Engineering of multi-functional nucleolin-targeted nucleic acid delivery system.

针对基因表达的新疗法，如基于核酸(NA)的结构，显示出巨大的前景 为了更有效地治疗复杂的疾病。然而，实施这些措施的主要障碍是 临床使用的化合物是它们有效地输送到组织和细胞中，这是由于它们的高度 带电的性质和不能通过质膜。在这里，我们建议制定并测试一个 基于化学修饰纳米金的新型安娜给药系统 化合物(信号转导和转录激活因子3诱骗寡核苷酸(STAT3d))，已显示 头颈部鳞状细胞癌的治疗效果。一种新型载体系统 预计将克服此类技术目前面临的多重限制，因为它(1)允许 治疗性NA在静脉注射后全身给药，(2)允许NA优先靶向 癌细胞，(3)允许NA穿透细胞膜，(4)允许分子通过 荧光成像，以及(5)允许在以下情况下赋予辐射敏化的附加益处 肿瘤细胞摄取基于GNP的递送系统。新型NA治疗药物(NA-1)的研究进展 GNP-STAT3d)将通过以下具体目标实现：(1)优化和表征 核仁靶向寡核苷酸(ODN)/金纳米颗粒(GNP)递送系统(NA-GNP-STAT3d)， 以及(2)NA-GNP-STAT3d系统在减弱STAT3d介导的基因中的作用 STAT3d在HNSCC中的表达及其与GNP联合放射增敏作用的检测 HNSCCs在培养中的存活能力。

New therapeutics that target gene expression such as nucleic acid (NA) based constructs show great promise for treating complex diseases more effectively. However a major roadblock to the implementation of these compounds for clinical use is their efficient delivery into tissues and cells which is impeded due to their highly charged nature and inability to pass across the plasma membrane. Here we propose to formulate and test a novel delivery system based on chemically modified gold nanoparticles (GNPs) for delivery of an NA-based compound (signal transducer and activator of transcription 3 decoy oligonucleiotide (STAT3d)) that has shown effectiveness in the treatment of head and neck squamous cell carcinoma (HNSCC). The novel carrier system is expected to overcome multiple limitations currently faced by this type of technology in that it (1) allows the therapeutic NA to be administered systemically after IV injection, (2) allows the NA to preferentially target cancer cells, (3) allows the NA to permeate the cell membrane, (4) allows the molecule to be tracked via fluorescence imaging, and (5) allows for the additive benefit of radiation sensitization to be conferred after uptake of the GNP-based delivery system in tumor cells. Development of the novel NA-based therapeutic (NA- GNP-STAT3d) will be accomplished through the following specific aims: (1) optimization and characterization of a nucleolin-targeted oligonucleotide (ODN)/gold nanoparticle (GNP) delivery system (NA-GNP-STAT3d), and (2) mapping the efficacy of the NA-GNP-STAT3d system in attenuating STAT3d-mediated gene expression in HNSCC and testing the combined effect of STAT3d and GNP-mediated radiosensitization on the viability of HNSCCs in culture.