Sakamoto Kotaro, Iwata Seigo, Jin Zihao, Chen Lu, Miyaoka Tatsunori, Yamada Mei, Katahira Kaiga, Yokoyama Rei, Ono Ami, Asano Satoshi, Tanimoto Kotaro, Ishimura Rika, Nakagawa Shinsaku, Hirokawa Takatsugu, Ago Yukio, Miyako Eijiro
Research & Development Department, Ichimaru Pharcos Company Limited, 318-1 Asagi, Motosu, 501-0475 Gifu, Japan.
Graduate School of Advanced Science and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, 923-1292 Ishikawa, Japan.
JACS Au. 2024 Jun 20;4(8):2811-2817. doi: 10.1021/jacsau.4c00311. eCollection 2024 Aug 26.
Establishing drug delivery systems (DDSs) for transporting drugs from peripheral tissues to the brain is crucial for treating central nervous system diseases. We previously reported the interactions of (1) KS-133, a selective antagonist peptide, with vasoactive intestinal peptide receptor 2 (VIPR2), a drug target for schizophrenia, and (2) KS-487, a selective binding peptide, with the cluster IV domain of low-density lipoprotein receptor-related protein 1 (LRP1), which is involved in crossing the blood-brain barrier. We developed a novel DDS-based strategy for treating schizophrenia using KS-487 as a brain-targeting peptide and KS-133 as a drug. Dibenzocyclooctyne-KS-487 was conjugated with N-indocyanine green (ICG) using a click reaction and administered intravenously into mice. Fluorescence was clearly observed from ICG in the brains of the mice. Nanoparticles (NPs) encapsulating ICG and displaying KS-487 were prepared and subcutaneously administered to mice, resulting in a significant accumulation of ICG in the brain. Pharmacokinetic analysis of NPs containing KS-133 and displaying KS-487 (KS-133/KS-487 NPs) revealed the time-dependent transport of KS-133 into the brain. KS-133/KS-487 NPs were subcutaneously administered to mouse models of schizophrenia, which significantly improved cognitive dysfunction. This is the first study to demonstrate the potential therapeutic efficacy of a multifunctionalized multipeptide NP in inhibiting VIPR2.
建立将药物从外周组织输送到大脑的给药系统（DDS）对于治疗中枢神经系统疾病至关重要。我们之前报道了（1）选择性拮抗剂肽KS-133与精神分裂症药物靶点血管活性肠肽受体2（VIPR2）之间的相互作用，以及（2）选择性结合肽KS-487与参与穿越血脑屏障的低密度脂蛋白受体相关蛋白1（LRP1）的IV簇结构域之间的相互作用。我们开发了一种基于DDS的新型策略来治疗精神分裂症，使用KS-487作为脑靶向肽，KS-133作为药物。通过点击反应将二苯并环辛炔-KS-487与N-吲哚菁绿（ICG）偶联，并静脉注射到小鼠体内。在小鼠大脑中清楚地观察到了ICG发出的荧光。制备了包封ICG并展示KS-487的纳米颗粒（NP），并皮下注射给小鼠，导致ICG在大脑中显著积累。对含有KS-133并展示KS-487的NP（KS-133/KS-487 NP）的药代动力学分析揭示了KS-133向大脑的时间依赖性转运。将KS-133/KS-487 NP皮下注射到精神分裂症小鼠模型中，显著改善了认知功能障碍。这是第一项证明多功能化多聚肽NP在抑制VIPR2方面具有潜在治疗效果的研究。
