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

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 sple...

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Detalles Bibliográficos
Autores principales: Watanabe, Sumiyo, Hayashi, Kotaro, Toh, Kazuko, Kim, Hyun Jin, Liu, Xueying, Chaya, Hiroyuki, Fukushima, Shigeto, Katsushima, Keisuke, Kondo, Yutaka, Uchida, Satoshi, Ogura, Satomi, Nomoto, Takahiro, Takemoto, Hiroyasu, Cabral, Horacio, Kinoh, Hiroaki, Tanaka, Hiroyoshi Y., Kano, Mitsunobu R., Matsumoto, Yu, Fukuhara, Hiroshi, Uchida, Shunya, Nangaku, Masaomi, Osada, Kensuke, Nishiyama, Nobuhiro, Miyata, Kanjiro, Kataoka, Kazunori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482185/
https://www.ncbi.nlm.nih.gov/pubmed/31019193
http://dx.doi.org/10.1038/s41467-019-09856-w
Descripción
Sumario: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.