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In Vivo Nucleic Acid Delivery System Based on the Development of Unique Functional Lipids
Balancing world-class functional delivery of nucleic acids and safety
We have developed a unique group of functional lipids for the safe and efficient in vivo delivery of siRNA. The lipid nanoparticles containing these lipids showed world-class functional delivery of siRNA in hepatocytes due to their excellent endosomal escape ability and high safety due to their biodegradability.
Research
The key to the practical application of siRNA is the development of superior delivery technology, but there is still much room for improvement in the delivery efficiency. In addition, from the viewpoint of practicality, it is also important to secure a wide safe therapeutic window. It is also highly desirable to develop platform technologies that can provide appropriate formulations for different purposes without being limited to specific applications. To achieve these goals, we have developed a unique group of pH-sensitive cationic lipids. We achieved the modulation of acid dissociation constants, which is an important factor for the pharmacokinetics of lipid nanoparticles, enabling a target-specific molecular design. The lipid nanoparticles containing the novel lipid CL4H6 induced gene silencing in hepatocytes with world-class efficiency. No significant hepatotoxicity was also observed even after the administration of approximately 3,000-fold higher dose for 50% gene silencing, thus a high level of safety was confirmed. CL4H6 was rapidly degraded and eliminated after siRNA delivery.
Yusuke Sato Assistant Professor -
Mitochondria-targeted Nanocapsules (MITO-Porter)
Technology to introduce drugs, proteins and nucleic acids into mitochondria
The mitochondrion is attracting attention as an organelle that contributes to the treatment of diseases, maintenance of beauty and health and the development of the life sciences. We have successfully developed a mitochondria-targeted nanocapsule (MITO-Porter) and are aiming to commercialize this nanocapsule.
Research
The mitochondria-targeted nanocapsules (MITO-Porter) in this study can pass through the cell and mitochondrial membranes to deliver target molecules inside the mitochondria. Conventional technologies using functional elements severely limit the size and type of molecules to be delivered, but the strategy using MITO-Porter, which encapsulates the target molecule, enables mitochondrial delivery independent of the molecular species.
When we prepared MITO-Porter with GFP (green) encapsulated and observed intracellular fluorescence microscopy, we observed many yellow signals that overlap with mitochondria (red), confirming efficient molecular delivery inside the mitochondria. We have also succeeded in introducing genes and nucleic acids into mitochondria, which had been impossible with existing nucleic acid delivery agents (targeting the nucleus and cytoplasm). We are also developing nanocapsules that can be adapted to living organisms.Yuma Yamada Professor -
Sonoporation: Development of a New Drug Delivery Method Using Ultrasound and Microbubbles
Realization of tissue targeting capability at the cellular level
We were the first in the world to show that, by irradiating cells with pulsed ultrasound while microbubbles of several microns in diameter are attached to the cells, we can temporarily increase the cell membrane permeability. We are now promoting research aimed at realizing drug and gene delivery to living organisms.
Research
○ Acoustic perforation (sonoporation) using microbubbles and pulsed ultrasound: Pulsed ultrasound irradiation of microbubbles in contact with the cell membrane enables temporary perforation only at the attachment site (Fig. 1). We have realized a method to deliver drugs or genes into any desired position in the target cell by adding drugs or genes to the microbubbles and controlling the attachment site with optical tweezers.
○ Succeeding with therapeutic site identification and drug delivery by using microbubbles and an ultrasound system: A microbubble, which has the target function of adhering only to the cells to be treated, is injected into a vein. To identify the therapeutic site, the tissue where the bubbles have accumulated is detected using an ultrasound contrast method. Pulsed ultrasound waves are then generated to break the bubbles, allowing temporary perforation of the cell membrane and drug delivery (Fig. 2). By adding drugs or genes to the bubbles, highly efficient drug delivery only to the target cells can be realized.Nobuki Kudo Associate Professor
