In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers
In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers
复制标题
DOI：
10.1038/s41467-019-09856-w
复制
发表时间：
2019-04-24
影响因子：
16.6
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Watanabe, Sumiyo;Hayashi, Kotaro;Kataoka, Kazunori
稳定脆弱的寡核苷酸，通常是小干扰RNA(SiRNA)，是寡核苷酸治疗最关键的问题之一。以前的许多研究都将寡核苷酸封装成类似于100纳米的纳米颗粒。然而，这样的纳米颗粒不可避免地会在肝脏和脾中积聚。此外，一些难治性癌症，例如胰腺和脑肿瘤，具有固有的屏障特性，阻止这种纳米颗粒渗透到肿瘤微环境中。在这里，我们报告了一种使用具有精确调节链长的Y型嵌段阳离子(YBC)的癌症靶向寡核苷酸递送的替代方法。值得注意的是，YBC中的正电荷数量被调整为与每个寡核苷酸链中的负电荷数量(即20)相匹配。YBC与血流中的单个寡核苷酸会合，产生动态离子对，称为单位多离子络合物(UPIC)。由于UPIC在血液中的寿命显著延长，并且体积明显较小(类似于18 nm)，UPIC有效地将寡核苷酸输送到胰腺肿瘤和脑瘤模型中，发挥了显著的抗肿瘤活性。
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 similar to 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 (similar to 18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.