MicroRNA Therapy for Lymph Node Metastatic Breast Cancer

MicroRNA 治疗淋巴结转移性乳腺癌

基本信息

批准号：
8367166
负责人：
Zdravka O Medarova
金额：
$ 39.61万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-14 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8367166
关键词：
Anatomy Animal Behavior Apoptosis Apoptotic Appearance Autopsy Biological Availability Bioluminescence Body Weight Breast Cancer Cell CA-15-3 Antigen Cell Line Cell Proliferation Cell Survival Clinical Code Communities Complex Coupled Cyclic Peptides Development Disease Down-Regulation Drug Kinetics Enzymes Evaluation Fluorescence Microscopy Goals Histology Histopathology Human Image Inflammatory Interferon-alpha Interleukin-6 Intravenous Liver Luciferases Lung Lymphatic Magnetic Resonance Imaging Magnetism Mammary Neoplasms Mediating Metastatic Neoplasm to Lymph Nodes Methods MicroRNAs Mus Neoplasm Metastasis Organ Outcome Peptides Physiological Prevention Primary Neoplasm Process RNA Research Site Specificity Staging Survival Analysis TNF gene Therapeutic Time Toxic effect Transfection Treatment Efficacy Tumor Cell Invasion Tumor Cell Line Tumor Volume Weight anticancer research base cell motility chemotherapy cytokine design dosage gene therapy in vitro testing in vivo knock-down locked nucleic acid lymph nodes malignant breast neoplasm metastatic process migration mouse model nanodrug nanoparticle nanotherapy neoplastic cell novel strategies optical imaging prevent tumor uptake

项目摘要

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. PUBLIC HEALTH RELEVANCE: A major focus of the breast cancer research and clinical community is on developing methods to effectively interfere with the disease after it has spread from the primary site. In the proposed research, we will utilize an imaging-capable nanodrug, which distributes to tumors and the lymphatics in vivo. The nanodrug will carry gene therapy, uniquely targeting the metastatic capabilities of tumor cells, through inhibiting specific small no-coding RNA molecules. We hope to be able to visualize the distribution of therapy in vivo by MRI and optical imaging and to successfully prevent and/or reverse the formation of metastases.

描述（由申请人提供）：该提案的目的是评估一种新的淋巴结转移性乳腺癌纳米疗法的方法。具有成像能力的纳米果，分布在肿瘤上，淋巴管的设计旨在携带靶向microRNA-10B（miR-10b）的锁定核酸（LNA）敲低探针，已知介导乳腺癌细胞和miR-21的肿瘤侵入和迁移，与肿瘤细胞增殖和存活有关。在我们的初步研究中，我们证明了该方法的可行性。我们已经表明，用miR-10b靶向的纳米果治疗浸润性乳腺肿瘤细胞会导致miRNA-10B下调88％，仅应用1.5 nmoles/ml的LNA，消除了肿瘤细胞的侵袭和迁移。在体内，我们获得了结果，表明在静脉内输送肿瘤小鼠后，纳米糖的肿瘤靶向版本会导致可通过体内成像检测到可观的肿瘤摄取，并且重要的是，重要的是，消除了从生物发光的可触发成像细胞转移的肿瘤中的肿瘤中的肿瘤中的肿瘤tumor tumormph lymph lymph lymph lymph lymph nodods。如果淋巴结转移出现后开始治疗，则纳米糖会阻止转移过程。这些早期的发现构成了当前应用的基础，我们建议在其中扩展这些研究，以调解长期预防，逮捕和回归转移。这将通过同时靶向促值miR10b以及促生殖和抗凋亡的miR-21来实现。还将探索与化学疗法的联合治疗。交付将与交付过程的并发非侵入性成像相结合。我们将评估转移负担的变化，并将我们的成像结论与离体研究进行比较。公共卫生相关性：乳腺癌研究和临床界的主要重点是开发方法以有效地干扰该疾病后，该方法已从主要部位传播后。在拟议的研究中，我们将利用具有成像能力的纳米果，该纳米果会在体内分配给肿瘤和淋巴管。纳米果会通过抑制特定的小无编码RNA分子来携带基因疗法，以独特的靶向肿瘤细胞的转移能力。我们希望能够通过MRI和光学成像在体内可视化治疗的分布，并成功预防和/或逆转转移的形成。