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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163461-02
Application #
8530182
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Tandon, Pushpa
Project Start
2012-08-14
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$371,967
Indirect Cost
$158,193
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ghosh, Subrata K; Yigit, Mehmet V; Uchida, Masashi et al. (2014) Sequence-dependent combination therapy with doxorubicin and a survivin-specific small interfering RNA nanodrug demonstrates efficacy in models of adenocarcinoma. Int J Cancer 134:1758-66
Yoo, Byunghee; Kavishwar, Amol; Ghosh, Subrata K et al. (2014) Detection of miRNA expression in intact cells using activatable sensor oligonucleotides. Chem Biol 21:199-204
Yoo, Byunghee; Ghosh, Subrata K; Kumar, Mohanraja et al. (2014) Design of nanodrugs for miRNA targeting in tumor cells. J Biomed Nanotechnol 10:1114-22
Yigit, M V; Ghosh, S K; Kumar, M et al. (2013) Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrest of lymph node metastasis. Oncogene 32:1530-8