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Boron neutron capture therapy (BNCT) is expected to be a promising next-generation cancer treatment. In 2020, Japan, which has led the research on this treatment modality, was the first country in the world to approve BNCT. The boron agents that have been clinically applied in BNCT include a caged boron compound (mercaptoundecahydrododecaborate: BSH) and a boron-containing amino acid (p-boronophenylalanine: BPA). In particular, the BPA preparation Steboronine ® is the only approved drug for BNCT. However, the problem with BPA is that it is poorly retained in the tumor and has very low solubility in water. This cannot be overlooked for BNCT, which requires large amounts of boron in the tumor. The high dosage volume, together with low tumor retention, leads to reduced therapeutic efficacy and increased physical burden on the patient. In the case of BSH, its insufficient penetration into the tumor is problematic. Based on drug delivery system (DDS) technology, we have developed a next-generation boron pharmaceutical superior to Steboronine ® . Our approach involves the redevelopment of BPA using innovative ionic liquid formulation technology. Here, we describe previous boron agents and introduce our recent efforts in the development of boron compounds.

Liposomes have been reported to be useful nanocarrier, however, there are number of challenges to resolve before they can be optimized for drug delivery. Liposomes are taken up by cell in the reticuloendothelial system (RES). Polyethyleneglycol (PEG) modification on the liposomal membrane forms a fixed aqueous layer and thus prevents uptake by the RES. The physicochemical properties of liposomes that are most commonly evaluated particle size and zeta potential are not sufficient indicator of the passive targeting effect by PEG modification. In contrast, the fixed aqueous layer thickness (FALT) around liposomal surface was clear to be regulated to be the utilized action in the body. It was showed that the FALT value of PEG-modified liposomes containing doxorubicin increased with the increase in the molecular weight of PEG. Furthermore, PEG modification with a combination of high- and low- molecular weight PEGs on liposomal membranes showed in optimal results with respect to FALT and a higher antitumor effect. In addition, we designed and synthesized a novel PEG-lipid, different double arms PEG (DDA-PEG), which consisted of two PEG chains of 500 and 2000 in one molecule to develop more useful PEG-modified liposomes. DDA-PEG was found to have superior antitumor activity and was associated with the prevention of tumor metastasis. Furthermore, we sought to (-)-epigallocatechin-3-O-gallate (EGCG) functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. EGCG-PEG-modified liposome appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects.

Nanoparticles, including liposomes and lipid nanoparticles, have garnered global attention due to their potential applications in pharmaceuticals, vaccines, and gene therapies. These particles enable targeted delivery of new drug modalities such as highly active small molecules and nucleic acids. However, for widespread use of nanoparticle-based formulations, it is crucial to comprehensively analyze their characteristics to ensure both efficacy and safety, as well as enable consistent production. In this context, this review focuses on our research using atomic force microscopy (AFM) to study liposomes and lipid nanoparticles. Our work significantly contributes to the capability of AFM to measure various types of liposomes in an aqueous medium, providing valuable insights into the mechanical properties of these nanoparticles. We discuss the applications of this AFM technique in assessing the quality of nanoparticle-based pharmaceuticals and developing membrane-active peptides.

Copyright of Kobunshi Ronbunshu is the property of Society of Polymer Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Kobunshi Ronbunshu is the property of Society of Polymer Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Kobunshi Ronbunshu is the property of Society of Polymer Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Molecular crowding and confinement in small spaces are remarkable features of living cells. To reveal the physicochemical aspects of these features, the effects of confinement-size and droplet surface on them should be separated from them. Water-in-oil microdroplets covered with a lipid layer (droplet system) have suitable characters to separate them, because the droplet sizes and lipid species covering the droplet are easily controlled. Here, we introduce recent achievements using the droplet system that has revealed effects of confinements on protein expression, accelerated phase-separation of biopolymer blends, and behaviors of highly concentrated biopolymers. [ABSTRACT FROM AUTHOR]

Magnetic nanoparticle-incorporated liposomes (magnetic liposomes) are considered a promising site-specific drug delivery carrier. Although there are many reports on the development of magnetic liposomes, most of them focus on the characteristics of magnetic nanoparticles, rather than liposomes. Therefore, we first evaluated the effect of the physicochemical properties of magnetic liposomes on their interaction with cells. The highest cellular uptake and retention under a magnetic field was observed using small magnetic cationic liposomes. However, magnetic cationic liposomes exhibited strong cytotoxicity. Based on these results, we constructed complexes of less toxic magnetic anionic liposomes (Mag-AL) and atelocollagen (ATCOL), a biocompatible cationic biomaterial. The cellular associated amount of Mag-AL under a magnetic field was significantly increased when Mag-AL was complexed with ATCOL, and it was comparable to that of magnetic cationic liposomes. Additionally, Mag-AL/ATCOL complexes produced no cytotoxic effect. Moreover, liver accumulation of Mag-AL/ATCOL complexes was significantly increased at a magnetic field-exposed region after intravenous injection in rats. These results indicate that Mag-AL/ATCOL complexes may be a safe and efficient magnetic responsive drug carrier. Next, we applied Mag-AL/ATCOL complexes to prepare magnetized cells for effective cell therapy. Mesenchymal stem cells (MSCs), which have the capacity to suppress tissue inflammation, were efficiently magnetized by incubation with Mag-AL/ATCOL complexes under a magnetic field. Intramuscularly injected magnetized MSCs were significantly retained in mouse skeletal muscle in the presence of a magnetic field and modulated tissue inflammatory responses. These results suggest that magnetized MSCs are useful for muscle regeneration.

In the development of drug delivery system (DDS)-based anticancer drugs, the techniques for the intratumor mapping and quantification of active pharmaceutical ingredients (API) in pharmaceuticals must be pivotal for predicting pharmacological effects and adverse events. X-ray fluorescence spectrometry (XRF) is a potent analytical tool for mapping/quantifying platinum pharmaceutics such as oxaliplatin (l-OHP) and its liposomal formulation. In recent studies, we employed XRF to visualize the intratumor micro-distribution of l-OHP in a tumor-bearing model mouse intravenously injected with either free l-OHP or l-OHP liposomes. The intratumor distribution of l-OHP within tumor sections could be determined by XRF to detect platinum atoms. After treatment with the liposomal formulation, the l-OHP was localized near the tumor vessels and, via repeated injections, increasingly accumulated in tumors by a much greater degree than treatment with free l-OHP. The repeated injections of l-OHP liposomes improved the vascular permeability via inducing the apoptosis of tumor cells near the tumor vessels, which should improve the tumor microenvironment and enhance the intratumor accumulation of repeated doses of l-OHP liposomes. The proposed process was also used to visualize the intratumor distribution of l-OHP in rectal cancer specimens resected from a patient who had received l-OHP-based preoperative chemotherapy. We further revealed that neutralization of an acidic tumor microenvironment via oral administration with NaHCO 3 could improve the therapeutic efficacy of weakly basic anticancer agent-encapsulating liposomes. Collectively, mapping/quantifying the intratumor API in DDS drugs and/or improving the tumor microenvironment would be an effective means to accelerate the clinical development of DDS-based anticancer drugs.

Increase in vascular permeability of the blood-brain barrier (BBB) is a distinct pathology following ischemic stroke. In previous studies, we demonstrated that liposomal drug delivery system (DDS)-based delivery of neuroprotectants is useful for treating cerebral ischemia/reperfusion injury. Additionally, our previous studies reported that combination therapy with liposomal fasudil plus tissue plasminogen activator (t-PA), a thrombolytic agent, brings about decrease in the risk of t-PA-derived cerebral hemorrhage and prolong the therapeutic time window of t-PA for treating acute ischemic stroke. However, accumulation of systemically administered liposomes into the brain parenchyma is still limited, and new technologies are needed that can overcome the BBB. The unique properties of leukocytes and exosomes, one of the extracellular vesicles, make them promising candidates for overcoming biological barriers (including the BBB) for drug delivery, as leukocytes and certain exosomes were reported to be able to permeate through the inflamed BBB in the ischemic stroke area. We prepared leukocyte-mimetic liposomes (LM-Lipo) via transfer of leukocyte membrane proteins by employing a phenomenon called intermembrane protein transfer, and demonstrated that LM-Lipo could pass through the layer of inflamed endothelial cells via regulation of intercellular junctions, like leukocytes. Additionally, we showed that LM-Lipo efficiently penetrated into spheroids of cancer cells, and inhibited their growth by entrapped doxorubicin. Taken together, it was suggested that imparting leukocyte-like characteristics to liposomes may be an effective approach to overcoming biological barriers. Herein, we summarize our findings regarding liposomal DDS for ischemic stroke therapy and recent approaches to develop biomembrane-mimetic DDS using leukocytes and exosomes.

Because active-targeted liposomes are very complex formulations, quality characteristics of functional lipids have not been defined yet, and this is a major obstacle in clinical application of active targeted liposomes. We have developed high functionality and quality (HFQ) lipids, which define quality characteristics of functional lipids for clinical drug delivery system (DDS) applications. Because HFQ lipids are designed to enable facile and rapid functionalization of DDS carrier by simple and one-step mixing, we are expanding applications for not only liposomes but also exosomes and cells. Recently, we developed multi-color deep imaging by tissue clearing for analysis of spatial distribution of DDS in various tissues. Nanocarriers are usually non-uniformly distributed in solid tumors because of their heterogeneity. Especially, in refractory cancer such as pancreatic cancer, the presence of collagen and blood vessels greatly affects intra-tumor distribution of DDS carrier. Therefore information on spatial relations between the tissue structure and DDS carrier is important to regulate precisely intra-tumor distribution of DDS carrier. Recently, our group has established multi-color deep imaging to analyze spatial distribution of stromal collagen, liposomes, and blood vessels in pancreatic tumor tissue. In this review, we present recent research in developing HFQ lipids. Moreover, current status of research on DDS for pancreatic cancer treatment is reviewed.

Novel dosage form designs aiming at patient centric drug therapy are summarized here based on my carrier research in this field. The common key word for this research is particle design. The topics will be divided into two parts, based on the type of particle: coarse particles (powder) and colloidal particles. The former includes the preparation and characterization of functional particles prepared using a spray dryer. Solid dispersions, solvent deposition particles and dry emulsion systems are described. Polymer coated liposomes are described as a useful drug delivery carrier in several administration routes. As chitosan, a mucoadhesive polymer, was used as a coating polymer, the resultant chitosan-coated liposome was found to work as a good carrier for peptide drugs such as insulin and calcitonin in the gastrointestinal tract after oral administration. In another administration route (inhalation), polymer-coated liposomes enhanced the absorption of the drugs. Liposomal carriers applied to the surface of the eye as eye drops are able to deliver drugs to the posterior part of the eye, such as the retina. As a typical example of patient centric dosage form design, particle designs for the preparation of orally disintegrating tablets and films were introduced in one of our recent studies on oral dosage form design.

Bioactive gas molecules, including oxygen, nitric oxide and carbon monoxide (CO), exhibit a variety of physiological activities, and are associated with the onset and progress of some disorders. These facts have led researchers to the development of bioactive gas donors for the treatment of intractable disorders. Hemoglobin is likely an ideal carrier of bioactive gases, since hemoglobin in red blood cells innately carries oxygen in the form of oxyhemoglobin, nitric oxide in the form of S-nitrosohemoglobin, and CO in the form of carbonylhemoglobin. In this study, we attempted to develop a biomimetic CO delivery system using a preparation of hemoglobin. Our strategy for the preparation of this hemoglobin-based CO carrier involves CO being exogenously bound to red blood cells or hemoglobin-encapsulated liposomes, called hemoglobin-vesicles (HbV), which mimic the structure and function of red blood cells. We accumulated evidence that the CO donors-CO-bound red blood cells and CO-bound HbV-showed therapeutic efficacy against intractable disorders in animal models. Here, we describe the potential of hemoglobin-based CO donors, especially CO-bound red blood cells and CO-bound HbV, for the treatment of certain disorders. Hemoglobin-based strategies for the delivery of other bioactive gases for novel drug development are also discussed.

We previously showed that increased permeability of the blood-brain barrier (BBB) after ischemic stroke enables extravasation of nano-sized liposomes and accumulation in the ischemic region, and that delivery of neuroprotective agents using liposomal drug delivery systems (DDS) is applicable for treating cerebral ischemia/reperfusion (I/R) injury. However, entry of liposomes into the brain parenchyma was limited in the early stages after I/R possibly due to microvascular dysfunction induced by pathological progression. As such, new approaches to overcome the BBB are needed. Leukocytes can pass through inflamed BBB in I/R region due to membrane proteins displayed on their surface. We thus hypothesized that incorporation of leukocyte membrane proteins onto liposomal membranes would impart leukocyte-mimicking functions to liposomes and that leukocyte-mimetic liposomes (LM-Lipo) may pass through inflamed endothelial cells and BBB, similar to leukocytes. LM-Lipo prepared using intermembrane protein transfer from human leukemia cells showed significantly increased association to inflamed human umbilical vein endothelial cells relative to plain liposomes. Moreover, LM-Lipo passed through inflamed endothelial cell layer by regulating intercellular junctions. These results suggest that imparting leukocyte-like properties to liposomes via intermembrane protein transfer would be an effective strategy to overcome inflamed endothelial barriers. In this review, we describe our findings on ischemic stroke treatment using liposomal DDS and the potential of LM-Lipo to overcome inflamed endothelial barriers.

Hydrophobically-modified hydroxypropylmethylcellulose (HM-HPMC) is a thickener with a long hydrophobic alkyl side chain. In this study, we investigated the gelation ability and rheological properties of a liposome/HM-HPMC mixed solution. The liposome suspension and the HM-HPMC aqueous solution each had low viscosities, but the viscosity increased rapidly when they were mixed. This is thought to be due to the formation of a 3D network structure caused by the hydrophobic group of HM-HPMC penetrating into the liposomal bilayer membrane, crosslinking the liposomes together. This hypothesis was supported by the fact that gelation did not occur when hydroxypropylmethylcellulose without a hydrophobic group was used. The viscosity of the liposome/HM-HPMC mixed solution decreased rapidly when a shear was applied, but immediately returned to the original gel state when the shear was removed, indicating a reversible reaction. When a strong shear is applied, the hydrophobic group of HM-HPMC detaches from the liposome. When the shear is removed, the liposome is again cross-linked by HM-HPMC. From these results, it was revealed that liposome cross-linked gels can be prepared when HM-HPMC is used.

The blood supply system for transfusions in Japan functions well. However, in cases of sudden hemorrhagic shock, the swift supply of red blood cell (RBC) product might be difficult, particularly when medical care is required in remote regions and in obstetric medicine, where there is always a risk of hemorrhage. Blood pressure maintenance by infusion of volume expanders, such as crystalloids or colloids, may be insufficient to preserve the function of vital organs because they do not contain any oxygen-carrying molecules. If artificial RBCs were at hand, they could be used as a blood substitute until blood products are received from blood banks. This would save patients without degrading their quality of life. In the 1990s, we developed an artificial RBC in the form of a hemoglobin vesicle (Hb-V). Hb-V is a liposomal microparticle that encloses oxygen-carrying human Hb molecules. Different from RBCs, it has no blood type and is stable at room temperature, ensuring a long shelf-life. Its excellent biocompatibility and oxygen-carrying capacity have been proven in a number of animal experiments, and its production technique has also been established. Therefore, translational research is being designed with the aid of the Japan Agency of Medical Research and Development.

Nucleic acid therapy is expected to be a next generation medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel delivery system. The modification of polyethylene glycol (PEG), i.e., PEGylation, is useful for achieving the delivery of MENDs to tumors via an enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits the cellular uptake and endosomal escape of MEND, which results in significant loss of action, and therefore lost effectiveness, of the cargo therapeutic. For successful nucleic acid delivery in cancer treatment, the crucial problem associated with the use of PEG, known as the "PEG dilemma", must be solved. In this review, we describe the development and application of MEND in overcoming the PEG dilemma based on manipulating both the pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release using a cleavable PEG lipid, a pH-sensitive fusogenic peptide, and a pH-sensitive cationic lipid. We also developed dual-ligand liposomes with a controlled diameter of around 300 nm, then modified these with a specific ligand and a cell penetrating peptide designed to target the neovasculature of tumors. Dual-ligand liposomes could induce an anti-tumor effect in drug resistant tumors by delivering drugs to tumor blood vessels, rather than to the cancer cells themselves. Here, we review our recent efforts to develop a novel liposomal drug delivery system (DDS) by manipulating pharmacokinetics and intracellular trafficking for drug therapy and nucleic acid medicine.

Hemoglobin vesicles (HbVs) in which human hemoglobin is encapsulated in a phospholipid bilayer membrane (liposome) have been developed as artificial red blood cells. Although the effectiveness of HbVs, including their physicochemical characteristics and pharmacological effects, has been reported, data on the pharmacokinetic properties of HbVs are limited. Previously, we developed two kinds of radiolabeled HbV, 125 I-HbV and 3 H-HbV, in which the internal hemoglobin and lipid membranes were labeled with 125 I and 3 H, respectively. Using these isotope-labeled HbVs, we clarified the detailed pharmacokinetic properties of HbVs in healthy animals and experimental animal disease models of hemorrhagic shock, chronic cirrhosis, and hyperlipidemia. This review describes our previous results regarding the pharmacokinetic properties of HbVs, and we discuss the safety and usefulness of HbVs from the viewpoint of their pharmacokinetic characteristics. Furthermore, we have modified HbVs by employing them as a carbon monoxide (CO) carrier because the hemoglobin inside HbVs reversibly binds to CO, resulting in CO-bound HbVs (CO-HbVs). Here we report the potential of CO-HbVs for the treatment of intractable inflammatory disorders based on their therapeutic efficiency in experimental animal models.

Tocopheryl phosphoric acid (TPA, a hydrophilic vitamin E derivative) loaded liposome and glycerin containing phospholipid nanoparticles (GPLNP) were prepared using the film rehydration and extrusion method. Nanoparticle formulations were evaluated for size, zeta potential, and in vitro permeation across hairless mouse skin, and 31 P NMR spectral analysis was performed. The prepared formulations were stable for 2 weeks, and their mean nanoparticle size varied between 90 and 140 nm. Although glycerin did not affect the particle size of the empty (no TPA) system, TPA-loading resulted in the reduction of particle size and conferred a negative charge. The 31 P NMR spectral analysis showed that the presence of glycerin in the formulation changed the nanoparticle structure from a bilayer to a nonbilayer. Moreover, it was suggested that TPA molecules interacted with phospholipid by entrapping nanoparticles in the formulations. TPA did not permeate across the hairless mouse skin after 48 h. However, the TPA concentration in the hairless mouse skin after permeation study increased in the nanoparticle systems and the 30% GPLNP formulation was the best formulation for the accelerated TPA permeation in the hairless mouse skin. These results demonstrate that 30% GPLNP improved TPA permeation in the hairless mouse skin model. And it was strongly suggested that glycerin has an important role for changing the structure of nanoparticles and enhancing the skin permeation of TPA.