2018 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), ナノ医療イノベーションセンター, 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 / Star-shaped polymers / Preterm birth / Preeclampsia |
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| Outline of Annual Research Achievements |
Drug prescription during gestation presents serious concerns. As the placenta acts as a barrier protecting the fetus, here we develop nanomedicines that avoid the passage of drugs through the placenta, while targeting disease sites. During 2018, we focused on the development of nanomedicines for treating major disorders associated with pregnancy, i.e. preterm birth and preeclampsia. For the first one, we developed cross-linked indomethacin-loaded polymeric micelles (indo/m) designed to avoid indomethacin transfer to fetus, whilst delivering the drug into inflammatory macrophages at the disease. In vitro, we confirm the stability of these micelles and the release of indomethacin only in macrophages. In vivo, indo/m safely prevented premature birth in a mouse model, with all mice surviving the experiment. In ex vivo human, placenta studies, we confirmed that indo/m cannot access the fetal side. To treat preeclampsia, we developed 8-arm PEG-thrombomodulin conjugates (rThrom/p) and micelles loading simvastatin (Sim/m). Both systems were effective to suppress preeclampsia and avoid fetal death without side effects in in vivo models. Fluorescent labeled rThrom/p and Sim/m showed selective accumulation in the preeclamptic placentas of mice, demonstrating the targeting ability of these nanomedicines.
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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 published 7 articles by using the materials developed in this study. The research has also been presented in several invited talks at international and domestic conferences. In addition, we have filed a patent application, and we are negotiating with the technology transfer office of the universities and companies for preparing a start up and applying related funding.
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| Strategy for Future Research Activity |
This year we will characterize the indo/m, rThrom/p and Sim/m in vitro to gather important information on the molecular biology mechanisms for the enhanced drug activity. We will evaluate the inflammatory signaling, such as NF-Kb signaling, in activated macrophages after indo/m treatment. The ability of rThrom/p for multivalent binding, due to the conjugation of several thrombomodulin molecules in the star shape of the 8-arm PEG, will also be assessed by doing in vitro cellular experiments and surface plasmon resonance studies. The inhibitory activity of sim/m against 3-hydroxy-3-methylglutaryl-coenzyme A reductase will be tested in vitro by using hepatocytes and endothelial cells. Moreover, we will study the pharmacokinetics and the biodistribution of the indo/m, rThrom/p and Sim/m in mice. The toxicities of these drugs will also be confirmed by histological evaluation and by determining the blood toxicity parameters, such as BUN, ALT, AST, etc.. Finally, we will confirm the in vivo transfer of these systems through the placenta of guinea pigs, which is a better model than mouse placenta and present comparable feature with that of human placenta. The results will be summarized into 2 research papers.
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