Nano-structured systems have been attracting attention as carriers that can selectively transport bioactive substances such as nucleic acid medicine to a target location in the body. However, none of these systems have been able to cross the blood-brain barrier （BBB） via a systemic route to realize safe and efficient delivery of their cargo to the brain parenchyma. To tackle this problem, the authors focused on a transport protein, glucose transporter-1（GLUT1）, which is highly expressed in brain capillary endothelial cells （BCECs）, to facilitate the transport of nano-structured systems across the BBB. GLUT1 is known to migrate from the luminal side to the abluminal side in response to a rapid increase of blood glucose concentration from the hypoglycemic state. Utilizing such unique characteristic of GLUT1, the authors designed a self-assembled supramolecular nanocarrier with glucose integrated on the surface at an optimal configuration. Results obtained in vivo have shown significant accumulation of the nanocarrier within the brain parenchyma, at an efficiency that far surpasses that of conventional strategies. Precise control of glucose density on the surface of the nanocarrier allowed selection of the accumulation point in the brain, and a particularly high degree of accumulation in the neurocytes was achieved. The developed method can be used for efficiently delivering a variety of drug modalities to the brain, which offers new treatment strategies to cure neurological disorders such as the Alzheimer’s disease.

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Clarifying the pathology of dementias such as Alzheimer’s disease and designing their therapeutic targets are potentially important for facilitating the development of drugs against the dementia. The biologics for treatment of dementia such as peptides, antibodies, and neurotrophic factors need drug delivery systems （DDS） that can efficiently bring them to the brain from administration sites. This review summarizes the nose-to-brain drug delivery strategy using cell-penetrating peptides （CPPs） that we have recently established. Our works suggest that intranasal coadministration with CPPs can effectively enhance the transport of biologics such as peptide drugs and antibodies to the brain parenchyma. Furthermore, the drugs delivered to the brain via the enhanced nose-to-brain transport can have the therapeutic potential in the dementia mouse models. The transport mechanisms associated with the enhanced nose-to-brain delivery of biologics via intranasal coadministration with CPPs are also summarized in this review.

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The blood-brain barrier （BBB） regulates the transport of substances between the brain and blood by forming tight junctions of brain microvascular endothelial cells. It is important for the development of drug delivery technology into the brain and effective CNS drugs to construct in vitro BBB models that enable the evaluation of transport into the human brain. However, evaluations in experimental animals, or existing models of human cells, have revealed their problems with species differences and tight junction formation. Recently, a method has been developed to differentiate brain microvascular endothelial cells from human iPS cells, which is expected to be a new human BBB model. In order to apply it to drug discovery and disease research, it is necessary to evaluate the variety of functional proteins in the BBB as well as the ability to form tight junctions in this human BBB model. In this review, we describe our research regarding the function of transporters in human iPS cells-derived BBB model and outline the usefulness of this model, including the differentiation methods and applications in disease research.

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Success in coronavirus infectious disease （COVID）-19 mRNA vaccines is prompting research and development of mRNA therapeutics in various medical fields. Particularly the central nervous system （CNS） has numerous intractable diseases demanding new therapeutic modalities. Proper mRNA delivery systems to the brain are essential for the mRNA-based treatment of CNS diseases. The delivery routes to CNS include local administration to the brain parenchyma and cerebrospinal fluid, systemic delivery across the blood-brain barrier （BBB）, and a nose-to-brain route. Polyplex micelles （PMs） loading mRNA show promise in the local administration, providing efficient protein expression in the broad area of the CNS tissue with minimal inflammatory responses and demonstrating their therapeutic potential in treating CNS diseases. For example, mRNA encoding an antibody fragment targeting amyloid beta reduced amyloid beta burden in the mouse brain after intraventricular delivery using PM. Moreover, in CRISPR/Cas9-based genome editing, PM loading Cas9 mRNA and single guide RNA enabled site-specific genome cleavage in the neurons, astrocytes, and microglia in the mouse brain after intraparenchymal delivery. Meanwhile, local delivery requires arduous and invasive procedures, limiting the target diseases. Thus, mRNA delivery systems for reaching CNS from the blood and nose are under intensive development, which would broaden the target CNS diseases of mRNA therapeutics.

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Many neurodegenerative diseases are diseases of high unmet medical need. Tauopathies such as Alzheimer’s disease, progressive supranuclear palsy, and frontotemporal lobar degeneration cause intracellular accumulation of tau aggregates due to abnormal phosphorylation of tau protein, which then propagate through neurons, resulting in neurodegeneration. Even if a drug that inhibits the accumulation of tau aggregates in neurons is found, it will be difficult to develop an effective therapeutic agent to prevent and fundamentally treat the progression of neurodegenerative diseases unless a DDS technology that can efficiently deliver the drug into the neurons and transfer the drug across neurons is developed. In this paper, the authors describe the development of a nose-to-brain system that is applicable to neurodegenerative diseases and can deliver neuropeptides to the site of action more efficiently than intraventricular administration via intra-neuronal axonal transfer and show central effects.

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The blood-brain barrier （BBB） is a major obstacle to the delivery of drugs to the central nervous system. In the BBB, the spaces between adjacent brain microvascular endothelial cells are sealed by multiprotein complexes known as tight junctions （TJs）. Claudin-5 （CLDN-5） is the essential protein for TJ in the BBB, which restricts the influx of small molecules up to approximately 800 Da. Thus, among the many components of the TJs, CLDN-5 has received the most attention as a target for drug delivery to the brain by loosening the TJ seal. Many researchers have attempted to develop technologies to selectively inhibit the CLDN-5 and open TJ in the BBB. In this review, we introduce the use of CLDN-5 binders have been shown to enhance the permeation of small molecules from the blood into the brain without apparent adverse effects and the safety concerns of CLDN-5-targeted technologies with respect to their clinical application.

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Blood-brain barrier restricts the transport of molecules between blood and brain parenchyma. Although blood-brain barrier is required to protect the brain from an invasion of harmful molecules, it is also an obstacle in the drug delivery to treat the disease in the brain. Therefore, several drug delivery systems are tried to be developed for efficient drug delivery to the brain. Recently, it has taken much attention that the combination of ultrasound and microbubbles, which is an ultrasound contrast agent, to increase the permeability of blood brain barrier. Ultrasound exposure induces the compression and expansion of microbubbles, and the mechanical behavior of microbubbles affects endothelial cells in the brain, resulting in enhancing the permeability of blood-brain barrier. It has been reported that the optimized ultrasound condition and characteristics of microbubble achieved less-invasive and efficient drug delivery to the brain. In this review, we introduce our study for brain targeted drug delivery using the combination of ultrasound and microbubbles and describe the current studies and prospects.

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Lutathera^Ⓡ injection is the first peptide receptor radionuclide therapy radiopharmaceutical in Japan for the treatment of somatostatin receptor（SSTR） positive neuroendocrine tumor（NET）. After somatostatin analogue labeled with radioactive Lutetium 177（¹⁷⁷Lu） is administered, it binds to somatostatin receptors, is taken up into tumor cells, and beta rays released from ¹⁷⁷Lu induce DNA damage and exert a cell growth-inhibitory effect. International Phase III study NETTER -1 demonstrated the efficacy and safety of this product in patients with SSTR-positive, unresectable or metastatic midgut NET. Lutathera^Ⓡ was approved in 31 European countries in September 2017, followed by the US, Canada, South Korea, Taiwan, and other countries. In Japan, efficacy and safety were confirmed in a Japanese phase I/II study in patients with SSTR positive unresectable or metastatic pancreatic, gastrointestinal, or pulmonary NET, and approval was obtained in June 2021.

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