ORCID Profile
0000-0002-8591-413X
Current Organisations
University of Tokyo
,
Kawasaki Institute of Industrial Promotion
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Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.JCONREL.2014.05.048
Abstract: The ubiquitin-proteasome system is central in the regulation of cellular proteins controlling cell cycle progression and apoptosis, drawing much interest for developing effective targeted cancer therapies. Herein, we developed a novel pH-responsive polymeric-micelle-based carrier system to effectively deliver the proteasome inhibitor MG132 into cancer cells. MG132 is covalently bound to the block copolymer composed of polyethylene glycol (PEG) and polyaspartate through an acid-labile hydrazone bond. This bond is stable at physiological condition, but hydrolytically degradable in acidic compartments in the cell, such as late-endosomes and lysosomes, and thus, it was used for controlled release of MG132 after EPR-mediated preferential accumulation of the micelles into the tumor. MG132-loaded micelles have monodispersed size distribution with an average diameter of 45nm, and critical micelle concentration is well below 10(-7)M. In vitro studies against several cancer cell lines confirmed that MG132-loaded micelles retained the cytotoxic effect, and this activity was indeed due to the inhibition of proteasome by released MG132 from the micelles. Real-time in vitro confocal-microscopy experiments clearly indicated that MG132-conjugated micelles disintegrated only inside the target cells. By intravital confocal micro-videography, we also confirmed the prolonged circulation of MG132 loaded micelles in the bloodstream, which lead to tumor specific accumulation of micelles, as confirmed by in vivo imaging 24h after injection. These micelles showed significantly lower in vivo toxicity than free MG132, while achieving remarkable antitumor effect against a subcutaneous HeLa-luc tumor model. Our findings create a paradigm for future development of polymeric-micelle-based carrier system for other peptide aldehyde type proteasome inhibitors to make them effective cohort of the existing cancer therapeutic regiments.
Publisher: Elsevier BV
Date: 07-2017
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.JCONREL.2017.04.033
Abstract: Current therapeutic strategies against glioblastoma multiforme (GBM) are futile mainly because of the poor access of drugs into malignant tissues, which is hindered by the tight blood-brain tumor barrier in the GBM vasculature. Nanomedicines have shown potential for circumventing the vascular barriers of GBM, particularly by targeting markers on the luminal side of endothelial cells in the blood vessels of GBM for achieving effective and selective translocation into the tumor. Thus, as the αvβ3 and αvβ5 integrins overexpressed on the endothelial cells of GBM can be targeted by cyclic-Arg-Gly-Asp (cRGD) peptide, herein, we developed cRGD-installed micellar nanomedicines loading epirubicin, the potent antiglioblastoma agent, through a pH-sensitive hydrazone-bond for effective treatment of GBM. These cRGD-installed epirubicin-loaded polymeric micelles (cRGD-Epi/m) achieved faster and higher penetration into U87MG cell-derived 3D-spheroids than the micelles without cRGD, conceivably through a cRGD-integrin mediated pathway. In vivo, the cRGD-installed micelles effectively suppressed the growth of an orthotopic GBM model by delivering high levels of epirubicin throughout the tumor tissue. These results indicate significant prospects for cRGD-Epi/m as an effective and translationable treatment against GBM.
Publisher: Springer Science and Business Media LLC
Date: 02-2011
DOI: 10.1038/BJC.2011.6
Publisher: Elsevier BV
Date: 12-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1BM00689D
Abstract: C75-CoA is a capable inhibitor of fatty acid oxidation but is anionic and has low cellular permeability. We prepared charge-neutralizing poly-ion complex micelles to efficiently deliver the drug into glioma cells and neurons in 2D and 3D cultures.
Publisher: Elsevier BV
Date: 03-2022
Publisher: Elsevier BV
Date: 2021
Publisher: American Chemical Society (ACS)
Date: 06-08-2020
Publisher: American Chemical Society (ACS)
Date: 24-02-2021
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.XPHS.2017.03.031
Abstract: Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.
Publisher: American Chemical Society (ACS)
Date: 08-02-2021
Publisher: American Chemical Society (ACS)
Date: 12-06-2019
Abstract: Dexamethasone is a glucocorticoid steroid with anti-inflammatory properties used to treat many diseases, including cancer, in which it helps manage various side effects of chemo-, radio-, and immunotherapies. Here, we investigate the tumor microenvironment (TME)-normalizing effects of dexamethasone in metastatic murine breast cancer (BC). Dexamethasone normalizes vessels and the extracellular matrix, thereby reducing interstitial fluid pressure, tissue stiffness, and solid stress. In turn, the penetration of 13 and 32 nm dextrans, which represent nanocarriers (NCs), is increased. A mechanistic model of fluid and macromolecule transport in tumors predicts that dexamethasone increases NC penetration by increasing interstitial hydraulic conductivity without significantly reducing the effective pore diameter of the vessel wall. Also, dexamethasone increases the tumor accumulation and efficacy of ∼30 nm polymeric micelles containing cisplatin (CDDP/m) against murine models of primary BC and spontaneous BC lung metastasis, which also feature a TME with abnormal mechanical properties. These results suggest that pretreatment with dexamethasone before NC administration could increase efficacy against primary tumors and metastases.
Publisher: American Chemical Society (ACS)
Date: 20-05-2020
Publisher: American Chemical Society (ACS)
Date: 21-04-2020
No related grants have been discovered for Kazunori Kataoka.