Jenkins Samir V, Nima Zeid A, Vang Kieng B, Kannarpady Ganesh, Nedosekin Dmitry A, Zharov Vladimir P, Griffin Robert J, Biris Alexandru S, Dings Ruud P M
1Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR USA.
2Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, AR USA.
NPJ Precis Oncol. 2017 Sep 1;1(1):27. doi: 10.1038/s41698-017-0030-1. eCollection 2017.
An ongoing need for new cancer therapeutics exists, especially ones that specifically home and target triple-negative breast cancer. Because triple-negative breast cancer express low or are devoid of estrogen, progesterone, or Her2/Neu receptors, another target must be used for advanced drug delivery strategies. Here, we engineered a nanodrug delivery system consisting of silver-coated gold nanorods (AuNR/Ag) targeting epithelial cell adhesion/activating molecule (EpCAM) and loaded with doxorubicin. This nanodrug system, AuNR/Ag/Dox-EpCAM, was found to specifically target EpCAM-expressing tumors compared to low EpCAM-expressing tumors. Namely, the nanodrug had an effective dose (ED) of 3 μM in inhibiting 4T1 cell viability and an ED of 110 μM for MDA-MD-231 cells. Flow cytometry data indicated that 4T1 cells, on average, express two orders of magnitude more EpCAM than MDA-MD-231 cells, which correlates with our ED findings. Moreover, due to the silver coating, the AuNR/Ag can be detected simultaneously by surface-enhanced Raman spectroscopy and photoacoustic microscopy. Analysis by these imaging detection techniques as well as by inductively coupled plasma mass spectrometry showed that the targeted nanodrug system was taken up by EpCAM-expressing cells and tumors at significantly higher rates than untargeted nanoparticles ( < 0.05). Thus, this approach establishes a plasmonically active nanodrug theranostic for triple-negative breast cancer and, potentially, a delivery platform with improved multimodal imaging capability for other clinically relevant chemotherapeutics with dose-limiting toxicities, such as platinum-based or taxane-based therapies.
对新型癌症治疗方法的持续需求依然存在，尤其是针对三阴性乳腺癌的特异性靶向治疗方法。由于三阴性乳腺癌表达低水平或不表达雌激素、孕激素或Her2/Neu受体，因此必须采用其他靶点来实现先进的药物递送策略。在此，我们构建了一种纳米药物递送系统，该系统由靶向上皮细胞黏附/激活分子（EpCAM）的银包被金纳米棒（AuNR/Ag）组成，并负载了阿霉素。与低表达EpCAM的肿瘤相比，这种纳米药物系统AuNR/Ag/Dox-EpCAM被发现能够特异性靶向表达EpCAM的肿瘤。具体而言，该纳米药物在抑制4T1细胞活力方面的有效剂量（ED）为3 μM，对MDA-MD-231细胞的ED为110 μM。流式细胞术数据表明，4T1细胞平均表达的EpCAM比MDA-MD-231细胞多两个数量级，这与我们的ED结果相关。此外，由于银包被，AuNR/Ag可以通过表面增强拉曼光谱和光声显微镜同时进行检测。通过这些成像检测技术以及电感耦合等离子体质谱分析表明，与未靶向的纳米颗粒相比，靶向纳米药物系统被表达EpCAM的细胞和肿瘤摄取的速率显著更高（P < 0.05）。因此，这种方法建立了一种用于三阴性乳腺癌的具有等离子体活性的纳米药物诊疗方法，并有可能成为一种具有改进的多模态成像能力的递送平台，用于其他具有剂量限制性毒性的临床相关化疗药物，如铂类或紫杉烷类疗法。
