Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
J Control Release. 2021 Jul 10;335:527-540. doi: 10.1016/j.jconrel.2021.05.035. Epub 2021 May 29.
Inflammation and neovascularization are key pathological events in human age-related macular degeneration (AMD). Activated microglia/macrophages (mi/ma) and retinal pigmented epithelium (RPE) play an active role in every stage of disease progression. Systemic therapies that can target these cells and address both inflammation and neovascularization will broaden the impact of existing therapies and potentially open new avenues for early AMD where there are no viable therapies. Utilizing a clinically relevant rat model of AMD that mirrors many aspects that of human AMD pathological events, we show that systemic hydroxyl-terminated polyamidoamine dendrimer-triamcinolone acetonide conjugate (D-TA) is selectively taken up by the injured mi/ma and RPE (without the need for targeting ligands). D-TA suppresses choroidal neovascularization significantly (by >80%, >50-fold better than free drug), attenuates inflammation in the choroid and retina, by limiting macrophage infiltration in the pathological area, significantly suppressing pro-inflammatory cytokines and pro-angiogenic factors, with minimal side effects to healthy ocular tissue and other organs. In ex vivo studies on human postmortem diabetic eyes, the dendrimer is also taken up into choroidal macrophages. These results suggest that the systemic hydroxyl dendrimer-drugs can offer new avenues for therapies in treating early/dry AMD and late/neovascular AMD alone, or in combination with current anti-VEGF therapies. This hydroxyl dendrimer platform but conjugated to a different drug is undergoing clinical trials for severe COVID-19, potentially paving the way for faster clinical translation of similar compounds for ocular and retinal disorders.
炎症和新生血管形成是人类年龄相关性黄斑变性（AMD）的关键病理事件。活化的小胶质细胞/巨噬细胞（mi/ma）和视网膜色素上皮（RPE）在疾病进展的每个阶段都发挥着积极的作用。能够针对这些细胞并解决炎症和新生血管形成的系统性治疗方法将扩大现有治疗方法的影响，并为尚无可行治疗方法的早期 AMD 开辟新途径。利用与人类 AMD 病理事件有许多相似之处的临床相关 AMD 大鼠模型，我们发现系统给予羟端基聚酰胺胺树枝状大分子-曲安奈德偶联物（D-TA）可被损伤的 mi/ma 和 RPE 选择性摄取（无需靶向配体）。D-TA 可显著抑制脉络膜新生血管形成（>80%，比游离药物好 50 倍以上），通过限制病理性区域的巨噬细胞浸润，减弱脉络膜和视网膜的炎症，显著抑制促炎细胞因子和促血管生成因子，对健康眼组织和其他器官的副作用极小。在对人死后糖尿病眼的离体研究中，树枝状大分子也被摄取到脉络膜巨噬细胞中。这些结果表明，系统给予羟端基树枝状大分子-药物可为治疗早期/干性 AMD 和晚期/新生血管性 AMD 提供新途径，单独使用或与目前的抗 VEGF 治疗联合使用。这种羟端基树枝状大分子平台但与不同的药物偶联，正在用于严重 COVID-19 的临床试验，为类似化合物用于眼部和视网膜疾病的更快临床转化铺平了道路。
