Cyclic Peptides KS-133 and KS-487 Multifunctionalized Nanoparticles Enable Efficient Brain Targeting for Treating Schizophrenia

Kotaro Sakamoto; Seigo Iwata; Zihao Jin; Lu Chen; Tatsunori Miyaoka; Mei Yamada; Kaiga Katahira; Rei Yokoyama; Ami Ono; Satoshi Asano; Kotaro Tanimoto; Rika Ishimura; Shinsaku Nakagawa; Takatsugu Hirokawa; Yukio Ago; Eijiro Miyako

doi:10.1021/jacsau.4c00311

Cyclic Peptides KS-133 and KS-487 Multifunctionalized Nanoparticles Enable Efficient Brain Targeting for Treating Schizophrenia

JACS Au. 2024 Jun 20;4(8):2811-2817. doi: 10.1021/jacsau.4c00311. eCollection 2024 Aug 26.

Authors

Kotaro Sakamoto¹, Seigo Iwata², Zihao Jin^{3

4}, Lu Chen³, Tatsunori Miyaoka³, Mei Yamada³, Kaiga Katahira³, Rei Yokoyama^{4

5}, Ami Ono^{4

6}, Satoshi Asano⁴, Kotaro Tanimoto⁶, Rika Ishimura⁷, Shinsaku Nakagawa^{3

7

8}, Takatsugu Hirokawa^{9

10}, Yukio Ago^{3

4

8}, Eijiro Miyako²

Affiliations

¹ Research & Development Department, Ichimaru Pharcos Company Limited, 318-1 Asagi, Motosu, 501-0475 Gifu, Japan.
² Graduate School of Advanced Science and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, 923-1292 Ishikawa, Japan.
³ Laboratory of Biopharmaceutics, Osaka University, 1-6 Yamada-oka, Suita, 565-0871 Osaka, Japan.
⁴ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Hiroshima, Japan.
⁵ Laboratory of Molecular Neuropharmacology, Osaka University, 1-6 Yamada-oka, Suita, 565-0871 Osaka, Japan.
⁶ Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Hiroshima, Japan.
⁷ Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, 565-0871 Osaka, Japan.
⁸ Global Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, 565-0871 Osaka Japan.
⁹ Division of Biomedical Science, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575 Tsukuba, Japan.
¹⁰ Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, 305-8575 Tsukuba, Japan.

Abstract

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 N₃-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.