Wu Min, Sherwin Trevor, Brown William L, Stockley Peter G
Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA.
Nanomedicine. 2005 Mar;1(1):67-76. doi: 10.1016/j.nano.2004.11.011.
Acute myelogenous leukemia (AML) is the most common type of acute leukemia in adults. Because conventional treatments are associated with substantial side effects, novel therapeutic strategies are required. Antisense oligodeoxynucleotides (ODNs) have shown promise as the basis of emerging therapies for fighting cancer, although in vivo application is hampered by high sensitivity to cellular nuclease degradation. Encapsidation of ODNs in a drug-delivery capsule would reduce such degradation, thereby increasing the potency of therapy. MS2 bacteriophage capsid proteins may be used as novel virus-like particles (VLPs) to deliver ODNs. Here we report an analysis of the uptake mechanism of this VLP system and preliminary examples of its use to deliver a number of ODNs, including some targeting p120 messenger RNAs, a biomarker overexpressed in myelogenous leukemia cells.
The ODNs were synthesized as covalent extensions to the translational repressor/assembly initiation signal (TR), a 19 nt stem-loop, of the RNA phage MS2. The VLPs were constructed by soaking ODN-TR directly into recombinant RNA-free capsid shells. Targeting of the encapsidated ODNs into cells was achieved by a receptor-mediated endocytosis pathway identified by immunofluorescence microscopy or by transmission electron microscopy with gold-labeled antibodies.
After covalent decoration with transferrin on their surface, the VLPs containing ODNs demonstrated increased effectiveness in killing target leukemia cells expressing transferrin receptors, suggesting that this system is worthy of more extensive analysis.
The findings suggest that RNA phage VLPs may be useful as a new nanomaterial for targeted delivery of antisense ODNs, or other macromolecular drug candidates.
急性髓系白血病（AML）是成人中最常见的急性白血病类型。由于传统治疗伴有严重的副作用，因此需要新的治疗策略。反义寡脱氧核苷酸（ODN）已显示出有望成为对抗癌症的新兴疗法的基础，尽管其体内应用受到对细胞核酸酶降解高度敏感的阻碍。将ODN包裹在药物递送胶囊中可减少这种降解，从而提高治疗效果。MS2噬菌体衣壳蛋白可用作新型病毒样颗粒（VLP）来递送ODN。在此，我们报告了对该VLP系统摄取机制的分析以及其用于递送多种ODN的初步实例，包括一些靶向p120信使RNA的ODN，p120信使RNA是一种在髓系白血病细胞中过表达的生物标志物。
将ODN合成为RNA噬菌体MS2的翻译阻遏物/组装起始信号（TR，一个19个核苷酸的茎环）的共价延伸物。通过将ODN-TR直接浸泡到无重组RNA的衣壳壳中来构建VLP。通过免疫荧光显微镜或用金标记抗体的透射电子显微镜鉴定的受体介导的内吞途径，将包裹的ODN靶向细胞。
在其表面用转铁蛋白进行共价修饰后，含有ODN 的VLP在杀死表达转铁蛋白受体的靶白血病细胞方面显示出更高的有效性，这表明该系统值得进行更广泛的分析。
这些发现表明，RNA噬菌体VLP可能作为一种新型纳米材料用于反义ODN或其他大分子候选药物的靶向递送。
Zotero 插件