Research Institute for Science & Technology, Tokyo University of Science

Development of Cell Therapy System Using DNA Hydrogel - Recently, DNA nanotechnology has been attracting attention because it can artificially design various nucleic acid structures by utilizing the characteristics of DNA, in which complementary base sequences form double strands. We have designed a base sequence that links two types of DNA nanostructures to each other, and have succeeded in developing a DNA hydrogel that gels by self-assembly by mixing them. In this study, we will attempt to develop a cell therapy system by encapsulating cells in DNA hydrogels that have various functions.

Development of Cell Therapy System Using DNA Hydrogel - Recently, DNA nanotechnology has been attracting attention because it can artificially design various nucleic acid structures by utilizing the characteristics of DNA, in which complementary base sequences form double strands. We have designed a base sequence that links two types of DNA nanostructures to each other, and have succeeded in developing a DNA hydrogel that gels by self-assembly by mixing them. In this study, we will attempt to develop a cell therapy system by encapsulating cells in DNA hydrogels that have various functions.

Development of Curative Treatment for COPD through Alveolar Regeneration": Despite being the third leading cause of death in the world, only symptomatic treatment is available for chronic obstructive pulmonary disease (COPD). In order to achieve a curative treatment for COPD, we will discover a new compound that regenerates alveoli and develop a system to efficiently deliver the compound to the point of action using an approach of alveolar regeneration based on induction of cell differentiation. 　Development of therapeutic agents for depression and dementia using DDS technology based on a new concept": The number of patients with central nervous system diseases such as depression and dementia is increasing year by year, and although research has been conducted for many years to develop new drugs with high therapeutic efficacy, both drug contribution and treatment satisfaction are still low. The number of patients with these diseases is increasing every year. In this study, we will develop a clinically applicable drug delivery system (DDS) to deliver neuropeptides that can treat depression and dementia from the nose to the brain, and elucidate the mechanism of their transfer to the brain.

Development of Curative Treatment for COPD through Alveolar Regeneration": Despite being the third leading cause of death in the world, only symptomatic treatment is available for chronic obstructive pulmonary disease (COPD). In order to achieve a curative treatment for COPD, we will discover a new compound that regenerates alveoli and develop a system to efficiently deliver the compound to the point of action using an approach of alveolar regeneration based on induction of cell differentiation. 　Development of therapeutic agents for depression and dementia using DDS technology based on a new concept": The number of patients with central nervous system diseases such as depression and dementia is increasing year by year, and although research has been conducted for many years to develop new drugs with high therapeutic efficacy, both drug contribution and treatment satisfaction are still low. The number of patients with these diseases is increasing every year. In this study, we will develop a clinically applicable drug delivery system (DDS) to deliver neuropeptides that can treat depression and dementia from the nose to the brain, and elucidate the mechanism of their transfer to the brain.

Drug delivery system using nanoparticles - Development of drug-containing nanoparticles for transdermal administration using biodegradable polymers. 　Synthesis of novel biodegradable polymers suitable for drug-incorporated micelles. Evaluation of physicochemical properties and therapeutic efficacy of micelles.

Preparation of polymeric microparticles with controllable surface properties and shape, and control of their interaction with cells - Microparticles are used as drug carriers, and the interaction between microparticles and cells, such as the cellular uptake of these microparticles, is known to be affected by physicochemical properties such as the particle size, shape, and surface properties of the microparticles. It is thought that the physical properties of these particles can be dynamically controlled in the vicinity of the target cells to actively control their uptake. Therefore, we are synthesizing microparticles whose surface properties and shape can be controlled by temperature, and analyzing the interaction between these microparticles and cells. 　Creation of organic-inorganic hybrid capsules for the treatment of bone defects Research Summary: To treat bone defects such as osteoporosis, it is necessary to simultaneously achieve bone regeneration and drug therapy. In order to achieve this goal, we are preparing organic-inorganic hybrid materials that can carry multiple drugs and promote bone regeneration. This material consists of an organic phase with drug-loading capacity inside and an inorganic phase with bone regeneration and drug-loading capacity in the shell. Therefore, it is expected to be a material that can achieve drug therapy and bone regeneration at the same time.

Research theme 1: Creation of organic-inorganic hybrid capsules for the treatment of bone defects In order to treat bone defects such as osteoporosis, it is necessary to achieve bone regeneration and drug therapy simultaneously. In order to achieve this goal, we are preparing organic-inorganic hybrid materials that can carry multiple drugs and promote bone regeneration. This material consists of an organic phase with drug-loading capacity inside and an inorganic phase with bone regeneration and drug-loading capacity in the shell. Therefore, it is expected to be a material that can achieve drug therapy and bone regeneration at the same time. Research theme 2: Synthesis of polymeric microparticles that control cell uptake by surface properties and shape Interactions between microparticles and cells, such as cell uptake, depend on the size, shape, and surface properties of the microparticles. If these properties can be controlled in the vicinity of the cell, the interaction between the particle and the cell can be controlled arbitrarily. Therefore, we have synthesized microparticles whose surface properties and shape can be controlled by temperature. These microparticles can change their surface hydrophilicity/hydrophobicity by changing the temperature, and can also change the shape of the particle core from rod-like to spherical to control the interaction with cells.

Development of Carrier-Free DDS Formulations Using DNA Dense Layers": If the distribution of drugs and genes in the body can be strictly controlled, it will be possible to achieve treatments with reduced side effects. For this purpose, it is common to use precisely designed drug/gene carriers (carriers) to form nanostructures. However, if the carrier itself is not sufficiently biodegradable or biocompatible, its toxicity is a major hindrance to its clinical application. In this research project, we aim to create carrier-free drug and gene delivery (carrier-free DDS) by fabricating nanostructures using only nucleic acid drugs and molecularly targeted drugs in order to fundamentally solve the potential toxicity of carriers (Collaborator: Prof. Akihiko Kikuchi (Tokyo Univ. of Science)). 　Development of a visual search kit for DNA affinity drugs: Compounds with strong affinity to DNA function as anticancer agents. The activity of these compounds is usually evaluated by gel electrophoresis using radiolabeled substrate DNA or by fluorescence detection based on fluorescence resonance energy transfer. However, these methods lack simplicity due to the complicated process including pretreatment and the time required for measurement. In this project, we aim to develop a kit for visual drug discovery using the brightly colored gold nanoparticles immobilized with double-stranded DNA in the form of brushes, which are aggregated and dispersed (Collaborator: Prof. Akihiko Kikuchi (Tokyo Univ. of Science)).

Physical Chemistry of Solubility and Dissolution Rates of Pharmaceutical and Polymeric Drugs". On a solid in contact with an aqueous solution, the drug molecules behave in a particular way, which is like an interfacial jockeying game. To explain this, the mathematical model cellular automaton is useful. Therefore, using logical and computational means, we will focus on kinetic analysis of experimental chemistry and quantum chemistry/molecular mechanics/dynamics.

「Research Topic": Colloidal Interface Science in DDS Research - Research Summary: Theoretical study of the motion of colloidal particles and the interaction between them in an electric field. tus today news introduced a study on the effect of fluid sliding on the surface of colloidal particles (September 26, 2019). Also, "Gel Electrophoresis of a Soft Particle" (H. Ohshima, Adv. Colloid Interface Sci., 271, 101977, 2019) is featured by Atlas of Science (January 13, 2021 (January 13, 2021).

Establishment of a novel anti-inflammatory concept through pharmacological regulation of aquaporins Aquaporins (AQPs) are known to be important water channels for efficient water metabolism in vivo, and their presence or absence also affects basic cellular functions such as proliferation and migration. We have also found that the expression of pro-inflammatory cytokines is increased in cells with AQPs, suggesting that AQPs may be a new target molecule for controlling pathological inflammation. In this project, we aim to validate the concept of inflammation control through the regulation of these AQPs and to establish pharmacological regulation methods. 　Research Theme 2: Research Outline Establishment of novel cancer immunotherapy by modulating the function of bone marrow-derived immunosuppressive cells (MDSCs) Bone marrow-derived immunosuppressive cells (MDSCs) are closely related to immune evasion of cancer cells and tumor growth. MDSCs are induced to differentiate from bone marrow cells during carcinogenesis, migrate to major tissues, and suppress the function of T cells and macrophages by releasing immunosuppressive factors. Therefore, suppression of MDSCs is expected to be a new concept of cancer immunotherapy, but there are no known drugs that pharmacologically modulate this process. The aim of this study is to investigate the effects of various drugs on the differentiation, migration, and functional expression of MDSCs and to propose novel MDSC inhibitors.

1. Development of patient-friendly formulations - In order to maximize the efficacy of a drug, it is important to select the appropriate dosage form and design the formulation. In this laboratory, we are developing semi-solid preparations, liquid preparations, and patch preparations, which are required in actual medical practice. We are also conducting research on nanoparticulation to improve the solubility and dispersibility of drugs contained in these formulations. 2. Drug Discovery and Drug Research for Wound Healing - In U.S., approximately 65 million people require wound care each year, and the need for wound care products is high on a global scale. In addition, the market for wound dressings is expected to grow further in the future, as the number of patients with bedsores is increasing due to the aging of society. Currently, wounds are treated by "surgical treatment," "treatment with dressings," and "drug therapy. In particular, dressing treatment, in which the wound is covered with a protective material, is a very common treatment method in the medical field, so a wound dressing material made of a new material that is easy for anyone to handle and has excellent functionality is highly desired. Currently, we are focusing on the preparation of hydrogels for wound healing, and are experimenting with various methods and materials.

Development of a nasal formulation of siRNA with enhanced bioadhesion - Since siRNA has properties that is difficult to be absorbed into the body and unstable, the only method of administration is injection, which is highly invasive to patients. Therefore, the development of a safe method of administration that is less invasive to patients is an important issue. We are currently conducting research on the possibility of developing a safe and less invasive method of intranasal administration of siRNA by encapsulating siRNA with a low-toxicity solubilizer and a polymer that enhances bioadhesion.

Developmental and Regenerative Medicine of Musculoskeletal System - Prevention and treatment of musculoskeletal diseases are important issues for prolongation of healthy life span and productive aging. The goal of our laboratory is to find new therapeutic methods for musculoskeletal diseases. Using genome editing and recombinant technologies, we will develop new disease model mice, identify the basic molecular and cellular principles underlying the formation, maintenance, and repair of the musculoskeletal system, discover the potential for pharmacological treatment of musculoskeletal diseases, and translate these findings into new therapeutic opportunities for intractable diseases.

Abnormalities in Cell Function and Chronic Inflammatory Diseases Caused by Changes in the ECM Environment - The extracellular matrix (ECM) environment is one of the ecological components whose composition changes significantly with aging. Tenascin-C is transiently expressed in inflammatory regions, but there is a bioactive region in this molecule that influences cell function through the regulation of cell adhesion. Therefore, we are investigating this region and its bioactivity to gain a new understanding of various age-related diseases, which are believed to be caused by chronic inflammation, and to create new therapeutic methods.