Multivalent nanoparticles bind the retinal and choroidal vasculature.
Multivalent nanoparticles bind the retinal and choroidal vasculature.
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DOI：
10.1016/j.jconrel.2015.10.033
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
R. Hennig;A. Ohlmann;Janina Staffel;K. Pollinger;Alexandra Haunberger;M. Breunig;F. Schweda;E. Tamm;A. Goepferich
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文献类型：
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作者：
R. Hennig;A. Ohlmann;Janina Staffel;K. Pollinger;Alexandra Haunberger;M. Breunig;F. Schweda;E. Tamm;A. Goepferich
血管紧张素II受体1型（AT1R）在眼后部血管中表达，在严重眼部疾病如糖尿病视网膜病变和年龄相关性黄斑变性的发病机制中具有重要意义。然而，小分子血管紧张素受体阻滞剂（ARB）尚未被证明是一个显着的治疗成功。我们在这里报告的纳米粒子系统组成的ARB分子呈现在量子点（Qdots）的表面上的多价的方式。作为多价受体结合的结果，纳米颗粒靶向具有高AT1R表达的细胞，并抑制其血管紧张素受体信号传导，IC50为3.8 nM，同时仅显示与低AT1R表达的细胞的微小关联。静脉注射到小鼠尾静脉后，多价纳米颗粒积聚在后眼的视网膜和脉络膜血管中。同时，与非靶向Qdot相比，多价配体展示使血管中的Qdot浓度加倍。值得注意的是，ARB靶向的量子点在表达AT1R的脱靶组织如肾脏中没有明显的积累。全身应用后，这种多价靶向方法有可能放大眼睛中的AT1R阻断，并同时将治疗有效载荷递送到眼部病变中。
The angiotensin II receptor type 1 (AT1R), which is expressed in blood vessels of the posterior eye, is of paramount significance in the pathogenesis of severe ocular diseases such as diabetic retinopathy and age-related macular degeneration. However, small molecule angiotensin receptor blockers (ARBs) have not proven to be a significant therapeutic success. We report here on a nanoparticle system consisting of ARB molecules presented in a multivalent fashion on the surface of quantum dots (Qdots). As a result of the multivalent receptor binding, nanoparticles targeted cells with high AT1R expression and inhibited their angiotensin receptor signaling with an IC50of 3.8 nM while showing only minor association to cells with low AT1R expression. After intravenous injection into the tail vein of mice, multivalent nanoparticles accumulated in retinal and choroidal blood vessels of the posterior eye. At the same time, multivalent ligand display doubled the Qdot concentration in the blood vessels compared to non-targeted Qdots. Remarkably, ARB-targeted Qdots showed no pronounced accumulation in AT1R-expressing off-target tissues such as the kidney. Following systemic application, this multivalent targeting approach has the potential to amplify AT1R blockade in the eye and concomitantly deliver a therapeutic payload into ocular lesions.