Faculty Profiles - ITO Akira

Papers - ITO Akira

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Expansion of human mesenchymal stem cells on poly (vinyl alcohol) microcarriers Open Access

Seibutsu-kogaku Kaishi Vol. 103 ( 2 ) page： 62 - 62 2025.2

Amphiphilic phospholipid polymers as a cryoprotectant for vitrification and nanowarming of rat livers

Kaneko, M; Takizawa, N; Wakabayashi, T; Kaneoka, H; Ito, A

JOURNAL OF BIOSCIENCE AND BIOENGINEERING Vol. 139 ( 1 ) page： 70 - 78 2025.1

Language：English Publisher：Journal of Bioscience and Bioengineering

Liver biobanking is a promising approach that saves the lives of patients with end-stage liver disease. Cryopreservation based on vitrification enables semi-permanent organ preservation, contributing to overcome the shortage of donors for liver transplants. A technical challenge in cryopreservation of transplantable organs lies in thawing methodology, and conventional convective warming cannot maintain the glassy state during thawing because of the large temperature gradient between the inner and outer parts of the organs, leading to ice formation and damage of cells in the organ. Nanowarming, in which magnetic nanoparticles are dispersed in a vitrification solution and heated by exposure of alternating magnetic field, can achieve uniform and rapid heating of organs. Herein, we report that amphiphilic phospholipid polymers composed of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate can function as a cryoprotectant for nanowarming. The amphiphilic phospholipid polymers enhanced the viability of primary rat hepatocytes after vitrification. Moreover, the polymers enhanced the dispersion stability of magnetic nanoparticles in vitrification solution, and the perfusion of the vitrification solution with magnetic nanoparticles into rat livers through portal vein provided uniform distribution of the nanoparticles in the liver. After perfusion, the vitrified liver was successfully thawed rapidly and uniformly by nanowarming, which maintained tissue integrity and cell viability.

DOI： 10.1016/j.jbiosc.2024.10.003

Web of Science

Scopus

PubMed

Regenerative Medicine Using Magnetic Nanoparticles Open Access

KANEKO Masahiro, ITO Akira

Journal of the Japan Society of Applied Electromagnetics and Mechanics Vol. 33 ( 4 ) page： 371 - 376 2025

Language：Japanese Publisher：The Japan Society of Applied Electromagnetics and Mechanics

Magnetite (Fe3O4) nanoparticles have been clinically used as MRI contrast agents and are known as highly
biocompatible magnetic nanoparticles. The magnetic nanoparticles have been applied to medical fields since they are attracted to magnetic fields and also generate heat in an alternating magnetic field. In this review, we introduce our research on “magnetic pattering of cells”, “skeletal muscle tissue engineering using magnetic force”, and “nanowarming” as a technology for thawing frozen cells using magnetic particles.

DOI： 10.14243/jsaem.33.371

Open Access

CiNii Research

Surace Modification of Magnetic Nanoparticles for Cancer Therapy Open Access

Kaneko Masahiro, Ito Akira

MEMBRANE Vol. 50 ( 1 ) page： 34 - 38 2025

Language：Japanese Publisher：THE MEMBRANE SOCIETY OF JAPAN

Since magnetic nanoparticles generate heat in a high–frequency alternating magnetic field, researchers have conducted magnetic hyperthermia, in which magnetic nanoparticles are delivered to tumors and magnetic–field– induced heating is used to destroy the tumor. If magnetic nanoparticles can be delivered to tumors, tumors can be heated by irradiating an alternating magnetic field from outside the body, enabling specific hyperthermia to kill only cancer cells with heat. The authors have previously produced magnetite cationic liposomes in which magnetic nanoparticles are embedded in liposomes made of positively charged lipids, antibody–conjugated magnetite nanoparticles in which antibody drugs are bound to the surface of magnetic nanoparticles, and mitochondria–targeted magnetite nanoparticles in which magnetic nanoparticles are coated with a polymer containing a compound that specifically accumulates in mitochondria. In addition, we have developed melanoma–targeted magnetite nanoparticles in which NPrCAP, a drug that molecularly targets the mechanism by which melanoma is bound to magnetic nanoparticles. In this paper, we will describe these functional magnetic nanoparticles and discuss the future prospects.

DOI： 10.5360/membrane.50.34

Open Access

CiNii Research

Development of Melanoma Targeted Chemo-Thermo-Immuno-Therapy by Employing Melanogenic NPrCAP-Magnetite Nanomedicine

Jimbow Kowichi, Hida Tokimasa, Kawakami Akinori, Ito Shosuke, Wakamatsu Kazumasa, Ito Akira, Honda Hiroyuki, Tamura Yasuaki, Torigoe Toshihiko

The Japanese Journal of Dermatology Vol. 134 ( 12 ) page： 3017 - 3034 2024.11

Language：Japanese Publisher：Japanese Dermatological Association

<p>Systemic target immuno-therapeutics and immune checkpoint inhibitors have been successfully introduced for high-risk unresectable white Caucasian melanomas. However, darker skinned Asian and Japanese patients do not receive these benefits, and new approaches for target therapy are urgently needed. We developed a new melanoma-targeting chemo-thermo-immuno-therapy (CTI therapy) by producing 17 melanogenesis substrates and selecting N-propionyl cysteaminylphenol (NPrCAP) through selective drug delivery and cytotoxicity to melanoma cells. NPrCAP generated reactive free radicals with tyrosinase and resulted in chemical cytotoxicity with production of many apoptotic and a few necrotic cells (chemo-immunotherapy). NPrCAP was further conjugated with magnetite nanoparticles and produced heat shock protein and necrotic cells after exposure to alternating magnetic fields (thermo-immunotherapy). The combined chemo-thermo-immuno (CTI) -therapy has been successfully tested in growth inhibition of experimental murine metastatic melanomas. Preliminary clinical trials have also shown significant regression of unresectable distant human melanomas and increased the life span of patients.</p>

DOI： 10.14924/dermatol.134.3017

CiNii Research

Bone morphogenetic protein signaling inhibitor improves differentiation and function of 3D muscle construct fabricated using C2C12

Ding, R; Xi, Y; Ito, A; Shimizu, K; Nagamori, E; Fujita, H; Kawamoto, T; Horie, M

JOURNAL OF BIOSCIENCE AND BIOENGINEERING Vol. 137 ( 6 ) page： 480 - 486 2024.6

Language：English Publisher：Journal of Bioscience and Bioengineering

Functional tissue-engineered artificial skeletal muscle tissue has great potential for pharmacological and academic applications. This study demonstrates an in vitro tissue engineering system to construct functional artificial skeletal muscle tissues using self-organization and signal inhibitors. To induce efficient self-organization, we optimized the substrate stiffness and extracellular matrix (ECM) coatings. We modified the tissue morphology to be ring-shaped under optimized self-organization conditions. A bone morphogenetic protein (BMP) inhibitor was added to improve overall myogenic differentiation. This supplementation enhanced the myogenic differentiation ratio and myotube hypertrophy in two-dimensional cell cultures. Finally, we found that myotube hypertrophy was enhanced by a combination of self-organization with ring-shaped tissue and a BMP inhibitor. BMP inhibitor treatment significantly improved myogenic marker expression and contractile force generation in the self-organized tissue. These observations indicated that this procedure may provide a novel and functional artificial skeletal muscle for pharmacological studies.

DOI： 10.1016/j.jbiosc.2024.03.005

Web of Science

Scopus

PubMed

Transplantable cell-encapsulation device using a semipermeable ethylene-vinyl alcohol copolymer membrane in a mouse diabetic model Open Access

Kaneko, M; Moriguchi, H; Futatsubashi, R; Ayano, S; Kobayashi, G; Ito, A

JOURNAL OF BIOSCIENCE AND BIOENGINEERING Vol. 136 ( 5 ) page： 415 - 422 2023.11

Language：English Publisher：Journal of Bioscience and Bioengineering

Cell-based therapy is an attractive approach, and encapsulation of therapeutic cells is a promising strategy because it prevents immune responses and allows transplanted cells to be retrieved in case of dysfunction. Bioartificial pancreas, in which insulin-secreting cells are encapsulated in a semipermeable membrane bag, is a new class of medical device for treating type-I diabetes. In this study, we developed a macroencapsulation device in which the pancreatic beta cell line MIN6 was encapsulated in a semipermeable bag made of an ethylene-vinyl alcohol copolymer membrane. In vitro evaluation of ATP and insulin levels revealed that MIN6 cells grown in Matrigel within the device secreted insulin in response to glucose levels. Transplantation of the device lowered blood glucose levels for 30 days in diabetic mice. Histological observation revealed that MIN6 cells formed spheroids in Matrigel, and no host cells were detected within the device. Blood levels of inflammatory cytokines in the transplanted mice were similar to those in non-transplanted mice, and antibody levels in the device were lower than those in the intraperitoneal fluid. These results suggest that the semipermeable ethylene-vinyl alcohol copolymer membrane developed in this study is useful for cell encapsulation in cell-based therapies, including beta-cell macroencapsulation for type-1 diabetes.

DOI： 10.1016/j.jbiosc.2023.09.001

A transplantable cell-encapsulation device using a semipermeable ethylene-vinyl alcohol membrane in a mouse diabetic model Reviewed

Masahiro Kaneko, Hiroaki Moriguchi, Ryo Futatsubashi, Satoru Ayano, Goro Kobayashi, Akira Ito

2023.9

機能性磁性ナノ粒子を用いた再生医療プロセスの開発 Invited

井藤　彰

セラミックス Vol. 58 ( 9 ) page： 584 - 587 2023.9

Expansion of human mesenchymal stem cells on poly(vinyl alcohol) microcarriers Reviewed

Masahiro Kaneko, Airi Sato, Satoru Ayano, Akio Fujita, Goro Kobayashi, Akira Ito

2023.8

Effective magnetic hyperthermia induced by mitochondria-targeted nanoparticles modified with triphenylphosphonium-containing phospholipid polymers. Reviewed Open Access

Masahiro Kaneko, Hiroto Yamazaki, Takahiro Ono, Masanobu Horie, Akira Ito

Cancer Science Vol. 114 page： 3750 - 3758 2023.7

Nanowarming of vitrified pancreatic islets as a cryopreservation technology for transplantation Open Access

Wakabayashi, T; Kaneko, M; Nakai, T; Horie, M; Fujimoto, H; Takahashi, M; Tanoue, S; Ito, A

BIOENGINEERING & TRANSLATIONAL MEDICINE Vol. 8 ( 4 ) page： e10416 2023.7

Language：English Publisher：Bioengineering and Translational Medicine

Biobanking of pancreatic islets for transplantation could solve the shortage of donors, and cryopreservation of vitrified islets is a possible approach. However, a technological barrier is rewarming of large volumes both uniformly and rapidly to prevent ice formation due to devitrification. Here, we describe successful recovery of islets from the vitrified state using a volumetric rewarming technology called “nanowarming,” which is inductive heating of magnetic nanoparticles under an alternating magnetic field. Convective warming using a 37°C water bath as the gold standard for rewarming of vitrified samples resulted in a decrease in the viability of mouse islets in large volumes (>1 ml) owing to devitrification caused by slow warming. Nanowarming showed uniform and rapid rewarming of vitrified islets in large volumes. The viability of nanowarmed islets was significantly improved and islets transplanted into streptozotocin-induced diabetic mice successfully lowered serum glucose. The results suggest that nanowarming will lead to a breakthrough in biobanking of islets for transplantation.

DOI： 10.1002/btm2.10416

Combination of magnetic hyperthermia and immunomodulators to drive complete tumor regression of poorly immunogenic melanoma Open Access

Nishikawa, A; Suzuki, Y; Kaneko, M; Ito, A

CANCER IMMUNOLOGY IMMUNOTHERAPY Vol. 72 ( 6 ) page： 1493 - 1504 2023.6

Language：English Publisher：Cancer Immunology, Immunotherapy

Hyperthermia using magnetic nanoparticles enables tumor-specific heating and can destroy tumor tissues. This approach works as in situ vaccination with tumor antigens released from dying tumor cells. However, in situ vaccination caused by magnetic hyperthermia is often insufficient to induce complete regression of poorly immunogenic tumors surrounded by an immunosuppressive microenvironment. In this study, we explored a novel strategy for immunotherapy using magnetic hyperthermia to regress poorly immunogenic melanoma. Magnetic hyperthermia induced tumor cell death in a B16-F10 melanoma mouse model. After hyperthermia treatment, we found elevated levels of HMGB1, which is known to be released from dying cells to promote inflammation, and the proinflammatory cytokine TNF-α was increased in serum of the mice. Systemic administration of glycyrrhizin, an HMGB1 inhibitor, reduced the levels of TNF-α in serum and successfully delayed the regrowth of tumors after magnetic hyperthermia. To achieve complete tumor regression, TLR9 activation by intratumor injection of CpG was combined with systemic administration of anti-PD-1 antibody and anti-CTLA-4 antibody. The combination therapy of magnetic hyperthermia at 46°C with the immunomodulators (glycyrrhizin+CpG+anti-PD-1+anti-CTLA-4) achieved complete tumor regression in 80% of growing 5-mm B16-F10 tumors. These findings have important implications for the development of novel cancer immunotherapy using magnetic hyperthermia for poorly immunogenic tumors.

DOI： 10.1007/s00262-022-03345-8

Web of Science

Scopus

PubMed

A Sulfur Containing Melanogenesis Substrate, N-Pr-4-S-CAP as a Potential Source for Selective Chemoimmunotherapy of Malignant Melanoma Invited Reviewed Open Access

Yasuaki Tamura, Akira Ito, Kazumasa Wakamatsu, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito, Kowichi Jimbow

International Journal of Molecular Sciences Vol. 24 ( 6 ) page： 5235 2023.3

A Sulfur Containing Melanogenesis Substrate, N-Pr-4-S-CAP as a Potential Source for Selective Chemoimmunotherapy of Malignant Melanoma International journal Open Access

Yasuaki Tamura, Akira Ito, Kazumasa Wakamatsu, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito, Kowichi Jimbow

International Journal of Molecular Sciences Vol. 24 ( 6 ) 2023.3

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

N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) is a substrate for tyrosinase, which is a melanin biosynthesis enzyme and has been shown to be selectively incorporated into melanoma cells. It was found to cause selective cytotoxicity against melanocytes and melanoma cells after selective incorporation, resulting in the induction of anti-melanoma immunity. However, the underlying mechanisms for the induction of anti-melanoma immunity remain unclear. This study aimed to elucidate the cellular mechanism for the induction of anti-melanoma immunity and clarify whether N-Pr-4-S-CAP administration could be a new immunotherapeutic approach against melanoma, including local recurrence and distant metastasis. A T cell depletion assay was used for the identification of the effector cells responsible for N-Pr-4-S-CAP-mediated anti-melanoma immunity. A cross-presentation assay was carried out by using N-Pr-4-S-CAP-treated B16-OVA melanoma-loaded bone marrow-derived dendritic cells (BMDCs) and OVA-specific T cells. Administration of N-Pr-4-S-CAP induced CD8+ T cell-dependent anti-melanoma immunity and inhibited the growth of challenged B16F1 melanoma cells, indicating that the administration of N-Pr-4-S-CAP can be a prophylactic therapy against recurrence and metastasis of melanoma. Moreover, intratumoral injection of N-Pr-4-S-CAP in combination with BMDCs augmented the tumor growth inhibition when compared with administration of N-Pr-4-S-CAP alone. BMDCs cross-presented a melanoma-specific antigen to CD8+ T cells through N-Pr-4-S-CAP-mediated melanoma cell death. Combination therapy using N-Pr-4-S-CAP and BMDCs elicited a superior anti-melanoma effect. These results suggest that the administration of N-Pr-4-S-CAP could be a new strategy for the prevention of local recurrence and distant metastasis of melanoma.

DOI： 10.3390/ijms24065235

Novel nano-thermal ablation therapy using functionalized heat-generating nanoparticles for solid cancer treatment Invited Reviewed

Tomio Morino, Noriyasu Kawai, Akira Ito, Takeshi Kobayashi, Takahiro Yasui

World Journal of Cancer and Oncology Research Vol. 2 ( 1 ) page： 29 - 46 2023.2

Molecular events in the melanogenesis cascade as novel melanoma-targeted small molecules: Principle and development Invited Reviewed Open Access

Kazumasa Wakamatsu, Akira Ito, Yasuaki Tamura, Tokimasa Hida, Takafumi Kamiya, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito, Kowichi Jimbow

Cancers Vol. 14 ( 22 ) page： 5588 2022.11

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development. International journal Open Access

Kazumasa Wakamatsu, Akira Ito, Yasuaki Tamura, Tokimasa Hida, Takafumi Kamiya, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito, Kowichi Jimbow

Cancers Vol. 14 ( 22 ) 2022.11

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

Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo-dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma.

DOI： 10.3390/cancers14225588

ハイパーサーミアにおける酸化鉄ナノフラワーの開発－ナノ構造と発熱能の関係－ Invited Reviewed Open Access

金子真大，井藤　彰

Vol. 38 ( 3 ) page： 63 - 64 2022.10

Induction of immunogenic cell death in murine colon cancer cells by ferrocene‐containing redox phospholipid polymers Reviewed

Masahiro Kaneko, Akio Yamaguchi, Akira Ito

Cancer Science Vol. 113 ( 10 ) page： 3558 - 3565 2022.10

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Papers - ITO Akira