Systemic Delivery of siRNA via LCP Nanoparticle Efficiently Inhibits Lung Metastasis
Systemic Delivery of siRNA via LCP Nanoparticle Efficiently Inhibits Lung Metastasis
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DOI：
10.1038/mt.2011.270
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发表时间：
2012-03-01
影响因子：
12.4
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
--
作者：
Yang, Yang;Li, Jun;Huang, Leaf
靶向递送仍然是小干扰RNA（siRNA）应用的主要挑战。我们已经开发了脂质/钙/磷酸盐（LCP）纳米颗粒（NP）以提高siRNA递送效率。通过微乳液技术制备LCP NP以形成钙/磷酸盐（CaP）核并进一步用阳离子脂质包覆。最终的NP在表面上接枝有聚乙二醇（PEG）和茴香酰胺（AA）配体，以靶向表达σ受体的B16 F10黑素瘤细胞。LCP NP表现出40 nm的粒径、+25 mV的zeta电位和91%的siRNA包封效率。在单次静脉内（i. v.）注射配制在靶向LCP NP中的抗荧光素酶siRNA（0.12 mg siRNA/kg）后，C57 BL/6小鼠中转移性B16 F10肿瘤负载肺中的荧光素酶活性降低了78%。在治疗实验中，靶向LCP NP中共配制的针对MDM 2、c-myc和VEGF的siRNA导致转移性结节中相应癌基因的同时沉默。在靶向NP中用siRNA治疗以相对低的剂量（0.36 mg/kg）显著减少肺转移（类似于70-80%），而对照组显示出很小的治疗效果。此外，与对照组相比，这种靶向LCP NP显著延长了动物的平均存活时间27.8%，而在治疗剂量下未显示出任何毒性。收稿日期：2011年9月2日;接受日期：2011年11月14日;在线发表日期：2011年12月20日。doi：10.1038/mt.2011.270
Targeted delivery remains the major challenge for the application of small interfering RNA (siRNA). We have developed a lipid/calcium/phosphate (LCP) nanoparticle (NP) to improve siRNA delivery efficiency. The LCP NP was prepared by using microemulsion technology to form calcium/phosphate (CaP) core and further coated with cationic lipids. The final NP was grafted with polyethylene glycol (PEG) and anisamide (AA) ligand on the surface to target sigma receptor-expressing B16F10 melanoma cells. The LCP NP exhibited a 40 nm particle size, a + 25 mV zeta-potential, and 91% siRNA encapsulation efficiency. After a single intravenous (i.v.) injection of antiluciferase siRNA (0.12 mg siRNA/kg) formulated in targeted LCP NP, luciferase activity in metastatic B16F10 tumor-loaded lungs decreased by 78% in C57BL/6 mice. In a therapeutic experiment, siRNA against MDM2, c-myc, and VEGF coformulated in the targeted LCP NP resulted in simultaneous silencing of the respective oncogenes in metastatic nodules. Treatment with siRNA in the targeted NP significantly reduced lung metastases (similar to 70-80%) at a relatively low dose (0.36 mg/kg), whereas control group showed little therapeutic effect. Moreover, this targeted LCP NP significantly prolonged the mean survival time of the animals by 27.8% compared to control group without showing any toxicity at the therapeutic dose. Received 2 September 2011; accepted 14 November 2011; published online 20 December 2011. doi:10.1038/mt.2011.270