Zochowska Monika, Piguet Anne-Christine, Jemielity Jacek, Kowalska Joanna, Szolajska Ewa, Dufour Jean-François, Chroboczek Jadwiga
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
Nanomedicine. 2015 Jan;11(1):67-76. doi: 10.1016/j.nano.2014.07.009. Epub 2014 Aug 5.
Adenovirus dodecahedron (Dd), a nanoparticulate proteinaceous biodegradable virus-like particle (VLP), was used as a vector for delivery of an oncogene inhibitor to hepatocellular carcinoma (HCC) rat orthotopic model. Initiation factor eIF4E is an oncogene with elevated expression in human cancers. Cell-impermeant eIF4E inhibitor, cap structure analog (cap) and anti-cancer antibiotic doxorubicin (Dox) were delivered as Dd conjugates. Dd-cap and Dd-dox inhibited cancer cell culture proliferation up to 50 and 84%, respectively, while with free Dox similar results could be obtained only at a 5 times higher concentration. In animal HCC model the combination treatment of Dd-cap/Dd-dox caused 40% inhibition of tumor growth. Importantly, the level of two pro-oncogenes, eIF4E and c-myc, was significantly diminished in tumor sections of treated rats. Attachment to Dd, a virus-like particle, permitted the first demonstration of cap analog intracellular delivery and resulted in improved doxorubicin delivery leading to statistically significant inhibition of HCC tumor growth.
腺病毒十二面体（Dd）是一种纳米颗粒状的可生物降解蛋白质类病毒样颗粒（VLP），被用作向肝细胞癌（HCC）大鼠原位模型递送癌基因抑制剂的载体。起始因子eIF4E是一种在人类癌症中表达上调的癌基因。细胞不透性的eIF4E抑制剂、帽结构类似物（cap）和抗癌抗生素阿霉素（Dox）以Dd偶联物的形式递送。Dd-cap和Dd-dox分别抑制癌细胞培养增殖达50%和84%，而对于游离Dox，仅在浓度高出5倍时才能获得类似结果。在动物HCC模型中，Dd-cap/Dd-dox联合治疗导致肿瘤生长抑制40%。重要的是，在治疗大鼠的肿瘤切片中，两种原癌基因eIF4E和c-myc的水平显著降低。与病毒样颗粒Dd的结合首次证明了帽类似物的细胞内递送，并改善了阿霉素的递送，从而导致对HCC肿瘤生长的统计学显著抑制。
