Publishing type：Research paper (scientific journal)  

DOI： 10.3390/polym15122626

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Medulloblastoma is a life-threatening disease with poor therapeutic outcomes. In chemotherapy, low drug accumulation has been a cause of these outcomes. Such inadequate response to treatments has been associated with low drug accumulation, particularly with a limited cellular uptake of drugs. Recently, the conjugation of drugs to ligand molecules with high affinity to tumor cells has attracted much attention for enhancing drug internalization into target cells. Moreover, combining tumor-targeting ligands with nano-scaled drug carriers can potentially improve drug loading capacity and the versatility of the delivery. Herein, we focused on the possibility of targeting CD276/B7-H3, which is highly expressed on the medulloblastoma cell membrane, as a strategy for enhancing the cellular uptake of ligand-installed nanocarriers. Thus, anti-CD276 antibodies were conjugated on the surface of model nanocarriers based on polyion complex micelles (PIC/m) via click chemistry. The results showed that the anti-CD276 antibody-installed PIC/m improved intracellular delivery into CD276-expressing medulloblastoma cells in a CD276-dependent manner. Moreover, increasing the number of antibodies on the surface of micelles improved the cellular uptake efficiency. These observations indicate the potential of anti-CD276 antibody-installed nanocarriers for promoting drug delivery in medulloblastoma.

DOI： 10.3390/polym15071808

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/jacs.2c12348

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/polym15061368

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-Aβ antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aβ oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology. RESULTS: During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aβ species, such as Aβ oligomers, toxic Aβ conformers, and pyroglutamated Aβs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aβ plaques, Aβ-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer's disease. CONCLUSIONS: The results indicated that the strategy of reducing toxic Aβ species in early dementia owing to Alzheimer's disease by providing sufficient antibodies in the brain may modify Alzheimer's disease progression.

DOI： 10.1186/s12951-023-01772-y

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms23126686

Web of Science

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/nano.202100368

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/nano.202100368

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1039/d2cc01058e

Web of Science

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41551-021-00803-z

researchmap

Other Link： https://www.nature.com/articles/s41551-021-00803-z

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/adma.202105254

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/adma.202105254

Language：Japanese   Publisher：(一社)日本認知症学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Dynamic bursting in tumor vasculature has recently sparked interest as a novel particle transportation route for drug delivery. These bursts facilitate the transport of sub-100 nm nanoparticles into tumors, though their contribution on the access of other blood-borne particles remains unknown. To evaluate the versatility of this phenomenon, the in vivo kinetics of a variety of intravenously injected particles and their penetration in tumor xenografts and allografts are compared. Dextran, polymeric micelles, liposomes, and polymeric vesicles with diameters ranging from 32 to 302 nm are found to colocalize in virtually all vascular bursts. By mathematical modeling, the burst vent size is estimated to be 625 nm or larger, indicating the dynamic and stochastic formation of large permeation routes in tumor vasculature. Furthermore, some burst vents are found to be µm-sized, allowing the transport of 1 µm microspheres. Moreover, antibody drugs and platelets are capable of utilizing vascular burst transportation, demonstrating the application of this phenomenon to other types of therapeutics and cellular components. These findings indicate the vast potential of vascular bursts, extending the biological and therapeutic significance of this phenomenon to a wide range of blood-borne particles and cells.

DOI： 10.1002/smll.202103751

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acsbiomaterials.1c00730

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/smll.202103751

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jddst.2021.102375

Web of Science

researchmap

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/smll.202103751

Scopus

researchmap

Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Self-assembled supramolecular structures based on polyion complex (PIC) formation between oppositely charged polymers are attracting much attention for developing drug delivery systems able to endure harsh in vivo environments. As controlling polymer complexation provides an opportunity for engineering the assemblies, an improved understanding of the PIC formation will allow constructing assemblies with enhanced structural and functional capabilities. Here, we focused on the influence of the mixing charge ratio between block aniomers and catiomers on the physicochemical characteristics and in vivo biological performance of the resulting PIC micelles (PIC/m). Our results showed that by changing the mixing charge ratio, the structural state of the core was altered despite the sizes of PIC/m remaining almost the same. These structural variations greatly affected the stability of the PIC/m in the bloodstream after intravenous injection and determined their biodistribution.

DOI： 10.3390/polym13010005

researchmap

Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.biomac.0c01192

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science ({AAAS})  

DOI： 10.1126/sciadv.abc7031

Scopus

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Proceedings of the National Academy of Sciences  

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood–brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal “off-target” accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.

DOI： 10.1073/pnas.2002016117

researchmap

Other Link： https://syndication.highwire.org/content/doi/10.1073/pnas.2002016117

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/anie.202004180

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/anie.202004180

researchmap

Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acsnano.9b09991

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.langmuir.0c00694

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood-brain barrier using glycemic control as an external trigger. Glucose-coated polymeric nanocarriers, which can be bound by glucose transporter-1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose-ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non-coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose-modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.

DOI： 10.1002/anie.201914751

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.biomaterials.2019.119491

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Drug Delivery System  

DOI： 10.2745/dds.34.216

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jconrel.2019.02.021

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Vesicular polyion complexes (PICs) were fabricated through self-assembly of rigid cylindrical molecules, small interfering RNAs (siRNAs), with flexible block catiomers of poly(ethylene glycol) (2 kDa) and cationic polyaspartamide derivative (70 units) bearing a 5-aminopentyl side chain. 100 nm-sized siRNA-assembled vesicular PICs, termed siRNAsomes, were fabricated in specific mixing ranges between siRNA and block catiomer. The siRNAsome membrane was revealed to consist of PIC units fulfilling a simple molar ratio (1:2 or 2:3) of block catiomer and siRNA. These ratios correspond to the minimal integer molar ratio to maximally compensate the charge imbalance of PIC, because the numbers of charges per block catiomer and siRNA are +70 and -40, respectively. Accordingly, the ζ-potentials of siRNAsomes prepared at 1:2 and 2:3 were negative and positive, respectively. Cross-section transmission electron microscopic observation clarified that the membrane thicknesses of 1:2 and 2:3 siRNAsomes were 11.0 and 17.2 nm, respectively. Considering that a calculated long-axial length of siRNA is 5.9 nm, these thickness values correspond to the membrane models of two (11.8 nm) and three (17.7 nm) tandemly aligned siRNAs associating with one and two block catiomers, respectively. For biological application, siRNAsomes were stabilized through membrane-cross-linking with glutaraldehyde. The positively charged and cross-linked siRNAsome facilitated siRNA internalization into cultured cancer cells, eliciting significant gene silencing with negligible cytotoxicity. The siRNAsome stably encapsulated dextran as a model cargo macromolecule in the cavity by simple vortex mixing. Confocal laser scanning microscopic observation displayed that both of the payloads were internalized together into cultured cells. These results demonstrate the potential of siRNAsomes as a versatile platform for codelivery of siRNA with other cargo macromolecules.

DOI： 10.1021/jacs.8b13641

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Therapeutic nanoreactors are of increasing interest in precise cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules at the target sites. However, engineering a nanoreactor with tumor activable cascade reactions for efficient cooperative cancer therapy remains a great challenge. Herein, we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment. The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities, respectively. The cascade reactions including glucose consumption to generate H2O2, accelerated iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (•OH), and •OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability. During this process, the orchestrated cooperative cancer therapy including starving therapy, chemodynamic therapy, and chemotherapy is realized for high-efficiency tumor suppression by the in situ consumed and produced compounds. The nanoreactor design with tumor-activable cascade reactions represents an insightful paradigm for precise cooperative cancer therapy.

DOI： 10.1021/acsnano.8b09082

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Apoptotic cells are known to suppress microglial inflammation in the brain by presenting phosphatidylserine. In this study, we newly designed polymeric particles that expose the anti-inflammatory site of phosphatidylserine to serve as an apoptotic cell-mimetic anti-inflammatory platform. The prepared anti-inflammatory particles showed no cytotoxicity and significantly inhibited the production of the inflammatory cytokine interleukin-6 against lipopolysaccharide stimulation in the microglia cell line MG6. This novel polymeric particle has potential for establishing a "cell-free" apoptotic cell-mimetic treatment for intracerebral inflammation.

DOI： 10.1021/acsbiomaterials.8b01510

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11239/jsmbe.Annual57.S138_1

researchmap

DOI： 10.1241/jstnews.2019.10_16

researchmap

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1016/j.jalz.2018.06.739

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/s41467-017-00952-3

Scopus

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ange.201706964

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ange.201706964

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ange.201508339

researchmap

Language：Japanese   Publisher：日本バイオマテリアル学会  

researchmap

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jconrel.2014.01.021

Web of Science

Scopus

researchmap

Language：English   Publishing type：Research paper (international conference proceedings)  

researchmap

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：English  

J-GLOBAL

researchmap