Atelocollagen-mediated intravenous siRNA delivery specific to tumor tissues orthotopically xenografted in prostates of nude mice and its anticancer effects.
Atelocollagen-mediated intravenous siRNA delivery specific to tumor tissues orthotopically xenografted in prostates of nude mice and its anticancer effects.
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DOI：
10.1089/nat.2014.0526
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发表时间：
2015-03
影响因子：
4
通讯作者：
Yuan Yuan-Yuan;N. Makita;Dongliang Cao;K. Mihara;K. Kadomatsu;Y. Takei
中科院分区：
文献类型：
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作者：
Yuan Yuan-Yuan;N. Makita;Dongliang Cao;K. Mihara;K. Kadomatsu;Y. Takei
基于短干扰RNA （siRNA）的癌症成功治疗依赖于肿瘤特异性siRNA的功能传递。在我们之前的报告中，我们已经展示了通过胶原蛋白衍生物间胶原（一种胶原衍生物）与siRNA形成复合物，将siRNA系统性地递送到裸鼠的人类前列腺癌细胞系PC-3皮下肿瘤。我们使用人类Bcl-xL的siRNA作为模型靶标。在本研究中，我们检测了裸鼠PC-3原位肿瘤的抗肿瘤作用，因为这些肿瘤与人类临床情况相似。静脉注射siRNA复合物（50 μg/次）可显著降低Bcl-xL的表达，诱导肿瘤细胞凋亡，抑制肿瘤细胞生长。肝转移在原位模型中也受到抑制。我们成功地通过cy3标记的siRNA显示了siRNA的肿瘤特异性积累，并通过反相高效液相色谱法直接定量了siRNA。肿瘤特异性递送是通过增强渗透性和滞留效应实现的，这是大分子药物的特点。血管内皮生长因子- a在肿瘤中的高表达为促进肿瘤的通透性提供了充分的条件，最终形成增强通透性和滞留性的效果。综上所述，我们的siRNA递送对裸鼠PC-3原位肿瘤具有特异性，在治疗肿瘤方面具有实际可行性。
Successful short interfering RNA (siRNA)-based therapy for cancers depends on functional siRNA delivery specific to tumors. In our previous report, we have shown systemic siRNA delivery specific to human prostate cancer cell line PC-3 subcutaneous tumors in nude mice by atelocollagen, a collagen derivative, for formulating a complex with siRNA. We used an siRNA for human Bcl-xL as a model target. In the present study, we examined the antitumor effect on PC-3 orthotopic tumors in nude mice, as these tumors resemble the human clinical situation. The systemic intravenous administration of the complex (siRNA, 50 μg/shot) significantly reduced Bcl-xL expression and induced apoptosis in the tumors, and suppressed their growth. Liver metastasis was also inhibited in the orthotopic model. We successfully showed tumor-specific accumulation of the siRNA by Cy3-labeled siRNA and the direct quantification of the siRNA via reverse-phase high-performance liquid chromatography. The tumor-specific delivery was achieved by the enhanced permeability and retention effect, which is characteristic of macromolecular drugs. The high expression of vascular endothelial growth factor-A in the tumors provided adequate conditions to promote the permeability in the tumors, and to finally form the enhanced permeability and retention effect. In conclusion, our siRNA delivery is specific to the PC-3 orthotopic tumors in nude mice, and is practically feasible to treat tumors.