Nanoparticle-based drug delivery system found that could transform schizophrenia treatment

Schizophrenia is a complex mental disorder characterized by a wide range of symptoms, such as hallucinations, impaired cognitive abilities, and disorganized speech or behavior. It is associated with abnormalities in neurotransmission due to an imbalance of chemical neurotransmitters. Current treatment strategies for schizophrenia include the use of antipsychotic drugs, which can cause side effects and are associated with a high risk of cardiovascular disease. In addition, patients often have an inadequate response to therapeutic drugs, as the blood-brain barrier (BBB), a protective barrier of cells, tightly regulates the movement of ions and molecules into the brain.

To overcome the BBB barrier and facilitate the transport of therapeutic drugs into brain tissue for the treatment of schizophrenia, researchers have explored the possibility of using receptor-mediated transcytosis (RMT) using the low-density lipoprotein receptor 1 (LRP1). This study was conducted by a team led by Associate Professor Eijiro Miyako from the Japan Advanced Institute of Science and Technology (JAIST) in collaboration with Professor Yukio Ago from Hiroshima University, Professor Shinsaku Nakagawa from Osaka University, Professor Takatsuga Hirokawa from the University of Tsukuba, and Dr. Kotaro Sakamoto, a senior leading scientist at Ichimaru Pharcos Co., Ltd. Their study was published in JACS Au on June 20, 2024.

The researchers were inspired by previous findings showing the interaction of the vasoactive intestinal peptide receptor 2 (VIPR2) gene duplication with schizophrenia and their own discovery of a new peptide, KS-133. This new peptide, KS-133, has selective antagonist activity to VIPR2, leading to its downregulation. However, the main limiting factor associated with KS-133 is its low permeability across the BBB.

To facilitate efficient transport of KS-133 to the brain, they developed a brain-targeting peptide, KS-487, that could specifically bind to LRP1 and affect RMT. Finally, the researchers developed a novel nanoparticle drug delivery system (DDS) in which the KS-133 peptide was encapsulated with the targeting peptide KS-487 and studied its efficacy in the treatment of schizophrenia.

The application of peptide formulations via DDS resulted in efficient drug distribution in the brain of mice. Drug release profiles assessed by pharmacokinetic analysis confirmed the role of the brain-targeted peptide in the transport of KS-133 into the brain. Furthermore, the efficacy of DDS was assessed in mice with induced schizophrenia by increasing the activation of VIPR2. Mice treated with KS-133/KS-487 nanoparticles showed significant improvement in cognitive function during novel object recognition tests, which can be explained by the inhibition of VIPR2.

Explaining the practical application and potential of their research, Dr. Miyako noted, "Existing drugs only involve mechanisms related to neurotransmitter modulation, and their therapeutic effects are limited, especially for cognitive dysfunction. Thus, our peptide formulation can be used as a new drug for restoring cognitive dysfunction in schizophrenia."

In conclusion, this study by Dr. Miyako and co-authors provides preclinical evidence for a novel therapeutic strategy targeting VIPR2 that may improve cognitive impairment in schizophrenia. “We will further expand our study to include cell and animal models as well as human clinical trials to confirm the efficacy and safety of this peptide formulation and promote its development as a new treatment for schizophrenia within 5 years,” concluded Dr. Miyako, who is optimistic about the long-term implications of their study.

We hope that the discovery and development of new DDSs using biocompatible peptides will revolutionize the schizophrenia treatment landscape!