Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles.
Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles.
复制标题
DOI：
10.1021/nn201397z
复制
发表时间：
2011-07-26
期刊：
影响因子：
17.1
通讯作者：
Peabody DS
中科院分区：
文献类型：
--
作者：
Ashley CE;Carnes EC;Phillips GK;Durfee PN;Buley MD;Lino CA;Padilla DP;Phillips B;Carter MB;Willman CL;Brinker CJ;Caldeira Jdo C;Chackerian B;Wharton W;Peabody DS
噬菌体MS2的病毒样颗粒（vlp）具有许多特征，使它们非常适合用于靶向递送治疗和显像剂。利用体内或体外合成技术可以快速大量生产MS2 VLPs。它们的衣壳可以通过基因插入或化学偶联在精确的位置进行修饰，促进靶向配体的多价展示。MS2 VLPs也在核酸存在下自组装，特异性封装siRNA和rna修饰的货物。在这里，我们报告了使用MS2 VLPs选择性地向人肝细胞癌（HCC）递送纳米颗粒、化疗药物、siRNA鸡尾酒和蛋白质毒素。与肝细胞、内皮细胞、单核细胞或淋巴细胞相比，经肽（SP94）修饰的MS2 VLPs对肝细胞的亲和力高104倍，并且可以将高浓度的包裹货物运送到肝细胞的细胞质中。负载阿霉素、顺铂和5-氟尿嘧啶的sp94靶向VLPs在药物浓度< 1 nM时选择性杀死HCC细胞系Hep3B，而包裹siRNA鸡尾酒的sp94靶向VLPs在siRNA浓度< 150 pM时沉默cyclin家族成员的表达，诱导Hep3B的生长停滞和凋亡。令人印象深刻的是，当MS2 VLPs加载蓖麻毒素a链（RTA）并修饰为共同显示SP94靶向肽和促进内体逃逸的富含组氨酸的fusogenic peptide （H5WYG）时，在RTA浓度为100 fM的情况下，杀死了几乎100%的Hep3B细胞（1 × 106个细胞/mL群体），而不影响对照细胞的活力。我们的研究结果表明，MS2 VLPs由于其对多价肽展示的耐受性和特异性封装各种不同货物的能力，在体外诱导癌症的选择性细胞毒性，并且代表了基于vlp的传递系统特性的显着改善。
Virus-like particles (VLPs) of bacteriophage MS2 possess numerous features that make them well-suited for use in targeted delivery of therapeutic and imaging agents. MS2 VLPs can be rapidly produced in large quantities using in vivo or in vitro synthesis techniques. Their capsids can be modified in precise locations via genetic insertion or chemical conjugation, facilitating the multivalent display of targeting ligands. MS2 VLPs also self-assemble in the presence of nucleic acids to specifically encapsidate siRNA and RNA-modified cargos. Here we report the use of MS2 VLPs to selectively deliver nanoparticles, chemotherapeutic drugs, siRNA cocktails, and protein toxins to human hepatocellular carcinoma (HCC). MS2 VLPs modified with a peptide (SP94) that binds HCC exhibit a 104-fold higher avidity for HCC than for hepatocytes, endothelial cells, monocytes, or lymphocytes and can deliver high concentrations of encapsidated cargo to the cytosol of HCC cells. SP94-targeted VLPs loaded with doxorubicin, cisplatin, and 5-fluorouracil selectively kill the HCC cell line, Hep3B, at drug concentrations < 1 nM, while SP94-targeted VLPs that encapsidate a siRNA cocktail, which silences expression of cyclin family members, induce growth arrest and apoptosis of Hep3B at siRNA concentrations < 150 pM. Impressively, MS2 VLPs, when loaded with ricin toxin A-chain (RTA) and modified to co-display the SP94 targeting peptide and a histidine-rich fusogenic peptide (H5WYG) that promotes endosomal escape, kill nearly 100% of Hep3B cells (1 × 106 cells/mL population) at an RTA concentration of 100 fM without affecting the viability of control cells. Our results demonstrate that MS2 VLPs, due to their tolerance of multivalent peptide display and their ability to specifically encapsidate a variety of disparate cargos, induce selective cytotoxicity of cancer in vitro and represent a significant improvement in the characteristics of VLP-based delivery systems.
登录
查看更多内容
影响因子：
1.9
作者：
Gurzov, Esteban N.;Izquierdo, Marta
通讯作者：
Izquierdo, Marta
影响因子：
15
作者：
Hooker, JM;Kovacs, EW;Francis, MB
通讯作者：
Francis, MB
影响因子：
10.8
作者：
Hooker, Jacob M.;Datta, Ankona;Francis, Matthew B.
通讯作者：
Francis, Matthew B.
影响因子：
2
作者：
Anilanmert, B;Yalçin, G;Dölen, E
通讯作者：
Dölen, E
影响因子：
38.3
作者：
Jiang, Wen;Kim, Betty Y. S.;Chan, Warren C. W.
通讯作者：
Chan, Warren C. W.