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In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers

Author

Listed:
  • Sumiyo Watanabe

    (The University of Tokyo
    Teikyo University School of Medicine
    The University of Tokyo)

  • Kotaro Hayashi

    (Kawasaki Institute of Industrial Promotion)

  • Kazuko Toh

    (Kawasaki Institute of Industrial Promotion)

  • Hyun Jin Kim

    (The University of Tokyo)

  • Xueying Liu

    (Kawasaki Institute of Industrial Promotion)

  • Hiroyuki Chaya

    (The University of Tokyo
    The University of Tokyo)

  • Shigeto Fukushima

    (Kawasaki Institute of Industrial Promotion)

  • Keisuke Katsushima

    (Nagoya University Graduate School of Medicine)

  • Yutaka Kondo

    (Nagoya University Graduate School of Medicine)

  • Satoshi Uchida

    (The University of Tokyo)

  • Satomi Ogura

    (Kawasaki Institute of Industrial Promotion
    The University of Tokyo)

  • Takahiro Nomoto

    (Tokyo Institute of Technology)

  • Hiroyasu Takemoto

    (Tokyo Institute of Technology)

  • Horacio Cabral

    (The University of Tokyo)

  • Hiroaki Kinoh

    (Kawasaki Institute of Industrial Promotion)

  • Hiroyoshi Y. Tanaka

    (Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences)

  • Mitsunobu R. Kano

    (Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
    Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems)

  • Yu Matsumoto

    (The University of Tokyo)

  • Hiroshi Fukuhara

    (Kyorin University Faculty of Medicine)

  • Shunya Uchida

    (Teikyo University School of Medicine)

  • Masaomi Nangaku

    (The University of Tokyo)

  • Kensuke Osada

    (The University of Tokyo)

  • Nobuhiro Nishiyama

    (Tokyo Institute of Technology)

  • Kanjiro Miyata

    (The University of Tokyo
    The University of Tokyo)

  • Kazunori Kataoka

    (Kawasaki Institute of Industrial Promotion
    The University of Tokyo)

Abstract

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

Suggested Citation

  • Sumiyo Watanabe & Kotaro Hayashi & Kazuko Toh & Hyun Jin Kim & Xueying Liu & Hiroyuki Chaya & Shigeto Fukushima & Keisuke Katsushima & Yutaka Kondo & Satoshi Uchida & Satomi Ogura & Takahiro Nomoto & , 2019. "In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09856-w
    DOI: 10.1038/s41467-019-09856-w
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    Cited by:

    1. Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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