MicroRNA delivery by cationic lipoplexes for lung cancer therapy.
MicroRNA delivery by cationic lipoplexes for lung cancer therapy.
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DOI：
10.1021/mp2002076
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发表时间：
2011-08-01
影响因子：
4.9
通讯作者：
Lee LJ
中科院分区：
文献类型：
--
作者：
Wu Y;Crawford M;Yu B;Mao Y;Nana-Sinkam SP;Lee LJ
肺癌是西方国家癌症死亡的主要原因，并且总体五年生存率很低。一些研究表明，microRNAs（miRNAs或miRs）通过充当肿瘤抑制因子、癌基因或两者而积极参与肿瘤的发展。在肺癌中，miRNAs可以作为诊断和预后的生物标志物，以及调节体外和体内肿瘤进展。然而，基于miRNA的治疗面临着一些挑战，包括缺乏组织特异性、缺乏最佳递送系统、细胞摄取差和全身毒性风险。在这里，我们报告了一种基于阳离子脂质的miRNA递送系统来解决这些挑战。在许多肺癌相关的miRNA中，肿瘤抑制因子miR-133 b被选为治疗靶点，因为它直接靶向促生存基因MCL-1，从而调节细胞存活和肺癌细胞对化疗药物的敏感性。在A549非小细胞肺癌（NSCLC）细胞中评估含有前体miR-133 b的脂质复合物的功效。与siPORT NeoFX转染剂相比，脂质体复合物以更有效的方式递送pre-miR-133 b，在体外成熟miR-133 b表达增加了2.3倍，MCL-1蛋白下调了1.8倍。在体内生物分布研究中，脂质复合物在肺组织中达到约30%的积累，这比siPORT NeoFX转染剂高约50倍。用含有前体miR-133 b的脂质复合物处理的小鼠在肺中的成熟miR-133 b表达比未处理的小鼠高52倍。我们的研究结果表明，阳离子脂质复合物是一种有前途的载体系统，用于肺癌治疗中基于miRNA的治疗剂的开发。
Lung cancer is the leading cause of cancer deaths in western countries and carries a poor overall five year survival rate. Several studies demonstrate that microRNAs (miRNAs or miRs) are actively involved in tumor development by serving as tumor suppressors, oncogenes or both. In lung cancer, miRNAs may serve as both diagnostic and prognostic biomarkers as well as regulate in vitro and in vivo tumor progression. However, miRNA-based therapy is faced with several challenges including lack of tissue specificity, lack of optimal delivery systems, poor cellular uptake and risk of systemic toxicity. Here, we report a cationic lipid based miRNA delivery system to address some of these challenges. Among many lung cancer related miRNAs, miR-133b, a tumor suppressor, was selected as a therapeutic target because it directly targets the prosurvival gene MCL-1 thus regulating cell survival and sensitivity of lung cancer cells to chemotherapeutic agents. The efficacy of pre-miR-133b containing lipoplexes was evaluated in A549 non-small cell lung cancer (NSCLC) cells. Compared with siPORT NeoFX transfection agent, lipoplexes delivered pre-miR-133b in a more efficient manner with ∼2.3-fold increase in mature miR-133b expression and ∼1.8-fold difference in MCL-1 protein downregulation in vitro. In the in vivo biodistribution study, lipoplexes achieved ∼30% accumulation in lung tissue, which was ∼50-fold higher than siPORT NeoFX transfection agent. Mice treated with pre-miR-133b containing lipoplexes had mature miR-133b expression in lung ∼52-fold higher than untreated mice. Our results demonstrated that cationic lipoplexes are a promising carrier system for the development of miRNA-based therapeutics in lung cancer treatment.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
10.8
作者：
Ishiwata, H;Suzuki, N;Kitagawa, T
通讯作者：
Kitagawa, T
影响因子：
4.9
作者：
Li, Shyh-Dar;Huang, Leaf
通讯作者：
Huang, Leaf
血清中 microRNA 的表征：一类用于诊断癌症和其他疾病的新型生物标志物
影响因子：
44.1
作者：
Chen, Xi;Ba, Yi;Zhang, Chen-Yu
通讯作者：
Zhang, Chen-Yu
影响因子：
11.2
作者：
Johnson, Charles D.;Esquela-Kerscher, Aurora;Slack, Frank J.
通讯作者：
Slack, Frank J.