Yang Zhaogang, Yu Bo, Zhu Jing, Huang Xiaomeng, Xie Jing, Xu Songlin, Yang Xiaojuan, Wang Xinmei, Yung Bryant C, Lee L James, Lee Robert J, Teng Lesheng
College of Pharmacy, The Ohio State University, 500 W 12th Ave, 43210, Columbus, Ohio, USA.
Nanoscale. 2014 Aug 21;6(16):9742-51. doi: 10.1039/c4nr01510j. Epub 2014 Jul 8.
The siRNA LOR-1284 targets the R2 subunit of ribonucleotide reductase (RRM2) and has shown promise in cancer therapy. In this study, transferrin (Tf) conjugated lipid nanoparticles (Tf-NP-LOR-1284) were synthesized by microfluidic hydrodynamic focusing (MHF) and evaluated for the targeted delivery of LOR-1284 siRNA into acute myeloid leukemia (AML) cells. The in vitro study showed that Tf-NP-LOR-1284 can protect LOR-1284 from serum nuclease degradation. Selective uptake of Tf-NP-LOR-1284 was observed in MV4-11 cells. In addition, qRT-PCR and Western blot results revealed that Tf-NP-LOR-1284 was more effective than the free LOR-1284 in reducing the R2 mRNA and protein levels. The Tf-NP-LOR-1284 showed prolonged circulation time and increased AUC after i.v. administration relative to the free LOR-1284. Furthermore, Tf-NP-LOR-1284 facilitated increased accumulation at the tumor site along with the decreased R2 mRNA and protein expression in a murine xenograft model. These results suggest that Tf-conjugated NPs prepared by MHF provide a suitable platform for efficient and specific therapeutic delivery of LOR-1284 into AML cells.
小干扰RNA（siRNA）LOR-1284靶向核糖核苷酸还原酶（RRM2）的R2亚基，在癌症治疗中显示出前景。在本研究中，通过微流控流体动力学聚焦（MHF）合成了转铁蛋白（Tf）偶联脂质纳米颗粒（Tf-NP-LOR-1284），并评估了其将LOR-1284 siRNA靶向递送至急性髓系白血病（AML）细胞的能力。体外研究表明，Tf-NP-LOR-1284可保护LOR-1284免受血清核酸酶降解。在MV4-11细胞中观察到Tf-NP-LOR-1284的选择性摄取。此外，定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹结果显示，Tf-NP-LOR-1284在降低R2 mRNA和蛋白质水平方面比游离LOR-1284更有效。相对于游离LOR-1284，静脉注射后Tf-NP-LOR-1284显示出延长的循环时间和增加的曲线下面积（AUC）。此外，在小鼠异种移植模型中，Tf-NP-LOR-1284促进了肿瘤部位的蓄积增加，同时R2 mRNA和蛋白质表达降低。这些结果表明，通过MHF制备的Tf偶联纳米颗粒为将LOR-1284高效、特异性地治疗性递送至AML细胞提供了一个合适的平台。
