MicroRNA Therapy for Lymph Node Metastatic Breast Cancer

描述（由申请人提供）：本提案的目的是评估淋巴结转移性乳腺癌纳米治疗的新方法。分布到肿瘤和肿瘤细胞的具有成像能力的纳米药物将被设计为携带锁定核酸（LNA）敲低探针，靶向已知介导肿瘤侵袭和乳腺癌细胞迁移的microRNA-10 b（miR-10 b）和与肿瘤细胞增殖和存活有关的miR-21。在我们的初步研究中，我们已经证明了所提出的方法的可行性。我们已经证明，用miR-10 b靶向纳米药物治疗侵袭性乳腺肿瘤细胞，仅应用1.5 nmol/ml LNA就导致miRNA-10 b下调88%，并消除了肿瘤细胞的侵袭和迁移。在体内，我们已经获得的结果表明，在静脉内递送到荷瘤小鼠后，肿瘤靶向版本的纳米药物导致通过体内成像可检测到的强大的肿瘤摄取，并且重要的是，导致消除从原发性肿瘤到淋巴结的生物发光成像可检测的肿瘤细胞转移。如果在淋巴结转移出现后开始治疗，纳米药物会阻止转移过程。这些早期的发现形成了当前应用的基础，我们建议扩展这些研究，以介导转移的长期预防、抑制和消退。这将通过同时靶向促转移miR 10 b和促增殖和抗凋亡miR-21来实现。还将探索与化疗的联合治疗。输送将与输送过程的同时非侵入性成像相结合。我们将评估转移负荷的变化，并将我们的成像结论与体外研究进行比较。

DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate a new approach for nanotherapy of lymph node metastatic breast cancer. Imaging-capable nanodrugs, which distribute to tumors and the lymphatics will be designed to carry locked-nucleic acid (LNA) knockdown probes targeting microRNA-10b (miR-10b), known to mediate tumor invasion and migration of breast cancer cells and miR-21, implicated in tumor cell proliferation and survival. In our preliminary studies, we have demonstrated the feasibility of the proposed method. We have shown that treatment of invasive breast tumor cells with the miR-10b-targeted nanodrug results in an 88% downregulation of miRNA-10b with the application of just 1.5 nmoles/ml of LNA and abolishes the invasion and migration of the tumor cells. In vivo, we have obtained results suggesting that after intravenous delivery to tumor-bearing mice, a tumor-targeted version of the nanodrug leads to robust tumor uptake detectable by in vivo imaging and, importantly, results in elimination of bioluminescence imaging-detectable tumor cell metastasis from the primary tumor to lymph nodes. If treatment is initiated after the appearance of lymph node metastases, the nanodrug arrests the metastatic process. These earlier findings form the basis for the current application, in which we propose to extend these studies in order to mediate long-term prevention, arrest, and regression of metastases. This will be accomplished by concurrently targeting the pro-metastatic miR10b and the pro-proliferative and anti-apoptotic miR-21. Combination treatment with chemotherapy will also be explored. The delivery will be coupled with the concurrent non-invasive imaging of the delivery process. We will evaluate changes in metastatic burden and will compare our imaging conclusions to ex vivo studies.