Involvement of trigeminal axons in nose-to-brain delivery of glucagon-like peptide-2 derivative
Involvement of trigeminal axons in nose-to-brain delivery of glucagon-like peptide-2 derivative
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三叉神经轴突参与胰高血糖素样肽 2 衍生物从鼻到脑的递送
DOI：
10.1016/j.jconrel.2022.09.047
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发表时间：
2022
影响因子：
10.8
通讯作者：
Yamashita Chikamasa
中科院分区：
文献类型：
--
作者：
Akita Tomomi;Oda Yusuke;Kimura Ryosuke;Nagai Mio;Tezuka Ayano;Shimamura Mizuki;Washizu Kaho;Oka Jun-Ichiro;Yamashita Chikamasa
在我们之前的研究中，我们创建了具有功能序列PAS-CPP的胰高血糖素样肽-2（GLP-2）衍生物，以实现呼吸上皮和三叉神经的有效摄取。通过将八精氨酸用于细胞穿透肽（CPP）和将组织蛋白酶D序列的一部分的反向序列FFLIPKG用于穿透加速序列（PAS），我们发现该衍生物通过巨胞饮作用被细胞摄取并有效地从内体逃逸并离开细胞。经鼻给药（in.）以与脑室内（icv.）本研究的目的是阐明以与icv给药相同的剂量静脉给药PAS-CPP-GLP-2的药物作用的原因。本结果表明，尽管静脉给药的PAS-CPP-GLP-2进入了脑脊液，但它几乎没有穿透脑的血管周围空间，因此，只有少量的给药剂量可能到达脑中的作用部位。与此相反，定性地表明，给药的PAS-CPP-GLP-2从三叉神经经三叉神经感觉主核迁移到中枢神经系统，然后通过三叉神经丘系。本结果表明，通过三叉神经轴突的鼻-脑递送是可能的，这被认为是一种跨细胞途径。由于药物可以被递送到神经中，因此预期其不仅作为中枢递送途径应用，而且还用于治疗神经系统疾病。
In our previous study, we created a glucagon-like peptide-2 (GLP-2) derivative with the functional sequence PAS-CPP to achieve efficient uptake by the respiratory epithelium and trigeminal nerve. By using octaarginine for cell penetrating peptides (CPP) and FFLIPKG, a reverse sequence of a part of the cathepsin D sequence for the penetration accelerating sequence (PAS), we found that the derivative was taken up by the cells through macropinocytosis and efficiently escaped from the endosomes and exited the cells. Moreover, it showed drug effects by intranasal (in.) administration at the same dose as intracerebroventricular (icv.) administration, which is direct drug administration into the brain.The purpose of this study was to elucidate the cause of the drug effect ofin.administered PAS-CPP-GLP-2 at the same dose as that byicv.administration. The present results suggested that althoughicv.administered PAS-CPP-GLP-2 entered the cerebrospinal fluid, it barely penetrated the perivascular space of the brain, and therefore, only a small amount of the administered dose may have reached the site of action in the brain. In contrast, it was qualitatively suggested thatin.administered PAS-CPP-GLP-2 migrates from the trigeminal nerve to the central nervous system via the principal sensory trigeminal nucleus and then through the trigeminal lemniscus.The present results show that nose-to-brain delivery by trigeminal axons, which is assumed to be a transcellular pathway, may be possible. As the drug can be delivered into the nerve, it is expected to be applied not only as a central delivery route but also for the treatment of neurological diseases.