Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier.
Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier.
复制标题
Claudin-1靶向纳米颗粒用于治疗衰老引起的血脑屏障改变。
DOI：
10.1021/acsnano.1c08432
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发表时间：
2021-11-23
期刊：
影响因子：
17.1
通讯作者：
Kievit, Forrest M.
中科院分区：
文献类型：
--
作者：
Bony, Badrul Alam;Tarudji, Aria W.;Miller, Hunter A.;Gowrikumar, Saiprasad;Roy, Sourav;Curtis, Evan T.;Gee, Connor C.;Vecchio, Alex;Dhawan, Punita;Kievit, Forrest M.
关键词：
衰老引起的血脑屏障（BBB）改变越来越被视为导致认知能力下降的慢性进行性神经系统疾病的主要事件。为了增加向大脑的输送，希望有效地治疗这些疾病，人们把重点放在了开发血脑屏障可渗透材料上。然而，这些策略缺乏针对疾病进展区域的特异性。在这里，我们报道了一种纳米颗粒（ccc2 - np）的开发，该纳米颗粒靶向cludin -1表达增加的区域，从而降低血脑屏障的完整性。通过动态对比增强磁共振成像（DCE-MRI），我们发现与非靶向NPs和2月龄小鼠相比，12月龄小鼠大脑中的ccc2 - np积累和保留显著增加。此外，我们发现ccc2 - np在高cladin -1表达的脑内皮细胞中积累，表明NPs与靶标特异性结合，通过荧光成像、体外测试和生物物理分析验证了这一点。我们的研究结果进一步表明，claudin-1在衰老过程中降低血脑屏障完整性的作用，并表明claudin-1表达的改变可以被NPs积极靶向。这些发现有助于制定在衰老过程中纵向监测紧密连接蛋白表达变化的策略，并可作为在疾病发展的早期阶段靶向递送治疗药物的递送策略。
Aging-induced alterations to the blood-brain barrier (BBB) are increasingly being seen as a primary event in chronic progressive neurological disorders that lead to cognitive decline. With the goal of increasing delivery into the brain in hopes of effectively treating these diseases, a large focus has been placed on developing BBB permeable materials. However, these strategies have suffered from lack of specificity towards regions of disease progression. Here we report on the development of a nanoparticle (C1C2-NP) that targets regions of increased claudin-1 expression that reduces BBB integrity. Using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) we find that C1C2-NP accumulation and retention is significantly increased in brains from 12-month-old mice as compared to non-targeted NPs and brains from 2-month-old mice. Furthermore, we find C1C2-NP accumulation in brain endothelial cells with high claudin-1 expression, suggesting target-specific binding of the NPs, which was validated through fluorescence imaging, in vitro testing, and biophysical analyses. Our results further suggest a role of claudin-1 in reducing BBB integrity during aging and show altered expression of claudin-1 can be actively targeted with NPs. These findings could help develop strategies for longitudinal monitoring of tight junction protein expression changes during aging as well as be used as a delivery strategy for site-specific delivery of therapeutics at these early stages of disease development.
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影响因子：
4.1
作者：
Bharadwaj, Vimala N.;Copeland, Connor;Stabenfeldt, Sarah E.
通讯作者：
Stabenfeldt, Sarah E.
影响因子：
3.3
作者：
Deoni, SCL;Peters, TM;Rutt, BK
通讯作者：
Rutt, BK
影响因子：
4.1
作者：
Bony, Badrul Alam;Miller, Hunter A.;Kievit, Forrest M.
通讯作者：
Kievit, Forrest M.
紧密连接链内和之间异质claudin物种相互作用的方式。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
4.6
作者：
Bharadwaj VN;Lifshitz J;Adelson PD;Kodibagkar VD;Stabenfeldt SE
通讯作者：
Stabenfeldt SE