Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release Pub Date : 2025-10-11 DOI:10.1016/j.jconrel.2025.114314

Saito Inoue, Keisuke Shirakura, Atsuya Shirono, Jumpei Taguchi, Yoshiki Ikeda, Satomi Tomita, Risa Funatsu, Kosuke Muraoka, Yosuke Hashimoto, Keisuke Tachibana, Nobumasa Hino, Takefumi Doi, Yui Ikemi, Kazuto Nunomura, Bangzhong Lin, Shinsaku Nakagawa, Kazutake Tsujikawa, Shota Tanaka, Masanori Obana, Yasushi Fujio, Yoshiaki Okada

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Abstract

The blood–brain barrier (BBB) protects the brain from harmful substances, but it also limits drug delivery, hindering the treatment of brain diseases. Claudin 5, a tight junction protein in endothelial cells, plays a key role in maintaining the BBB integrity. Although modulation of Claudin 5 is a promising strategy for transiently opening the BBB, the currently available modulators often cause adverse effects due to strong or prolonged activity. Thus, we aimed to develop a moderate Claudin 5 modulator that enables safe and transient opening of the BBB. We identified a Claudin 5-binding small molecule (CL5B), capable of binding Claudin 5 via a high-throughput screening of 9600 compounds using a Claudin 5 antibody and proteoliposomes. CL5B increased endothelial permeability and tracer permeation across the endothelial monolayer by altering the localization of Claudin 5 without affecting its expression. In mice, CL5B transiently opened the BBB for less than 30 min, delivering drugs specifically to the brain. Notably, CL5B-facilitated delivery of methylscopolamine, a drug with limited brain penetration, alleviated seizure symptoms in a mouse epilepsy model. These findings demonstrate that CL5B is a safe BBB modulator that enhances brain drug delivery and holds therapeutic potential for brain diseases.

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克劳丁5结合小分子可瞬间打开血脑屏障，安全增强脑内药物传递

血脑屏障（BBB）保护大脑免受有害物质的侵害，但它也限制了药物的输送，阻碍了脑部疾病的治疗。Claudin 5是内皮细胞中的紧密连接蛋白，在维持血脑屏障完整性中起关键作用。虽然Claudin 5的调制是一种很有前途的策略，可以瞬间打开血脑屏障，但目前可用的调节剂由于活性强或时间长，往往会引起不良反应。因此，我们的目标是开发一种适中的Claudin 5调制器，使血脑屏障安全和瞬态打开。我们通过使用Claudin 5抗体和蛋白脂质体对9600种化合物进行高通量筛选，鉴定出一种Claudin 5结合小分子（CL5B），能够结合Claudin 5。CL5B通过改变Claudin 5的定位而不影响其表达，从而增加内皮通透性和示踪剂穿过内皮单层的通透性。在小鼠中，CL5B短暂打开血脑屏障的时间不到30 min，将药物特异性地递送到大脑。值得注意的是，在小鼠癫痫模型中，cl5b促进了甲基东莨菪碱（一种大脑渗透有限的药物）的递送，减轻了癫痫发作症状。这些发现表明，CL5B是一种安全的血脑屏障调节剂，可增强脑药物传递，具有治疗脑疾病的潜力。

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来源期刊

Journal of Controlled Release 医学-化学综合

CiteScore

18.50

自引率

5.60%

发文量

700

审稿时长

39 days

期刊介绍： The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.