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

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, Hiroyasu Takemoto, Horacio Cabral, Hiroaki Kinoh, Hiroyoshi Y. Tanaka, Mitsunobu R. Kano, Yu Matsumoto, Hiroshi Fukuhara, Shunya UchidaMasaomi Nangaku, Kensuke Osada, Nobuhiro Nishiyama, Kanjiro Miyata, Kazunori Kataoka

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article number1894
Pages (from-to)1894
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - Apr 24 2019

Keywords

  • Animals
  • Antineoplastic Agents/chemical synthesis
  • Brain Neoplasms/genetics
  • Carbocyanines/chemistry
  • Cell Cycle Proteins/antagonists & inhibitors
  • Cell Line, Tumor
  • Drug Carriers/chemical synthesis
  • Fluorescent Dyes/chemistry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Injections, Intravenous
  • Male
  • Mice
  • Nanostructures/administration & dosage
  • Oligonucleotides/chemical synthesis
  • Pancreatic Neoplasms/genetics
  • Polyethylene Glycols/chemistry
  • Polylysine/chemistry
  • Protein-Serine-Threonine Kinases/antagonists & inhibitors
  • Proto-Oncogene Proteins/antagonists & inhibitors
  • RNA, Long Noncoding/antagonists & inhibitors
  • RNA, Small Interfering/chemical synthesis
  • Static Electricity
  • Survival Analysis
  • Xenograft Model Antitumor Assays

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Watanabe, S., Hayashi, K., Toh, K., Kim, H. J., Liu, X., Chaya, H., Fukushima, S., Katsushima, K., Kondo, Y., Uchida, S., Ogura, S., Nomoto, T., Takemoto, H., Cabral, H., Kinoh, H., Tanaka, H. Y., Kano, M. R., Matsumoto, Y., Fukuhara, H., ... Kataoka, K. (2019). In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers. Nature communications, 10(1), 1894. [1894]. https://doi.org/10.1038/s41467-019-09856-w