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 Uchida; Masaomi Nangaku; Kensuke Osada; Nobuhiro Nishiyama; Kanjiro Miyata; Kazunori Kataoka

doi:10.1038/s41467-019-09856-w

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

Nat Commun. 2019 Apr 24;10(1):1894. doi: 10.1038/s41467-019-09856-w.

Authors

Sumiyo Watanabe^{1

2

3}, Kotaro Hayashi⁴, Kazuko Toh⁴, Hyun Jin Kim¹, Xueying Liu⁴, Hiroyuki Chaya^{1

5}, Shigeto Fukushima⁴, Keisuke Katsushima⁶, Yutaka Kondo⁶, Satoshi Uchida⁷, Satomi Ogura^{4

5}, Takahiro Nomoto⁸, Hiroyasu Takemoto⁸, Horacio Cabral⁷, Hiroaki Kinoh⁴, Hiroyoshi Y Tanaka⁹, Mitsunobu R Kano^{9

10}, Yu Matsumoto¹, Hiroshi Fukuhara¹¹, Shunya Uchida², Masaomi Nangaku³, Kensuke Osada⁷, Nobuhiro Nishiyama⁸, Kanjiro Miyata^{12

13}, Kazunori Kataoka^{14

15}

Affiliations

¹ Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
² Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
³ Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8544, Japan.
⁴ Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.
⁵ Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
⁶ Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
⁷ Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
⁸ Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8503, Japan.
⁹ Department of Pharmaceutical Biomedicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama Prefecture, 700-8530, Japan.
¹⁰ Department of Pharmaceutical Biomedicine, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama Prefecture, 700-8530, Japan.
¹¹ Department of Urology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
¹² Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. miyata@bmw.t.u-tokyo.ac.jp.
¹³ Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. miyata@bmw.t.u-tokyo.ac.jp.
¹⁴ Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan. kataoka@ifi.u-tokyo.ac.jp.
¹⁵ Institute for Future Initiatives, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. kataoka@ifi.u-tokyo.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism*
Antineoplastic Agents / pharmacokinetics
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Brain Neoplasms / mortality
Brain Neoplasms / therapy*
Carbocyanines / chemistry
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Drug Carriers / chemical synthesis
Drug Carriers / pharmacokinetics
Fluorescent Dyes / chemistry
Gene Expression Regulation, Neoplastic*
Humans
Injections, Intravenous
Male
Mice
Nanostructures / administration & dosage
Nanostructures / chemistry*
Oligonucleotides / chemical synthesis
Oligonucleotides / genetics*
Oligonucleotides / metabolism
Oligonucleotides / pharmacokinetics
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / therapy*
Polo-Like Kinase 1
Polyethylene Glycols / chemistry
Polylysine / chemistry
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA, Long Noncoding / antagonists & inhibitors
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism
RNA, Small Interfering / chemical synthesis
RNA, Small Interfering / genetics*
RNA, Small Interfering / metabolism
RNA, Small Interfering / pharmacokinetics
Static Electricity
Survival Analysis
Xenograft Model Antitumor Assays

Substances

Alexa Fluor 647
Antineoplastic Agents
Carbocyanines
Cell Cycle Proteins
Drug Carriers
Fluorescent Dyes
Oligonucleotides
Proto-Oncogene Proteins
RNA, Long Noncoding
RNA, Small Interfering
TUG1 long noncoding RNA, human
Polylysine
Polyethylene Glycols
Protein Serine-Threonine Kinases