Targeted delivery of antisense oligonucleotides by chemically self-assembled nanostructures.
Targeted delivery of antisense oligonucleotides by chemically self-assembled nanostructures.
复制标题
通过化学自组装的纳米结构靶向赋予反义寡核苷酸。
DOI：
10.1021/mp400164f
复制
发表时间：
2013-09-03
影响因子：
4.9
通讯作者：
Wagner CR
中科院分区：
文献类型：
--
作者：
Gangar A;Fegan A;Kumarapperuma SC;Huynh P;Benyumov A;Wagner CR
合成核酸在治疗各种疾病方面显示出巨大的潜力。然而，选择性递送至靶组织已被证明具有挑战性。已经探索了核酸与靶向肽、蛋白质和抗体的偶联作为其选择性组织递送的方法。然而，制备也可以经历细胞内释放以及递送多于一个拷贝的核酸的共价偶联的肽和蛋白质已被证明具有挑战性。最近，我们开发了一种新的方法，用于使用化学自组装纳米结构（CSAN）将核酸快速非共价缀合至靶向单链抗体（scFv）。CSAN已经通过两个二氢叶酸还原酶分子（DHFR 2）和靶向scFv在双甲氨蝶呤（bis-MTX）存在下的自组装来制备。根据二氢叶酸还原酶分子之间的连接体的长度和组成，纳米环的化合价可以从一个亚基调整到八个亚基。为了探索它们用于核酸治疗性递送的潜力以及通过掺入较小的环状靶向肽来扩展CSAN的能力的能力，我们制备了通过柔性肽接头与环状-RGD融合的DHFR 2蛋白，其靶向αvβ3整联蛋白，和与反义寡核苷酸连接的双-MTX化学二聚化剂（bis-MTX-ASO），其已显示沉默真核翻译起始因子4 E（eIF 4 E）的表达。然后用bis-MTX-阿索制备单体和多聚体cRGD-CSAN，并显示在过表达αvβ3的乳腺癌细胞系MDA-MB-231中发生内吞作用。显示双-MTX-阿索经历内体逃逸，导致eIF 4 E的敲低，其效率至少与通过寡转染胺递送的阿索相同。缀合的模块性、灵活性和常用方法可证明是用于将ASO以及其他核酸靶向递送至细胞的有用的通用方法。
Synthetic nucleic acids have shown great potential in the treatment of various diseases. Nevertheless, the selective delivery to a target tissue has proved challenging. The coupling of nucleic acids to targeting peptides, proteins and antibodies has been explored as an approach for their selective tissue delivery. Nevertheless, the preparation of covalently coupled peptides and proteins that can also undergo intracellular release as well as deliver more than one copy of the nucleic acid has proved challenging. Recently, we have developed a novel method for the rapid non-covalent conjugation of nucleic acids to targeting single chain antibodies (scFv) using chemically self-assembled nanostructures (CSANs). CSANs have been prepared by the self-assembly of two dihydrofolate reductase molecules (DHFR2) and a targeting scFv in the presence of bis-methotrexate (bis-MTX). The valency of the nanorings can be tuned from one to eight subunits, depending on the length and composition of the linker between the dihydrofolate reductase molecules. To explore their potential for the therapeutic delivery of nucleic acids as well as the ability to expand the capabilities of CSANs by incorporating smaller cyclic targeting peptides, we prepared DHFR2 proteins fused through a flexible peptide linker to cyclic-RGD, which targets αvβ3 integrins, and a bis-MTX chemical dimerizer linked to an antisense oligonucleotide (bis- MTX-ASO) that has been shown to silence expression of eukaryotic translation initiation factor 4E (eIF4E). Monomeric and multimeric cRGD-CSANs were then prepared with bis-MTX-ASO and shown to undergo endocytosis in the breast cancer cell line, MDA-MB-231, which over- express αvβ3. The bis-MTX-ASO was shown to undergo endosomal escape resulting in the knock down of eIF4E with at least the same efficiency as ASO delivered by oligofectamine. The modularity, flexibility and common method of conjugation may prove to be a useful general approach for the targeted delivery of ASOs, as well as other nucleic acids to cells.
登录
查看更多内容
影响因子：
4.7
作者：
Alam, Md Rowshon;Ming, Xin;Fisher, Michael;Lackey, Jeremy G.;Rajeev, Kallanthottathil G.;Manoharan, Muthiah;Juliano, Rudy L.
通讯作者：
Juliano, Rudy L.
影响因子：
11.2
作者：
Hayman TJ;Williams ES;Jamal M;Shankavaram UT;Camphausen K;Tofilon PJ
通讯作者：
Tofilon PJ
使用 RGD 结合的氧化铁纳米粒子无创监测原位胶质母细胞瘤治疗反应。
影响因子：
14
作者：
Zhang, Fan;Huang, Xinglu;Zhu, Lei;Guo, Ning;Niu, Gang;Swierczewska, Magdalena;Lee, Seulki;Xu, Hong;Wang, Andrew Y.;Mohamedali, Khalid A.;Rosenblum, Michael G.;Lu, Guangming;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan
影响因子：
15
作者：
Li Q;So CR;Fegan A;Cody V;Sarikaya M;Vallera DA;Wagner CR
通讯作者：
Wagner CR
影响因子：
13.3
作者：
Keum, Jung-Won;Ahn, Jin-Ho;Bermudez, Harry
通讯作者：
Bermudez, Harry