Tumor vasculature is a key determinant for the efficiency of nanoparticle-mediated siRNA delivery
Tumor vasculature is a key determinant for the efficiency of nanoparticle-mediated siRNA delivery
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DOI：
10.1038/gt.2011.146
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发表时间：
2012-07-01
期刊：
影响因子：
5.1
通讯作者：
Shen, Y.
中科院分区：
文献类型：
--
作者：
Li, L.;Wang, R.;Shen, Y.
使用临床可行的制剂将小干扰RNA(SiRNA)输送到肿瘤仍然是阻碍siRNA疗法用于癌症治疗发展的主要技术障碍。在过去的几年里，人们致力于探索新的递送策略，而对诸如肿瘤血管等生理限制因素对siRNA递送效率的影响的关注相对较少。利用前面描述的阳性读出肿瘤模型，成功地递送siRNA导致肿瘤切片内β-半乳糖苷酶上调，我们分析了肿瘤切片内局部靶基因敲除的空间分布与肿瘤缺氧的关系，发现稳定的核酸脂质颗粒(SNALP)是一种基于脂质纳米颗粒的递送系统，主要将siRNA递送到功能正常的肿瘤血管附近的区域。使用SNALP通过异位表达血管内皮生长因子增加肿瘤血管，从而使siRNA更有效地输送到肿瘤中。SNALP介导的靶向Ran GTPase的siRNA传递导致靶向敲除和显著的抗肿瘤效果，在高血管化的HepG2来源的肝肿瘤中，但在低血管化的HCT-116来源的肝肿瘤中没有。这些结果突出了肿瘤血管对siRNA传递的重大影响，并呼吁更有针对性地努力解决肿瘤渗出后的渗透问题，这是目前关注的一个领域。基因治疗(2012年)19775-780；DOI：10.1038/gt.2011.146；2011年9月29日在线发布
Delivering small interfering RNA (siRNA) to tumors using clinically viable formulations remains the primary technical hurdle that prevents the development of siRNA therapy for cancer treatment. Over the past several years, significant effort has been devoted to explore novel delivery strategies, whereas relatively little attention has been paid to understand the impact of physiological constrains such as tumor vasculature on the efficiency of siRNA delivery. Using the previously described positive-readout tumor models where successful siRNA delivery leads to an upregulation of beta-galactosidase within tumor sections, we analyzed the spatial distribution of localized target knockdown within tumor sections relative to tumor hypoxia and found that stable nucleic acid lipid particle (SNALP), a lipid nanoparticle-based delivery system, predominantly delivers siRNA to areas adjacent to functional tumor blood vessels. Increasing tumor vascularity by ectopic expression of VEGF resulted in more efficient siRNA delivery to tumors using SNALP. SNALP-mediated delivery of a siRNA-targeting Ran GTPase led to target knockdown and significant antitumor efficacy in the highly vascularized HepG2-derived liver tumors, but not in the poorly vascularized HCT-116-derived liver tumors. These results highlight the significant impact of tumor vasculature on siRNA delivery and call for a more focused effort on addressing tumor penetration after extravasation, an area of only limited attention currently. Gene Therapy (2012) 19, 775-780; doi:10.1038/gt.2011.146; published online 29 September 2011