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-- RNA干扰(RNAi)是一种很有前途的方法,可以用来作为针对人体不同疾病(如癌症)的治疗策略。然而,在体内,如何将小分子siRNA转移到肿瘤或者癌细胞聚集的区域一直是很难的课题。通过一种高效的自组装系统,来自美国哈佛医学院和中国四川大学华西医学院的课题组,发展了一套独特的纳米颗粒平台,通过由固体多聚阳离子脂类和脂类-多聚乙二醇构成的分子外壳,包裹着小分子siRNA的运输系统。

在465个非小细胞性肺癌(NSCLC)患者采集的组织,通过微阵列分析和免疫沉淀方法发现,在癌细胞中PHB1蛋白存在很高的表达量,也是与非小细胞性肺癌患者低存活率相关的。这证明了,PHB1蛋白是针对非PHB1的表达量或许对治疗非小细胞性肺癌有积极意义。中美的这个联合课题组,试图通过一种新的纳米颗粒转运系统将针对PHB1的siRNA送达癌细胞区域,进而达到抗癌细胞的效果。这种思路和前期东京大学片冈一则发表在ACS Nano的研究文章存在异曲同工之妙。

这种新一代的纳米多聚体尺寸很小,而且大小比较均一,能够高效地包裹和释放siRNA分子。这些纳米粒子在血液的半数浓度存留时间长达8小时。不仅如此,该颗粒还可以有些聚集到肿瘤区域,完成基因沉默,在活体内有很小的副作用。实验中siRNA是通过沉默蛋白质PHB1的基因,达到抑制非小细胞性肺癌细胞生长的。当沉默掉PHB1后,癌细胞的程序性死亡数量增加。16天后,对比对照组,实验组的癌细胞组织的重量轻约70%。该实验对抗癌效果的测试是在小鼠身上完成的。

这个研究证明了,PHB1可能作为一种潜在的抗非小细胞性肺癌的靶标,对抗癌药物研发有重要意义。PHB1结合siRNA对癌细胞生长抑制明显,而这其中新类型的纳米颗粒可以很好地转运整个系统到癌细胞区域。这个研究为抗癌药物研发提供了新的思路。然而从实验室进入临床,还有很多问题需要解决。或许该研究未来会给我们带来惊喜,让我们拭目以待吧。(生物谷Bioon.com)

 

Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment

RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid–polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t1/2 ∼8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.
(来源:生物谷)