As an expert in protein chemistry, Dr. Maeda conducted a wide range of research, including not only cancer treatment, but also cancer prevention, viral and bacterial infections, and left a great legacy of accomplishments. This article will focus on EPR effects, as they are introduced in his other books. Although the EPR effect has been proven worldwide in experimental mouse tumors, Dr. Maeda and the author have been discussing for a long time the fact that it is not widely accepted in clinical solid tumors. In order to make the EPR effect a sound theory in clinical practice, Dr. Maeda adopted a strategy to enhance tumor vascular hyperpermeability, which is a key factor in the EPR effect. The author adopted a strategy of adding cancer stroma targeting therapy to the EPR effect. Professor Maeda and the author believe that from the perspective of solid tumor treatment, the difference between cancer tissues and normal tissues defined by the EPR effect is more important than the molecular biological differences between cancer cells and normal cells.

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Mitochondria carry out various essential functions including ATP production, regulating apoptosis, and they also have their own genome, mitochondrial DNA. In recent years, mitochondrial dysfunctions have been implicated as being involved in a number of diseases. Therefore, drug delivery systems（DDS） targeting mitochondria represent a promising tool in various fields including the life sciences, drug discovery and gene therapy. Many mitochondrial DDS developments have been reported during the past decade, however, only a limited number of approaches are available for mitochondrial therapy. Because these strategies face many problems including cell internalization, size limitations and the physicochemical properties of the cargos, modification of a functional device, and the denaturation of the cargoes. To overcome these problems, the DDS development using nanotechnology has been attracting attention, and nano-DDS development research is underway to deliver cargoes to mitochondria. In this review, we described the development of nano-DDS targeting mitochondria and our research on MITO-Porter, a liposomal nano-DDS targeting mitochondria.

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Depression constitutes a significant global social issue. Numerous therapeutic medications have been developed in accordance with the monoamine hypothesis；nonetheless, the prevalence of treatment-resistant depression remains a pressing clinical concern. Hence, it is imperative to contemplate an alternative approach that extends beyond the confines of monoamine systems. Recently, substantial attention has been directed toward the gut-brain axis, a concept suggesting that the intestinal environment influences brain function. Nevertheless, the intricate mechanism associated with the gut-brain axis remain incompletely elucidated. In this study, our specific focus resides on intestinal reactive oxygen species（ROS）, as elevated ROS levels are known to disturb the intestinal environment. To investigate the impact of scavenging intestinal ROS on depression treatment via the gut-brain axis, a novel polymer-based antioxidant（siSMAPo^TN） was purposefully engineered for exclusive distribution within the intestinal tract following oral administration. siSMAPo^TN was designed to selectively scavenge intestinal ROS and protected the intestinal environment from harm induced by chronic restraint stress（CRS）. In addition, the administration of siSMAPo^TN resulted in the suppression of physiological and behavioral symptoms associated with depression in the CRS mouse model.

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Drug transporters recognize diverse drugs as substrate and play an important role as determinants of systemic circulation and tissue distribution of drugs in vivo. They are comprised of the members of Solute carrier （SLC） family （SLCO, SLC22, SLC47） and ATP binding cassette family （ABCB1, ABCC2, ABCC4, and ABCG2）. In this article, we introduce recent topics in drug transporter research, including our laboratory. （1） The three-dimensional structures of multispecific organic anion transporters in the liver, OATP1B1 and OATP1B3, have been solved that aid deep understanding of the mechanism for recognizing diverse compounds as substrates and suggest the driving force for active transport. （2） Cells derived from human tissues are indispensable to investigate roles of drug transporters in vitro. Microphysiological systems （or complex in vitro systems） that mimic human organ physiology have emerged and advanced in vitro models for ADME studies. Stem cells in the crypt of gut can differentiate to various cells including absorptive epithelial cells for in vitro drug transport and metabolism analysis. （3） Substrates of drug transporters includes endogenous metabolites whose plasma concentrations or renal clearance is tightly associated with the activities of drug transporters. They are considered as endogenous biomarkers to detect the variation in drug transporter activities in humans who receive administration of drugs that has potential to inhibit transporters at their clinically relevant doses.

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In this review chalenges for the development of plastic antibodies are summarized.

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The genetic information stored in dsDNA is transcribed into mRNA, which is then translated into protein to express its function. Nucleic acid therapeutics, as a modality that acts directly on nucleic acids, is being developed for the treatment of intractable diseases. In recent years, various mechanisms that control the spatio-temporal expression of genetic information, such as non-protein-codding ncRNAs, higher-order structures of nucleic acids, and small chemical modifications, have been elucidate, and the development of artificial functional molecules targeting these mechanisms is underway. This paper reviews the topic of nucleic acid therapeutics and artificial functional molecules that artificially manipulate gene functions.

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NGENLA^Ⓡ is the first long-acting recombinant growth hormone treatment for the indication of “short statue due to growth hormone deficiency without closed epiphyses” approved in January 2022. NGENLA is a groundbreaking medicine which offers a new once-weekly treatment option for children living with growth hormone deficiency. NGENLA can help reduce the burden associated with daily growth hormone administration and improve treatment adherence. This review summarizes the characteristics, pharmacokinetic property, and data from clinical studies of NGENLA.

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