Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrest of lymph node metastasis

Abstract

Metastases, and not the primary tumor from which they originate, are the main reason for mortality from carcinoma. Although the molecular mechanisms behind metastasis are poorly understood, it is clear that epigenetic dysregulation at the level of microRNA expression is a key characteristic of the metastatic process that can be exploited for therapy. Here, we describe an miRNA-targeted therapeutic approach for the prevention and arrest of lymph node metastasis. Therapy relies on the inhibition of the pro-metastatic microRNA-10b. It is delivered to primary and lymph node metastatic tumor cells using an imaging-capable nanodrug that is designed to specifically home to these tissues. Treatment of invasive human breast tumor cells (MDA-MB-231) with the nanodrug in vitro downregulates miR-10b and abolishes the invasion and migration of the tumor cells. After intravenous delivery to mice bearing orthotopic MDA-MB-231-luc-D3H2LN tumors, the nanodrug accumulates in the primary tumor and lymph nodes. When treatment is initiated before metastasis to lymph nodes, metastasis is prevented. Treatment after the formation of lymph node metastases arrests the metastatic process without a concomitant effect on primary tumor growth raising the possibility of a context-dependent variation in miR-10b breast oncogenesis.

Development of nanotheranostics against metastatic breast cancer — A focus on the biology & mechanistic approaches

“…MN-antimiR10b nanoparticles were also capable of inhibiting migration and proliferation of tumor cells in lymph node metastatic tumors. In vivo MRI revealed that the nanoparticles are effectively targeted to the tumor site (Yigit et al, 2013).…”

Design of Nanodrugs for miRNA Targeting in Tumor Cells

“…The model used here is based on dextran-coated iron oxide nanoparticles(MN) as delivery vehicles and LNA-modified antisense oligonucleotides as direct miRNA inhibitors. 11 …”

“…10 Recently, using a nanodrug specific for the pro-metastatic miR-10b 7 , we demonstrated effective prevention and arrest of lymph node metastasis in a murine model of breast cancer. 11 …”

“…A variety of heterobifunctional cross-linkers are commercially available and can be classified as permanent (non-labile) or temporary (labile) with various lengths, which can be mainly adjusted by the introduction of polyethylene glycol. 11–19 We compared three conjugation designs:…”

A bone-resorption surface-targeting nanoparticle to deliver anti-miR214 for osteoporosis therapy

“…22 Several delivery strategies have been studied to deliver miRNAs, such as silica nanoparticles, 23 ultrasmall magnetic nanoparticles, 24 liposomes, 25 and exosomes. 26 Among various delivery systems, polyurethane (PU) is a polymer composed of organic units joined by carbamate (urethane) links.…”