Sustained small interfering RNA delivery by mesoporous silicon particles.
Sustained small interfering RNA delivery by mesoporous silicon particles.
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DOI：
10.1158/0008-5472.can-09-3931
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Ferrari M
中科院分区：
文献类型：
--
作者：
Tanaka T;Mangala LS;Vivas-Mejia PE;Nieves-Alicea R;Mann AP;Mora E;Han HD;Shahzad MM;Liu X;Bhavane R;Gu J;Fakhoury JR;Chiappini C;Lu C;Matsuo K;Godin B;Stone RL;Nick AM;Lopez-Berestein G;Sood AK;Ferrari M
RNA干扰（RNAi）是沉默与多种病理条件相关的基因的有力方法;然而，由于缺乏安全、有效和持续的全身递送，体内RNAi递送仍然是一个主要挑战。在这里，我们报告了一种新的方法来克服这些限制，使用多阶段载体组成的中孔硅颗粒（阶段1微粒，S1 MP）加载中性纳米脂质体（二油酰磷脂酰胆碱，DOPC）含有小干扰RNA（siRNA）针对EphA 2癌蛋白，这是过度表达在大多数癌症，包括卵巢癌。我们的递送方法在两个独立的卵巢癌原位小鼠模型中在单次静脉内施用负载有EphA 2-siRNA-DOPC的SlMP后导致持续EphA 2基因沉默至少3周。此外，与单独的非编码对照siRNA（SKOV 3 ip 1，54%; HeyA 8，57%）相比，单次施用负载有-EphA 2-siRNA-DOPC的S1 MP显著降低了肿瘤负荷、血管生成和细胞增殖，而血清化学或促炎细胞因子没有显著变化。总之，我们提供了一种新型的多阶段siRNA递送系统的首次体内治疗验证，该系统用于持续的基因沉默，具有对卵巢肿瘤以外的病理学的广泛适用性。
RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms.