Targeted Delivery of Small Interfering RNA Using Reconstituted High-Density Lipoprotein Nanoparticles
Targeted Delivery of Small Interfering RNA Using Reconstituted High-Density Lipoprotein Nanoparticles
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DOI：
10.1593/neo.101372
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发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Sood, Anil K.
中科院分区：
文献类型：
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作者：
Shahzad, Mian M. K.;Mangala, Lingegowda S.;Sood, Anil K.
RNA干扰作为一种治疗方法具有巨大的潜力，特别是在恶性肿瘤的治疗中。然而，需要有效的和生物相容的递送方法用于小干扰RNA（siRNA）的全身递送。为了维持高水平的生长，肿瘤细胞通过过度表达其受体：清道夫受体B1（SR-B1）来抑制高密度脂蛋白（HDL）颗粒。在这项研究中，我们利用这种细胞特性来实现有效的siRNA递送，并通过将其掺入重组HDL（rHDL）纳米颗粒中来建立一种新的siRNA制剂。在这里，我们证明了rHDL纳米颗粒促进了由SR-B1介导的siRNA在体内的高效全身递送。此外，在治疗概念验证研究中，这些纳米颗粒可有效沉默卵巢癌和结直肠癌原位小鼠模型中两种对癌症生长和转移至关重要的蛋白质（信号转导和转录激活因子3和粘着斑激酶）的表达。这些数据表明，rHDL纳米颗粒是一种新型高效的siRNA载体，因此，这种新技术可以作为新的癌症治疗方法的基础。
RNA interference holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of small interfering RNA (siRNA). To maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing its receptor: scavenger receptor type B1 (SR-B1). In this study, we exploited this cellular characteristic to achieve efficient siRNA delivery and established a novel formulation of siRNA by incorporating it into reconstituted HDL (rHDL) nanoparticles. Here, we demonstrate that rHDL nanoparticles facilitate highly efficient systemic delivery of siRNA in vivo, mediated by the SR-B1. Moreover, in therapeutic proof-of-concept studies, these nanoparticles were effective in silencing the expression of two proteins that are key to cancer growth and metastasis (signal transducer and activator of transcription 3 and focal adhesion kinase) in orthotopic mouse models of ovarian and colorectal cancer. These data indicate that an rHDL nanoparticle is a novel and highly efficient siRNA carrier, and therefore, this novel technology could serve as the foundation for new cancer therapeutic approaches.