Image-guided breast tumor therapy using a small interfering RNA nanodrug.

Iron oxide nanoparticles offer a feasible tool for combined imaging and delivery of siRNA to tumors, stimulating active interest in exploring different imaging and delivery platforms suitable for detection by a variety of modalities. In this study we describe the synthesis and testing of a tumor-targeted nanodrug (MN-EPPT-siBIRC5) that is designed to specifically shuttle siRNA to human breast tumors. The nanodrug binds the tumor-specific antigen uMUC-1, which is found on over 90% of human breast adenocarcinomas. MN-EPPT-siBIRC5 consists of superparamagnetic iron oxide nanoparticles (for magnetic resonance imaging), the dye Cy5.5 (for near-infrared optical imaging), peptides (EPPT) that specifically target uMUC-1, and a synthetic siRNA that targets the tumor-specific anti-apoptotic gene BIRC5. Nanodrug uptake by human breast adenocarcinoma cells resulted in a significant downregulation of BIRC5. Following intravenous delivery into subcutaneous mouse models of breast cancer, the nanodrug demonstrated a preferential tumor uptake, which could be visualized by MRI and near-infrared optical imaging. Furthermore, MRI could be employed to quantitatively monitor nanodrug bioavailability in the tumor tissue throughout the course of treatment. Intravenous injection of the agent once a week over two weeks resulted in the induction of considerable levels of necrosis and apoptosis in the tumors translating into a significant decrease in tumor growth rate. Our strategy permits the simultaneous tumorspecific delivery of siRNA to tumors and the imaging of the delivery process. More generally, it illustrates the potential to apply this approach to many human cancer studies, including for basic tumor biology and therapy.

氧化铁纳米颗粒为肿瘤的联合成像及小干扰RNA（siRNA）递送提供了一种可行的工具，激发了人们积极探索适用于多种模式检测的不同成像和递送平台的兴趣。在本研究中，我们描述了一种肿瘤靶向纳米药物（MN - EPPT - siBIRC5）的合成及测试，该药物旨在将siRNA特异性地转运至人类乳腺肿瘤。这种纳米药物可与肿瘤特异性抗原uMUC - 1结合，uMUC - 1存在于90%以上的人类乳腺腺癌中。MN - EPPT - siBIRC5由超顺磁性氧化铁纳米颗粒（用于磁共振成像）、染料Cy5.5（用于近红外光学成像）、特异性靶向uMUC - 1的肽（EPPT）以及一种靶向肿瘤特异性抗凋亡基因BIRC5的合成siRNA组成。人类乳腺腺癌细胞对纳米药物的摄取导致BIRC5显著下调。在将纳米药物静脉注射到乳腺癌皮下小鼠模型后，纳米药物表现出优先的肿瘤摄取，这可通过磁共振成像和近红外光学成像观察到。此外，磁共振成像可用于在整个治疗过程中定量监测纳米药物在肿瘤组织中的生物利用度。在两周内每周静脉注射一次该药物，导致肿瘤中出现相当程度的坏死和凋亡，从而使肿瘤生长速率显著降低。我们的策略允许同时将siRNA特异性地递送至肿瘤以及对递送过程进行成像。更广泛地说，它展示了将这种方法应用于许多人类癌症研究的潜力，包括用于基础肿瘤生物学和治疗。