信使核糖核酸
部分
核糖核酸
胰腺癌
化学
生物化学
癌症
医学
立体化学
内科学
基因
作者
Satoshi Uchida,Hiroaki Kinoh,Takehiko Ishii,Aya Matsui,Theofilus A. Tockary,Kaori M. Takeda,Hirokuni Uchida,Kensuke Osada,Keiji Itaka,Kazunori Kataoka
出处
期刊:Biomaterials
[Elsevier]
日期:2016-03-01
卷期号:82: 221-228
被引量:126
标识
DOI:10.1016/j.biomaterials.2015.12.031
摘要
Systemic delivery of messenger RNA (mRNA) is technically challenging because mRNA is highly susceptible to enzymatic degradation in the blood circulation. In this study, we used a nanomicelle-based platform, prepared from mRNA and poly(ethylene glycol) (PEG)-polycation block copolymers. A cholesterol (Chol) moiety was attached to the ω-terminus of the block copolymer to increase the stability of the nanomicelle by hydrophobic interaction. After in vitro screening, polyaspartamide with four aminoethylene repeats in its side chain (PAsp(TEP)) was selected as the cationic segment of the block copolymer, because it contributes to enhance nuclease resistance and high protein expression from the mRNA. After intravenous injection, PEG-PAsp(TEP)-Chol nanomicelles showed significantly enhanced blood retention of mRNA in comparison to nanomicelles without Chol. We used the nanomicelles for treating intractable pancreatic cancer in a subcutaneous inoculation mouse model through the delivery of mRNA encoding an anti-angiogenic protein (sFlt-1). PEG-PAsp(TEP)-Chol nanomicelles generated efficient protein expression from the delivered mRNA in tumor tissue, resulting in remarkable inhibition of the tumor growth, whereas nanomicelles without Chol failed to show a detectable therapeutic effect. In conclusion, the stabilized nanomicelle system led to the successful systemic delivery of mRNA in therapeutic application, holding great promise for the treatment of various diseases.
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