Development of mRNA drug with RNA type aptamer conferring cell type specific translation activation function

2019 Fiscal Year Annual Research Report

• Project/Area Number: 18K19901
• Research Institution: The University of Tokyo
• Principal Investigator: Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
• Co-Investigator(Kenkyū-buntansha): 内田 智士 東京大学, 大学院工学系研究科(工学部), 特任助教 (20710726)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: mRNA / theophylline / polymer / protein translatiokn / aptamer

Outline of Annual Research Achievements

We developed mRNA-aptamer hybrids by combining mRNAs, and aptamers having a sequence for hybridization with mRNA and a binding site for theophylline. Then, PEG-theophylline conjugates were prepared by condensation. When the polymer was mixed with the mRNA-aptamer hybrids, it coated the hybrids, forming neutral nanoparticles of 50 nm in diameter. Conversely, mRNA-aptamer hybrids were negatively charged, which confirmed PEG coating. The nanoparticles were de-coated by adding free theophylline, recovering the negative charge. mRNA-aptamers translated proteins in cell free systems, and this translation was inhibited when coated with PEG-theophylline. After adding theophylline, protein translation was recovered, indicating that mRNA-aptamers-polymer nanoparticles can sense the surroundings.

Research Products

• [Journal Article] Enhanced MRI‐guided gadolinium (III) neutron capture therapy by polymeric nanocarriers promoting tumor accumulation and intracellular delivery. (2020)
  • Author(s): C. Qin, X. Hou, T. Khan, N. Nitta, M. Yanagawa, Y. Sakurai, M. Suzuki, S. Masunaga, H. Tanaka, Y. Sakurai, H. Takahashi, I. Aoki, H. Yanagie, H. Cabral
  • Journal Title: ChemNanoMat Volume: - Pages: -
  • DOI: 10.1002/cnma.201900730
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nanomedicines blocking adaptive signals in cancer cells overcome tumor TKI resistance (2020)
  • Author(s): H. Kinoh, H. Shibasaki, X. Liu, T. Yamasoba, H. Cabral, K. Kataoka
  • Journal Title: J. Control. Release Volume: 321 Pages: 132-144
  • DOI: 10.1016/j.jconrel.2020.02.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Polymeric micelles loading proteins through concurrent ion complexation and pH-cleavable covalent bonding for in vivo delivery (2020)
  • Author(s): A. Tao, G. L. Huang, K. Igarashi, T. Hong, S. Liao, F. Stellacci, Y. Matsumoto, T. Yamasoba, K. Kataoka, H. Cabral
  • Journal Title: Macromol. Biosci. Volume: 20 Pages: 1900161
  • DOI: 10.1002/mabi.201900161
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Single-stranded DNA-packaged polyplex micelle as adeno-associated-virus-inspired compact vector to systemically target stroma-rich pancreatic cancer. (2019)
  • Author(s): T. A. Tockary, W. Foo, A. Dirisala, Q. Chen, S. Uchida, S. Osawa, Y. Mochida, X. Liu, H. Kinoh, H. Cabral, K. Osada, K. Kataoka
  • Journal Title: ACS Nano Volume: 13 Pages: 12732-12742
  • DOI: 10.1021/acsnano.9b04676
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] One-pot synthesis of PEG-poly (amino acid) block copolymers assembling polymeric micelles with PEG-detachable functionality. (2019)
  • Author(s): T. Miyazaki, K. Igarashi, Y. Matsumoto, H. Cabral,
  • Journal Title: ACS Biomater. Sci. Eng. Volume: 5 Pages: 5727-5733
  • DOI: 10.1021/acsbiomaterials.8b01549
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bundling mRNA strands to prepare nano-assemblies with enhanced stability towards RNase for in vivo delivery. (2019)
  • Author(s): N. Yoshinaga, E. Cho, K. Koji, Y. Mochida, M. Naito, K. Osada, K. Kataoka, H. Cabral, S. Uchida
  • Journal Title: Angew. Chem. Int. Ed. Volume: 58 Pages: 11360-11363
  • DOI: 10.1002/anie.201905203
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dexamethasone increases cisplatin-loaded nanocarrier delivery and efficacy in metastatic breast cancer by normalizing the tumor microenvironment. (2019)
  • Author(s): J. Martin, M. Panagi, C. Wang, T. Khan, M. Martin, C. Voutouri, K. Toh, P. Papageorgis, F. Mpekris, C. Polydorou, G. Ishii, S. Takahashi, N. Gotohda, T. Suzuki, M. Wilhelm, V. Melo, S. Quader, J. Norimatsu, R. Lanning, M. Kojima, M. Stuber, T. Stylianopoulos, K. Kataoka, H. Cabral,
  • Journal Title: ACS Nano Volume: 13 Pages: 6396-6408
  • DOI: 10.1021/acsnano.8b07865
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PEG-oligoRNA hybridization of mRNA for developing sterically stable lipid nanoparticles toward in vivo administration. (2019)
  • Author(s): S. Kurimoto, N. Yoshinaga, K. Igarashi, Y. Matsumoto, H. Cabral, S. Uchida
  • Journal Title: Molecules Volume: 24 Pages: 1303
  • DOI: 10.3390/molecules24071303
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induced packaging of mRNA into polyplex micelles by regulated hybridization with a small number of cholesteryl RNA oligonucleotides directed enhanced in vivo transfection. (2019)
  • Author(s): N. Yoshinaga, S. Uchida, M. Naito, K. Osada, H. Cabral, K. Kataoka,
  • Journal Title: Biomaterials Volume: 197 Pages: 255-267
  • DOI: 10.1016/j.biomaterials.2019.01.023
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Development of polymeric micelles with 5-Boronopicolinic acid ligand to target sialylated epitopes in intratumoral microenvironment" (2019)
  • Author(s): T. Khan, K. Igarashi, A. Matsumoto, H. Cabral, K. Kataoka
  • Organizer: 32nd International Microprocesses and Nanotechnology Conference (MNC 2019)\
  • Int'l Joint Research
• [Presentation] Mechanistic analyses of polymer/lipid-based gene transfection processes through membrane integrity assay using proton sensing transistor (2019)
  • Author(s): E. Boonstra, H. Hatano, T. Goda, S. Uchida, H. Cabral, Y. Miyahara
  • Organizer: 4th International Symposium on Biomedical Engineering, ISBE 2019
  • Int'l Joint Research
• [Presentation] nteraction analysis between target membrane proteins and ligand molecules attached to the polymeric micelle with different molecular weight of hydrophilic shell (2019)
  • Author(s): N.Nakamura, Y. Anraku, S. Fukushima, K. Tou, H. Cabral, K. Kataoka
  • Organizer: 41st Annual Meeting of the Japanese Society for Biomaterials
  • Int'l Joint Research
• [Presentation] Development of novel flexible block catiomers for forming stable polyion complex micelles with mRNA directed to in vivo applications (2019)
  • Author(s): W. Yang, T. Miyazaki, S. Uchida, H. Cabral
  • Organizer: 2nd G'L'owing Polymer Symposium in Kanto
• [Presentation] Development of pH-sensitive polymeric micelles effectively utilizing polymer freeze drying by liquid nitrogen (2019)
  • Author(s): Y. Tachihara, Y. Nakagawa, Y. Anraku, K. Kataoka, H. Cabral
  • Organizer: 10th Research Meeting of Cryogenic Research Center
• [Presentation] 薬剤送達システムへの応用を指向したホストゲスト相互作用による高分子－環状薬剤複合体の構築 (2019)
  • Author(s): Y. Tachihara, Y. Nakagawa, Y. Anraku, K. Kataoka, H. Cabral
  • Organizer: Future Trend in Polymer Science 2018,
• [Presentation] Development of pH-Sensitive Polymeric Micelles for Targeted Delivery of the Macrocycle Valinomycin via Host Guest Interaction (2019)
  • Author(s): Y. Tachihara, Y. Nakagawa, Y. Anraku, K. Kataoka, H. Cabral
  • Organizer: 68th SPSJ Annual Meeting
  • Int'l Joint Research
• [Presentation] Development of Macrocyclic Drug-Loaded pH-Sensitive Polymeric Micelles by Using Host Guest Interaction (2019)
  • Author(s): Y. Tachihara, Y. Nakagawa, Y. Anraku, K. Kataoka, H. Cabral
  • Organizer: TEJIN MIRAI FORUM 2020