Abstract 2952: Image-guided miRNA therapy for metastatic breast cancer

Abstract

Abstract Metastases, and not the primary tumor from which they originate, are the main reason for mortality from breast carcinoma. New therapeutic approaches for metastatic breast cancer are urgently needed. The specific involvement of miRNAs in the development of metastases has been recently described and identified microRNA-10b (miR-10b) in initiation of breast cancer invasion and metastasis (Ma et al, Nature, 2007). Here, we describe a nanodrug for image-guided therapy of lymph node metastatic breast cancer. It consists of RGD-targeted ultrasmall magnetic nanoparticles that mediate their therapeutic effect by delivering locked nucleic acid to knockdown microRNA-10b (MN-anti-miR10b). Nanodrug bearing scrambled locked nucleic acid (MN-scr-miR) was also synthesized. The size and composition of the nanoparticles promote their extended persistence in the circulation (blood half-life >12 hrs) and transcytosis into the tumoral and lymph node interstitium. The nanodrug is detectable by magnetic resonance and optical imaging and is designed so that it targets both primary tumor cells and lymph node metastases. We show that treatment of invasive human breast tumor cells in vitro expressing luciferase (MDA-MB-231-luc) with the 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 showed that the nanodrug could be delivered to primary tumors as well as to lymph nodes and lymph node and lung metastasis. Therapeutic treatment of animal bearing orthotopic MDA-MB-231-luc tumors was performed with tail vein injections (10mg/kg of iron) delivered once a week for four weeks. Two therapeutic scenarios were used: 1) preventing tumor cell dissemination from the primary tumor beginning prior to the formation of detectable lymph node metastases and 2) beginning the treatment after the formation of lymph node metastasis but prior to metastasis to the lungs. In scenario (1) we observed that by the end of the treatment course, bioluminsecence signal from the tumors in the experimental animals treated with MN-anti-miR10b was at pre-metastatic levels, indicating a prevention of tumor cell metastasis from the primary tumor to lymph nodes. In contrast, there was visible dissemination of tumor cells to the lymph nodes of control animals treated with the MN-scr-miR. This therapeutic effect was highly reproducible. In scenario (2) there was a 20-fold increase in lymph node metastatic burden in controls treated with MN-scr-miR. By contrast, in the experimental animals treated with MN-anti-miR10b, there was a dramatic reduction of metastatic progression (p < 0.001, n = 6) and a prevention of tumor cell dissemination to the lungs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2952. doi:1538-7445.AM2012-2952