2016 Fiscal Year Annual Research Report
Development of a nano-pharmaceutical strategy for safely and effectively treating pregnant cancer patients
| Project/Area Number |
16H03179
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
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| Co-Investigator(Kenkyū-buntansha) |
永松 健 東京大学, 医学部附属病院, 准教授 (60463858)
持田 祐希 公益財団法人川崎市産業振興財団(ナノ医療イノベーションセンター), 川崎市産業振興財団, 主任研究員 (60739134)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | Nanomedicine / Placenta / Polymeric micelles / Cancer |
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| Outline of Annual Research Achievements |
Here, we are focusing on the development of nanomedicines for treating cancer in pregnant patients. Thus, we have developed a library of model nanomedicines, namely, polymeric micelles, with controlled characteristics, including size, surface chemistry and charge. These nanomedicines were prepared by polyion complex formation between PEG-polycation and PEG-polyanions in water, and chemically cross-linked for maintaining their properties in physiological conditions. The size of these micelles was modulated from 20- to 100-nm, and the surface charge was controlled by conjugating positively- or negatively-charged moieties to the a-end of PEG. The polymers were labeled with fluorescent probes for following their distribution in vivo. The nanomedicines were found to be safe in vitro after incubation with both cancer and primary cells. The pharmacokinetics and biodistribution of these nanomedicines were studied in virgin and pregnant mice. We found that all the micelles were long-circulating, and mainly accumulated in liver and spleen. In pregnant mice with gestational day 17, the micelles larger than 70-nm avoided accumulation in the placenta of mice. Moreover, by using (1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles with 70-nm diameter, we treated breast tumors more effectively than with the parent anticancer drug oxaliplatin. These 70-nm DACHPt-loaded micelles were found to be safe for mothers, as well as fetuses, maintaining the body weight of both and allowing the proper growth of the puppies.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
We have met the milestones proposed in this part of the project, including the preparation of a library of nanomedicines based on polymeric micelles with controlled size and surface charge, the evaluation of these novel nanomedicine platforms and the elucidation of the nanomedicines features for avoiding accumulation in the placenta, which were confirmed by testing a toxic formulation in pregnant mice, i.e. DACHPt-loaded polymeric micelles. Moreover, we have started using this nanomedicine platform for studying the effect of the nanomedicine design on the accumulation in different tissues, besides placenta, particularly focusing on cancer. In addition, by controlling the particle design based on these findings, we could effectively treat a model of breast cancer, while avoiding toxicity to the mother and the fetus. In addition, we have obtained permission for using human placenta, and we will be evaluating these nanomedicines to further validate our observations.
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| Strategy for Future Research Activity |
The effect of the design of the nanomedicines will be validated in human placentas by using an ex vivo perfusion model. Moreover, based on the results of this experiment and the above mentioned findings, we will develop polymeric micelles for the treatment of preeclampsia and premature delivery, which are major issues in pregnant patients. For the former project, we will develop polymeric micelles conjugating thrombomodulin, which is highly effective for treating preeclampsia, but poses serious risk for the fetus. For premature delivery, we will construct polymeric micelles incorporating indomethacin, avoiding the delivery of this drug to the fetus. These micelles will be evaluated in mice models of preeclampsia and preterm delivery, respectively. We expect that our results provide information for the development of safe therapies for pregnant patients.
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[Journal Article] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition"2017
Author(s)
Hailiang Wu, Anqi Tao, John D. Martin, Sabina Quader, Xueying Liu, Kei Takahashi, Louise Hespel, Yutaka Miura, Yoshihiro Hayakawa, Tatsuro Irimura, Horacio Cabral, Kazunori Kataoka
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Journal Title
J. Pharm. Sci,
Volume: -
Pages: -
DOI
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors.2017
Author(s)
P. Mi, H. Yanagie, N. Dewi, H.-C. Yen, X. Liu, M. Suzuki, Y. Sakurai, K. Ono, H. Takahashi, H. Cabral, K. Kataoka,
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Journal Title
J. Control. Release
Volume: 254
Pages: 1-9
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.2016
Author(s)
Y. Matsumoto, Y. Miyamoto, H. Cabral, Y. Matsumoto, K. Nagasaka, S. Nakagawa, D. Maeda, T. Yano, K. Oda, K. Kawana, N. Nishiyama, K. Kataoka, T. Fujii,
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Journal Title
Cancer Sci.
Volume: 107
Pages: 773-781
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery.2016
Author(s)
Y. Matsumoto, J. W. Nichols, K. Toh, T. Nomoto, H. Cabral, Y. Miura, R. J. Christie, N. Yamada, T. Ogura, M. R. Kano, Y. Matsumura, N. Nishiyama, T. Yamasoba, Y. -H. Bae, K. Kataoka,
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Journal Title
Nat. Nanotechnol.
Volume: 11
Pages: 533-538
DOI
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition,2017
Author(s)
J. D. Martin, H. Wu, A. Tao, S. Quader, X. Liu, K. Takahashi, L. Hespel, Y. Miura, Y. Hayakawa, T. Irimura, H. Cabral, K. Kataoka,
Organizer
11th Annual Symposium on Nanobiotechnology 2017
Place of Presentation
Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa,
Year and Date
2017-02-27 – 2017-02-27
Int'l Joint Research
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[Presentation] Development of porphyrin/polyaminoacid-based worm-like micelles for drug delivery2017
Author(s)
Y. Onuma, S. Fukushima, H. -J. Kim Y. Anraku, K. Miyata, K. Osada, H. Cabral, K. Kataoka,
Organizer
11th Annual Symposium on Nanobiotechnology 2017
Place of Presentation
Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa,
Year and Date
2017-02-27 – 2017-02-27
Int'l Joint Research
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[Presentation] Safe cancer therapy during pregnancy by using drug-loaded polymeric micelles,2017
Author(s)
J. Wan, K. Mizuno, B. Xiong, Y. Mochida, Y. Miura, K. Kataoka, H. Cabral
Organizer
11th Annual Symposium on Nanobiotechnology 2017
Place of Presentation
Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa,
Year and Date
2017-02-27 – 2017-02-27
Int'l Joint Research
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[Presentation] Intravital assessment of drug delivery activation through hoechst-loaded polymeric micelles,2017
Author(s)
S. Chen, S. Florinas, K. Toh, Y. Matsumoto, J. R. Christie, K. Kataoka, H. Cabral,
Organizer
11th Annual Symposium on Nanobiotechnology 2017
Place of Presentation
Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa,
Year and Date
2017-02-27 – 2017-02-27
Int'l Joint Research
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[Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition2016
Author(s)
J. D. Martin, H. Cabral, H. Wu, S. Quader, A. Tao, W. Liu, P. Mi, K. Takahashi, Y. Hayakawa, T. Irimura, K. Kataoka
Organizer
3rd COINS International Symposium "Towards Smart Health Society - Challenge of Kawasaki based Medical Innovation -"
Place of Presentation
Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa
Year and Date
2016-12-15 – 2016-12-15
Int'l Joint Research
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[Presentation] Intravital assessment of drug delivery activation through hoechst-loaded polymeric micelles,2016
Author(s)
S. Chen, S. Florinas, K. Toh, Y. Matsumoto, J. R. Christie, H. Cabral, K. Kataoka,
Organizer
The 11th SPSJ International Polymer Conference (IPC2016)
Place of Presentation
Fukuoka International Confress Center, Fukuoka,
Year and Date
2016-12-14 – 2016-12-14
Int'l Joint Research
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[Presentation] anomedicine strategies for enhancing efficacy against head and neck squamous cell carcinoma bearing cancer stem-like cells2016
Author(s)
H. Cabral, K. Miyano, M. Wang, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka,
Organizer
Frontiers2016 - Joint Symposium of the EPFL and the University of Tokyo,
Place of Presentation
Swiss Federal Institute of Technology(EPFL)Lausanne, Switzerland,
Year and Date
2016-12-06 – 2016-12-07
Int'l Joint Research
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[Presentation] Brain tumor targeting by cRGD peptide encircled polymeric micelles loaded with potent antiglioblastoma agent epirubicin2016
Author(s)
S. Quader, X. Liu, Y. Chen, P. Mi, T. Chida, T. Ishii, Y. Miura, N. Nishiyama, H. Cabral, K. Kataoka,
Organizer
3rd International Conference on Biomaterials Science (ICBS2016)
Place of Presentation
to Hall located at The University of Tokyo, Tokyo, Japan
Year and Date
2016-11-28 – 2016-11-29
Int'l Joint Research
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[Presentation] Effective treatment of locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells by cRGD peptide-installed cisplatin-loaded micelles2016
Author(s)
K. Miyano, H. Cabral, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka,
Organizer
3rd International Conference on Biomaterials Science (ICBS2016)
Place of Presentation
to Hall located at The University of Tokyo, Tokyo, Japan
Year and Date
2016-11-28 – 2016-11-29
Int'l Joint Research
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[Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition2016
Author(s)
J. D. Martin, H. Cabral, H. Wu, S. Quader, A. Tao, W. Liu, P. Mi, K. Takahashi, Y. Hayakawa, T. Irimura, K. Kataoka
Organizer
3rd International Conference on Biomaterials Science (ICBS2016)
Place of Presentation
to Hall located at The University of Tokyo, Tokyo, Japan
Year and Date
2016-11-28 – 2016-11-29
Int'l Joint Research
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[Presentation] Messenger RNA-based therapeutics for the treatment of Fas-ligand induced fulminant hepatitis mouse model2016
Author(s)
A. Matsui, H. Cabral, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka,
Organizer
3rd International Conference on Biomaterials Science (ICBS2016)
Place of Presentation
to Hall located at The University of Tokyo, Tokyo, Japan
Year and Date
2016-11-28 – 2016-11-29
Int'l Joint Research
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[Presentation] Ultrasmall DNA-loaded spherical polyplex micelles and their evaluation in hypovasculature pancreatic tumor2016
Author(s)
T. A. Tockary, K. Osada, W. Foo, A. Dirisala, K. M. Takeda, H. Cabral, X. Liu, K. Kataoka,
Organizer
3rd International Conference on Biomaterials Science (ICBS2016)
Place of Presentation
to Hall located at The University of Tokyo, Tokyo, Japan
Year and Date
2016-11-28 – 2016-11-29
Int'l Joint Research
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[Presentation] 環状RGDペプチドを修飾した白金制がん剤内包高分子ミセルを用いたリンパ節転移／治療抵抗性がんの治療2016
Author(s)
持田祐希, H. Cabral, 牧野惇, 三浦裕, M. Wang, 西山伸宏, 片岡一則,
Organizer
第65回高分子討論会,
Place of Presentation
神奈川大学横浜キャンパス, 横浜市, 神奈川県
Year and Date
2016-09-15 – 2016-09-16
Int'l Joint Research
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[Presentation] 難治性頭頸部扁平上皮癌に対するリガンド搭載シスプラチンミセルによる治療戦略2016
Author(s)
宮野一樹, 三浦裕, 松本有, 岩田要, 佐谷秀行, 宮園浩平, 西山伸宏, H. Cabral, 山岨達也, 片岡一則,
Organizer
第32回DDS学会学術大会,
Place of Presentation
グランシップ(静岡県コンベンションアーツセンター), 静岡市, 静岡県
Year and Date
2016-06-30 – 2016-06-30
Int'l Joint Research
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