Target Specific Intracellular Delivery of siRNA/PEI-HA Complex by Receptor Mediated Endocytosis
Target Specific Intracellular Delivery of siRNA/PEI-HA Complex by Receptor Mediated Endocytosis
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DOI：
10.1021/mp800176t
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发表时间：
2009-05-01
影响因子：
4.9
通讯作者：
Hahn, Sei Kwang
中科院分区：
文献类型：
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作者：
Jiang, Ge;Park, Kitae;Hahn, Sei Kwang
透明质酸（HA）通过与细胞膜上的受体相互作用，在组织完整性、血管生成、伤口愈合和细胞运动中发挥重要的生物学作用。在这项工作中，我们研究了HA修饰对受体介导的量子点标记HA衍生物（QDots）的内吞作用的影响。HA-QDot偶联物的修饰度小于约100。25mol%似乎比单独的QDots通过HA受体介导的内吞作用更有效地被B16 F1细胞摄取。在生物成像研究的基础上，开发了PEI含量为24.2mol%的聚乙烯亚胺PEI-HA偶联物作为siRNA靶向细胞内递送载体。siRNA/PEI-HA复合物在具有HA受体的B16 F1细胞中表现出比siRNA/PEI复合物更高的基因沉默效率。抗PGL 3-Luc siRNA/PEI-HA复合物似乎在50%-85%的范围内沉默PGL 3-Luc基因，这取决于高达50体积%的血清浓度。体内分布实验表明，siRNA/PEI-HA复合物主要在肝、肾、肿瘤等HA受体组织中聚集。此外，肿瘤内注射抗VEGF siRNA/PEI-HA复合物通过HA受体介导的对C57 BL/6小鼠中肿瘤细胞的内吞作用导致肿瘤生长的有效抑制。考虑到所有这些结果，抗VEGF siRNA/PEI-HA复合物被认为成功地用作靶特异性抗血管生成治疗剂，用于治疗具有HA受体的组织中的疾病，例如肝癌和肾癌。
Hyaluronic acid (HA) plays important biological roles in tissue integrity, angiogenesis, wound healing, and cell motility through the interaction with receptors on cell membranes. In this work, we investigated the effect of HA modification on the receptor-mediated endocytosis labeling HA derivatives with quantum dots (QDots). HA-QDot conjugates with a degree of modification less than ca. 25 mol % appeared to be more efficiently taken up to B16F1 cells by HA receptor mediated endocytosis than QDots alone. On the basis of bioimaging study, polyethyleneimine, PEI-HA conjugate with 24.2 mol % PEI content was developed as a target specific intracellular delivery carrier of siRNA. The siRNA/PEI-HA complex exhibited higher gene silencing efficiency in B16F1 cells with HA receptors than siRNA/PEI complex. Anti-PGL3-Luc siRNA/PEI-HA complex appeared to silence PGL3-Luc gene in the range of 50%-85% depending on the serum concentration up to 50 vol %. According to in vivo biodistribution test, siRNA/PEI-HA complex accumulated mainly in the tissues with HA receptors such as liver, kidney, and tumor. Furthermore, intratumoral injection of anti-VEGF siRNA/PEI-HA complex resulted in an effective inhibition of tumor growth by the HA receptor mediated endocytosis to tumor cells in C57BL/6 mice. Considering all these results, anti-VEGF siRNA/PEI-HA complex was thought to be applied successfully as target specific antiangiogenic therapeutics for the treatment of diseases in the tissues with HA receptors, such as liver cancer and kidney cancer.