Functional TNFα gene silencing mediated by polyethyleneimine/TNFα siRNA nanocomplexes in inflamed colon.
Functional TNFα gene silencing mediated by polyethyleneimine/TNFα siRNA nanocomplexes in inflamed colon.
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DOI：
10.1016/j.biomaterials.2010.09.062
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发表时间：
2011-02
期刊：
影响因子：
14
通讯作者：
Merlin, Didier
中科院分区：
文献类型：
--
作者：
Laroui, Hamed;Theiss, Arianne L.;Yan, Yutao;Dalmasso, Guillaume;Nguyen, Hang T. T.;Sitaraman, Shanthi V.;Merlin, Didier
关键词：
在炎症性肠病中，TNFα是主要的促炎细胞因子，主要由巨噬细胞和树突状细胞分泌。在这里，我们已经证明，TNFα siRNA/聚乙烯亚胺以20 g/L聚乙烯醇覆盖的纳米颗粒的最佳浓度加载到聚乳酸中，可有效地被发炎的巨噬细胞摄取，并抑制巨噬细胞分泌TNFα。这些纳米颗粒的直径约为380 nm，在pH 7.2时的zeta电位为−8 mV，并且无细胞毒性。TNFα siRNA与聚乙烯亚胺的复合、相互作用和对RNA酶的保护作用均高于壳聚糖。重要的是，与Chi或游离siRNA与Lipofectamine混合相比，TNFα siRNA与聚乙烯亚胺之间的复合促进了siRNA加载到纳米颗粒中的速率更高。经口给药包封的TNFα负载纳米颗粒可特异性降低LPS处理小鼠结肠组织中TNFα的表达/分泌。总之，我们已经证明：（1）通过非变性合成工艺制备了所提出的siRNA TNFα负载纳米颗粒;（2）TNFα siRNA与聚乙烯亚胺复合物在纳米颗粒中的高包封率;（3）聚乙烯亚胺对TNFα siRNA的有效酶促保护;（4）负载聚乙烯亚胺/TNFα siRNA的纳米颗粒无细胞毒性和生物降解性;和（5）在体外和体内在低TNFα siRNA剂量下显著的抗炎作用，其特异性且仅限于结肠细胞。我们的研究结果共同表明，聚乙烯亚胺/TNFα siRNA纳米复合物代表了IBD等疾病的有效治疗选择。
During inflammatory bowel disease, TNFα is the major pro-inflammatory cytokine mainly secreted from macrophages and dendritic cells. Here, we have demonstrated that TNFα siRNA/polyethyleneimine loaded into polylactide at an optimal concentration of 20 g/L nanoparticles covered with polyvinyl alcohol are efficiently taken up by inflamed macrophages and inhibit TNFα secretion by the macrophages. Those nanoparticles have a diameter of ~380 nm and zeta potential of −8 mV at pH 7.2, and are non-cytotoxic. Complexation, interactions and protection from RNAse between TNFα siRNA and polyethyleneimine were higher than those using chitosan. Importantly, complexation between TNFα siRNA and polyethyleneimine facilitated higher rates of siRNA loading into nanoparticles, compared to Chi or free siRNA mixed with Lipofectamine. Oral administration of encapsulated TNFα-loaded nanoparticles specifically reduced the TNFα expression/secretion in colonic tissue in LPS-treated mice. In conclusion, we have shown: (1) that proposed siRNA TNFα-loaded NPs are prepared via a non-denaturing synthetic process; (2) a high encapsulation rate of TNFα siRNA complexed to polyethyleneimine into NPs; (3) effective enzymatic protection of TNFα siRNA by polyethyleneimine; (4) non-cytotoxicity and biodegradability of nanoparticles loaded with polyethyleneimine/TNFα siRNA; and (5) in vitro and in vivo significant anti-inflammatory effects at low TNFα siRNA dose that is specific and restricted to the colonic cells. Our results collectively indicate that polyethyleneimine/TNFα siRNA nanocomplexes represent an efficient therapeutic option for diseases such as IBD.
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DOI：
10.2174/1568011053174855
发表时间：
2005-03-01
期刊：
Current medicinal chemistry. Anti-cancer agents
影响因子：
--
作者：
Gunther, Michael;Wagner, Ernst;Ogris, Manfred
通讯作者：
Ogris, Manfred
影响因子：
10.8
作者：
Zambaux, MF;Bonneaux, F;Vigneron, C
通讯作者：
Vigneron, C
影响因子：
2.4
作者：
KETTERER, B;NEUMCKE, B;LAUGER, P
通讯作者：
LAUGER, P
影响因子：
3.8
作者：
Raper, SE
通讯作者：
Raper, SE
影响因子：
11.2
作者：
Farokhzad, OC;Jon, SY;Langer, R
通讯作者：
Langer, R