Lipidation of polyethylenimine-based polyplex increases serum stability of bioengineered RNAi agents and offers more consistent tumoral gene knockdown in vivo.
Lipidation of polyethylenimine-based polyplex increases serum stability of bioengineered RNAi agents and offers more consistent tumoral gene knockdown in vivo.
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DOI：
10.1016/j.ijpharm.2018.06.026
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发表时间：
2018-08-25
影响因子：
5.8
通讯作者：
Yu AM
中科院分区：
文献类型：
--
作者：
Zhang QY;Ho PY;Tu MJ;Jilek JL;Chen QX;Zeng S;Yu AM
最近，我们已经建立了一种新的方法来在携带靶RNAi分子的活细胞中产生生物工程非编码RNA试剂（BERA）（例如，siRNA和miRNA），因此充当“前药”。以载GFP-siRNA的BERA（BERA/GFP-siRNA）为模型分子，研究脂质体-聚乙烯亚胺纳米复合物（lipopolyplex或LPP）对BERA的体内外抑制效率。与体内-jetPEI ®（IVJ-PEI）和聚合复合物制剂相比，LPP提供了对BERA/GFP-siRNA抵抗血清RNA酶降解的更大保护。当在4 °C下储存时，LPP纳米复合物的粒度和ζ电位在28天内保持稳定。此外，通过LPP和IVJ-PEI将相当水平的BERA/GFP-siRNA递送至表达荧光素酶/GFP的人SK-Hep 1-Luc-GFP或A549-Luc-GFP细胞，其被选择性地加工成靶GFP-siRNA，随后敲低GFP mRNA和蛋白质水平。此外，LPP携带的BERA/GFP-siRNA被成功地递送到异种移植肿瘤中，并且在原位肝细胞癌（HCC）SK-Hep 1-Luc-GFP异种移植小鼠模型中提供了肿瘤GFP mRNA水平的更一致的敲低，而IVJ-PEI制剂显示出更大的变化。这些发现表明，复合物的脂化改善了生物RNAi分子的血清稳定性，其被有效地递送到原位HCC组织以敲低靶基因表达。
Recently we have established a novel approach to produce bioengineered noncoding RNA agents (BERAs) in living cells that carry target RNAi molecules (e.g., siRNA and miRNA) and thus act as “prodrugs”. Using GFP-siRNA-loaded BERA (BERA/GFP-siRNA) as a model molecule, this study was to define the in vitro and in vivo knockdown efficiency of BERAs delivered by liposome-polyethylenimine nanocomplex (lipopolyplex or LPP). Compared to in vivo-jetPEI® (IVJ-PEI) and polyplex formulations, LPP offered greater protection of BERA/GFP-siRNA against degradation by serum RNases. Particle sizes and zeta potentials of LPP nanocomplex remained stable over 28 days when stored at 4 °C. Furthermore, comparable levels of BERA/GFP-siRNA were delivered by LPP and IVJ-PEI to luciferase/GFP-expressing human SK-Hep1-Luc-GFP or A549-Luc-GFP cells, which were selectively processed into target GFP-siRNA and subsequently knocked down GFP mRNA and protein levels. In addition, LPP-carried BERA/GFP-siRNA was successfully delivered into xenograft tumors and offered more consistent knockdown of tumoral GFP mRNA level in an orthotopic hepatocellular carcinoma (HCC) SK-Hep1-Luc-GFP xenograft mouse model, while IVJ-PEI formulation showed larger variation. These findings demonstrated that lipidation of polyplexes improved serum stability of biologic RNAi molecules, which was efficiently delivered to orthotopic HCC tissues to knock down target gene expression.
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影响因子：
4.9
作者：
Peng ZH;Xie Y;Wang Y;Li J;Oupický D
通讯作者：
Oupický D
DOI：
10.1007/978-1-4939-3718-9_12
发表时间：
2016-01-01
期刊：
NON-VIRAL GENE DELIVERY VECTORS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Ewe, Alexander;Aigner, Achim
通讯作者：
Aigner, Achim
影响因子：
3.3
作者：
Kim, JK;Choi, SH;Kim, CK
通讯作者：
Kim, CK
DOI：
10.1615/critrevtherdrugcarriersyst.v26.i6.10
发表时间：
2009
影响因子：
2.7
作者：
Puri A;Loomis K;Smith B;Lee JH;Yavlovich A;Heldman E;Blumenthal R
通讯作者：
Blumenthal R
影响因子：
9.7
作者：
Ewe, Alexander;Schaper, Andreas;Aigner, Achim
通讯作者：
Aigner, Achim