An efficient and low immunostimulatory nanoparticle formulation for systemic siRNA delivery to the tumor.
An efficient and low immunostimulatory nanoparticle formulation for systemic siRNA delivery to the tumor.
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DOI：
10.1016/j.jconrel.2008.07.006
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发表时间：
2008-10-06
影响因子：
10.8
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
--
作者：
Chono, Sumio;Li, Shyh-Dar;Conwell, Christine C.;Huang, Leaf
我们已经开发了一种纳米颗粒制剂[脂质体-鱼精蛋白-透明质酸纳米颗粒（LPH-NP）]，用于将siRNA全身递送到肿瘤中。LPH-NP是在自组装过程中制备的。简言之，将鱼精蛋白与siRNA和透明质酸的混合物混合以制备带负电荷的复合物。然后，加入阳离子脂质体，通过电荷-电荷相互作用用脂质包覆复合物，以制备LPH-NP。通过后插入法，用DSPE-PEG或DSPE-PEG-茴香酰胺进一步修饰LPH-NP。茴香酰胺是B16 F10黑色素瘤细胞中过表达的σ受体的靶向配体。制剂的粒径、ζ电位和siRNA包封效率分别为约115 nm、+25 mV和90%。使用荧光素酶siRNA来评估B16 F10细胞中的基因沉默活性，所述B16 F10细胞用荧光素酶基因稳定转导。在单次静脉内注射（0.15 mg siRNA/kg）后，靶向LPH-NP（用配体PEG化）使肺中转移性B16 F10肿瘤中80%的荧光素酶活性沉默。靶向LPH-NP在宽剂量范围（0.15 - 1.2mg siRNA/kg）内也显示出非常小的免疫毒性，而先前公开的制剂LPD-NP（脂质体-鱼精蛋白-DNA纳米颗粒）具有窄得多的治疗窗口（0.15- 0.45mg/kg）。
We have developed a nanoparticle formulation [liposomes-protamine-hyaluronic acid nanoparticle (LPH-NP)] for systemically delivering siRNA into the tumor. The LPH-NP was prepared in a self-assembling process. Briefly, protamine and a mixture of siRNA and hyaluronic acid were mixed to prepare a negatively charged complex. Then, cationic liposomes were added to coat the complex with lipids via charge-charge interaction to prepare the LPH-NP. The LPH-NP was further modified by DSPE-PEG or DSPE-PEG-anisamide by the post-insertion method. Anisamide is a targeting ligand for the sigma receptor over-expressed in the B16F10 melanoma cells. The particle size, zeta potential and siRNA encapsulation efficiency of the formulation were approximately 115 nm, +25 mV and 90%, respectively. Luciferase siRNA was used to evaluate the gene silencing activity in the B16F10 cells, which were stably transduced with a luciferase gene. The targeted LPH-NP (PEGylated with ligand) silenced 80% of luciferase activity in the metastatic B16F10 tumor in the lung after a single i.v. injection (0.15 mg siRNA/kg). The targeted LPH-NP also showed very little immunotoxicity in a wide dose range (0.15 – 1.2 mg siRNA/kg), while the previously published formulation, LPD-NP (liposome-protamine-DNA nanoparticle), had a much narrow therapeutic window (0.15–0.45 mg/kg).
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影响因子：
12.4
作者：
Li, Shyh-Dar;Chono, Sumio;Huang, Leaf
通讯作者：
Huang, Leaf
影响因子：
10.8
作者：
Ito, Tomoko;Iida-Tanaka, Naoko;Koyama, Yoshiyuki
通讯作者：
Koyama, Yoshiyuki
影响因子：
10.8
作者：
Li, Shyh-Dar;Chono, Sumio;Huang, Leaf
通讯作者：
Huang, Leaf
DOI：
10.1196/annals.1348.001
发表时间：
2006-01-01
期刊：
OLIGONUCLEOTIDE THERAPEUTICS
影响因子：
--
作者：
Li, Shyh-Dar;Huang, Leaf
通讯作者：
Huang, Leaf
影响因子：
11.5
作者：
Zhang, X;Chen, ZG;Shin, DM
通讯作者：
Shin, DM