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

靶向基因表达的新疗法如基于核酸（NA）的构建体显示出巨大的前景 来更有效地治疗复杂的疾病。然而，执行这些建议的一个主要障碍是， 用于临床用途的化合物的一个重要特征是它们有效地递送到组织和细胞中，这由于它们的高度依赖性而受到阻碍。 带电的性质和不能穿过质膜。在这里，我们建议制定和测试一个 基于化学改性的金纳米颗粒（GNP）的新型递送系统，用于递送基于NA的 一种化合物（信号转导子和转录激活子3诱饵寡核苷酸（STAT 3d））， 头颈部鳞状细胞癌（HNSCC）的治疗效果。该新型载体系统 预计将克服这种类型的技术目前面临的多种限制，因为它（1）允许 IV注射后全身给予治疗性NA，（2）允许NA优先靶向 癌细胞，（3）允许NA渗透细胞膜，（4）允许分子通过 荧光成像，以及（5）允许在荧光成像之后赋予辐射敏化的附加益处。 肿瘤细胞中基于GNP的递送系统的摄取。基于NA的新型治疗剂（NA- GNP-STAT 3d）将通过以下具体目标来实现：（1）优化和表征 核仁素靶向寡核苷酸（ODN）/金纳米颗粒（GNP）递送系统（NA-GNP-STAT 3d）， 和（2）绘制NA-GNP-STAT 3d系统在减弱STAT 3d介导的基因中的功效 STAT 3d和GNP介导的放射增敏对HNSCC中STAT 3d表达的联合作用 HNSCC在培养物中的活力。

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.