Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo
Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo
复制标题
DOI：
10.1073/pnas.0501753102
复制
发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Ochiya, T
中科院分区：
文献类型：
--
作者：
Takeshita, F;Minakuchi, Y;Ochiya, T
通过小干扰 RNA (siRNA) 沉默基因表达正在迅速成为遗传分析的强大工具，并代表了治疗产品开发的潜在策略。然而，目前还没有系统性递送 siRNA 来治疗骨转移癌的报道。因此，我们在此报告 i.v.注射与去端肽胶原复合的 GL3 荧光素酶 siRNA 可以有效降低小鼠胸部、颌骨和/或腿部发育的骨转移性前列腺肿瘤细胞的荧光素酶表达。我们还表明，siRNA/去端肽胶原复合物可以在注射后 24 小时有效递送至肿瘤，并且可以完整存在至少 3 天。此外，去端肽胶原介导的siRNA（例如zeste同源物2增强剂和磷酸肌醇3'-羟基激酶p110-α-亚基）的全身给药被选为抑制骨转移的候选靶标，从而有效抑制骨组织中转移性肿瘤的生长。此外，血清IL-12和IFN-α水平的上调与体内施用siRNA/去端肽胶原复合物无关。因此，对于前列腺癌骨转移的治疗，去端肽胶原介导的全身递送方法可能是实现siRNA最大功能的可靠且安全的方法。
Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3'-hydroxykinase p110-alpha-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-alpha levels was not associated with the in vivo administration of the siRNA/atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-miediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.