2010 Fiscal Year Final Research Report
Enhanced Antitumor Activity of Proteasome Inhibitor MG132-loaded Polymeric Micelle Drug Carriers, Analyzed by In Vivo Real-Time Confocal Microangiography
| Project/Area Number |
21791542
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | The University of Tokyo (2010)
Research Institute for Clinical Oncology, Saitama Cancer Center (2009) |
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Principal Investigator |
MATSUMOTO Yoko The University of Tokyo, 医学部附属病院, 助教 (10466758)
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| Project Period (FY) |
2009 – 2010
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| Keywords | ナノテクノロジー / プロテアソームインヒビター / DDS |
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| Research Abstract |
Macromolecular carriers for therapeutic agents are attractive as they can improve the performance of certain drugs by prolonged blood circulation, reduced nonspecific accumulation in normal tissues and preferential tumor accumulation due to the enhanced permeability and retention (EPR) effect. Core-shell type polyion complex (PIC) micelles have received considerable attention as a promising macromolecular carrier system. Antitumor drug-loaded micelles containing platinum and taxane have been reported to have strong target effects with decreased side effects. Proteasomes degrade or process intracellular proteins, some of which represent mediators of cell-cycle progression and apoptosis, such as the cyclins, caspases, BCL2 and nuclear factor ofκB (NF-κB). Proteasome inhibitor (PI) is attracting considerable attention as a new antitumor drug widely effective for various cancers. Bortezomib was the first PI to enter clinical development and was approved by the FDA in 2003 for the treatment
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of relapsed and refractory multiple myeloma. However, this drug has been known to cause strong side effects such as interstitial pneumonia. By applying PIC micelles technology to PI, we might possibly increase the antitumor effect and reduce side effects.
We developed a new class of polymeric micelles incorporating PI MG132 through the polymer-drug complex formation between MG132 and poly- (ethylene glycol)-b-poly (benzyl-L-glutamate) block copolymers (MG132/m). To analyze biodistribution of free MG132 and MG132/m, we used a Nikon A1R confocal laser scanning microscope system. Blood circulation and accumulation at the tumor (HeLa-H2BGFP cervical carcinoma) and normal tissue were evaluated by visual image.
To evaluate the in vivo antitumor effect of MG132/m, subcutaneous xenograft models were established by transplanting human cervical cells (Hela and CaSki) into severe combined immunodeficient (SCID) mice. The SCID mice were treated with free MG132 or MG132/m intravenously (1 mg/kg/dose) twice a week for 4 weeks.
In vivo real-time confocal micro-angiography demonstrated that MG132/m had prolonged blood circulation and effective accumulation into solid tumors. Analysis of tumor size following injection of MG132 or MG132/m indicated that MG132/m had a stronger growth inhibitory effect against cervical cancers.
Core-shell type polyion complex micelles could be an outstanding drug delivery system for MG132 and possibly other proteasome inhibitors in the treatment of cervical cancer. Less
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[Journal Article] Direct and instantaneous observation of intravenously injected substances using intravital confocal micro-videography.2010
Author(s)
Matsumoto Y, Nomoto T, Cabral H, Matsumoto Y, Watanabe S, Christie RJ, Miyata K, Oba M, Ogura T, Yamasaki Y, Nishiyama N, Yamasoba T, Kataoka K.
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Journal Title
Biomedical optics express.
Pages: 1209-1218
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[Presentation] Enhanced Antitumor Activity of Proteasome Inhibitor MG132-loaded Polymeric Micelle Drug Carriers, Analyzed by In Vivo Real-Time Confocal Microangiography2010
Author(s)
Yoko Matsumoto, Yu Matsumoto, Yuichiro Miyamoto, Horacio Cabral, Nobuhiro Nishiyama, Shunsuke Nakagawa, Tetsu Yano, Yuji Taketani, Kazunori Kataoka
Organizer
Third International NanoBio Conference
Place of Presentation
ETH Zurich, Switzerland
Year and Date
20100824-20100827
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[Remarks] ホームページ等
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