RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21
RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21
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DOI：
10.1016/j.ymthe.2016.11.016
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发表时间：
2017-07-05
影响因子：
12.4
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
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作者：
Lee, Tae Jin;Yoo, Ji Young;Croce, Carlo M.
已经提出靶向抑制致癌miRNA-21以通过拯救肿瘤抑制因子PTEN和PDCD 4来治疗胶质母细胞瘤。然而，抗miR 21序列的全身递送需要稳健且有效的递送平台来成功抑制该可药物化靶标。基于三向连接（3 WJ）的RNA纳米颗粒（RNP），人工来源于噬菌体phi 29 DNA包装马达的pRNA，最近显示出靶向胶质母细胞瘤。在这里，我们报告了构建的多价叶酸（FA）缀合的3 WJ RNP以携带抗miR-21 LNA序列（FA-3 WJ-LNA-miR 21）特异性靶向并递送抗miR-21 LNA，并在体外和体内敲低胶质母细胞瘤细胞中的miR-21表达，具有良好的生物分布。全身注射FA-3 WJ-LNA-miR 21 RNP有效地拯救了PTEN和PDCD 4，导致胶质母细胞瘤细胞凋亡和肿瘤生长消退。FA-3 WJ-LNA-miR 21 RNP也显著改善了总体存活率。这些结果表明，基于FA-3 WJ RNP的基因疗法对于发展中甚至复发性胶质母细胞瘤的成功靶向疗法的临床益处。
Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR21 sequences requires a robust and efficient delivery platform to successfully inhibit this druggable target. Three-way junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate(FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.