconazole, two potent and synergistic VEGF signaling inhibitors, to retinal and choroidal endothelial cells following systemic administration. The second strategy is a VEGF-signaling independent intervention and rests on our finding that ligand-decorated nanoparticles bind to cell surface receptors in a way that is superior to that of a free ligand. With such multivalent binding nanoparticles we will silence the angiotensin II receptor type 1 (AT1R) which exhibits pro-inflammatory effects in wet AMD as well as PDR. We will, thereby, attach AT1R antagonists either to quantum dots to identify the tissue binding sites of such particles, or branched polymers for therapeutic purposes. Such constructs can either be administered systemically or via intravitreal injection. Both, drug loaded therapeutic lipid particles and multivalent binding AT1R antagonists, will first be tested and optimized in vitro for their cell binding behavior in cell culture. The biodistribution of both will be tested and further refined in healthy mice. The efficacy of drug loaded lipid nanoparticles and multivalent AT1R antagonists with a particularly favorable distribution into the retinal and choroidal endothelium will be finally tested in a mouse model of oxygen-induced neovascularization.

年龄相关性黄斑变性 (AMD) 和糖尿病性视网膜病变是导致失明的主要原因，影响着全球超过 1 亿人。湿性 AMD 和增殖性糖尿病视网膜病变 (PDR) 具有内皮细胞过度增殖和血管通透性过高的共同致病机制。由于血管内皮生长因子 (VEGF) 驱动这两个过程，因此眼内注射 VEGF 抗体已成为一种非常成功的治疗策略。然而，由于 VEGF 是视网膜组织维持的关键因素，其非特异性消除会引发严重的副作用。该项目的目标是开发纳米颗粒以实现更具选择性的治疗策略。第一种方法是视网膜和脉络膜内皮特异性抗 VEGF 策略，基于我们的发现，即静脉注射后，靶向整合素受体的纳米颗粒会在视网膜血管中积聚。我们将设计脂质纳米颗粒，能够在全身给药后将环孢素 A 和伊曲康唑（两种有效且具有协同作用的 VEGF 信号抑制剂）转运至视网膜和脉络膜内皮细胞。第二种策略是独立于 VEGF 信号传导的干预，并基于我们的发现，即配体修饰的纳米颗粒以优于游离配体的方式与细胞表面受体结合。通过这种多价结合纳米粒子，我们将沉默 1 型血管紧张素 II 受体 (AT1R)，该受体在湿性 AMD 和 PDR 中表现出促炎作用。因此，我们将把 AT1R 拮抗剂附着在量子点上以识别此类颗粒的组织结合位点，或者附着在支化聚合物上以用于治疗目的。此类构建体可以全身施用或通过玻璃体内注射施用。载药治疗性脂质颗粒和多价结合 AT1R 拮抗剂都将首先在体外测试和优化其在细胞培养物中的细胞结合行为。两者的生物分布将在健康小鼠中进行测试并进一步完善。载药脂质纳米粒子和多价 AT1R 拮抗剂（特别有利地分布在视网膜和脉络膜内皮中）的功效最终将在氧诱导新血管形成的小鼠模型中进行测试。

项目成果

Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors.

• DOI: 10.1021/acs.molpharmaceut.5b00301
• 发表时间: 2015-08
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: R. Hennig;Anika Veser;S. Kirchhof;A. Goepferich

Multivalent nanoparticles bind the retinal and choroidal vasculature.

• DOI: 10.1016/j.jconrel.2015.10.033
• 发表时间: 2015-12
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: R. Hennig;A. Ohlmann;Janina Staffel;K. Pollinger;Alexandra Haunberger;M. Breunig;F. Schweda;E. Tamm;A. Goepferich

Nanoparticles Targeting Retinal and Choroidal Capillaries In Vivo.

体内靶向视网膜和脉络膜毛细血管的纳米颗粒

• DOI: 10.1007/978-1-4939-8669-9_25
• 发表时间: 2019
• 期刊: Methods in molecular biology
• 作者: Haunberger A;Goepferich A.
• 通讯作者: Goepferich A.

Intracellular availability of poorly soluble drugs from lipid nanocapsules

• DOI: 10.1016/j.ejpb.2019.03.007
• 发表时间: 2019-06-01
• 期刊: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
• 影响因子: 4.9
• 作者: Bohley, Marilena;Haunberger, Alexandra;Goepferich, Achim M.
• 通讯作者: Goepferich, Achim M.