Abstract
BackgroundIn our earlier work, we identified microRNA-10b (miR10b) as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR10b-targeted therapeutic consisting of an anti-miR10b antagomir conjugated to ultrasmall iron oxide nanoparticles (MN), termed MN-anti-miR10b. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b caused durable regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases.ResultsIn this study, we devised a method to efficiently radiolabel MN-anti-miR10b with Cu-64 (64Cu) and evaluated the pharmacokinetics and biodistribution of the radiolabeled product at two different doses: a therapeutic dose, referred to as macrodose, corresponding to 64Cu-MN-anti-miR10b co-injected with non-labeled MN-anti-miR10b, and a tracer-level dose of 64Cu-MN-anti-miR10b, referred to as microdose. In addition, we evaluated the uptake of 64Cu-MN-anti-miR10b by metastatic lesions using both in vivo and ex vivo positron emission tomography–magnetic resonance imaging (PET–MRI). A comparable distribution of the therapeutic was observed after administration of a microdose or macrodose. Uptake of the therapeutic by metastatic lymph nodes, lungs, and bone was also demonstrated by PET–MRI with a significantly higher PET signal than in the same organs devoid of metastatic lesions.ConclusionOur results demonstrate that PET–MRI following a microdose injection of the agent will accurately reflect the innate biodistribution of the therapeutic. The tools developed in the present study lay the groundwork for the clinical testing of MN-anti-miR10b and other similar therapeutics in patients with cancer.
Highlights
In our earlier work, we identified microRNA-10b as a master regulator of the viability of metastatic tumor cells
Biodistribution of 64Cu‐magnetic nanoparticles (MN)‐anti‐miR10b we evaluated the biodistribution of 64Cu-MN-anti-miR10b by positron emission tomography–magnetic resonance imaging (PET–MRI) and ex vivo gamma counting in a total of 13 mice bearing luciferase-expressing metastatic breast adenocarcinomas (4T1-luc2). 4T1-luc2 cells express luciferase and can be detected by non-invasive bioluminescence imaging (BLI)
Our findings point to the Discussion We previously identified microRNA-10b as a master regulator of the viability of metastatic tumor cells and designed the therapeutic miR-10b inhibitor, MN-anti-miR10b, for the treatment of metastatic cancer (Ma et al 2007; Yigit et al 2013; Yoo et al 2015)
Summary
We identified microRNA-10b (miR10b) as a master regulator of the viability of metastatic tumor cells. Conventional therapies targeted towards the primary tumor cell oftentimes do not affect the metastatic cell and, may promote metastasis This explains the poor outcomes in patients diagnosed with metastatic disease despite the good prognosis of patients with localized cancer of the same organ of origin (Steeg 2016). Metastamir addiction refers to a property of metastatic tumor cells, according to which they upregulate the expression of specific microRNAs as an adaptive advantage This advantage promotes the capacity of tumor cells to survive, invade surrounding tissue, and migrate in response to physiological stress caused by insufficient vascular supply, low pH, poor cell–cell contacts, and inadequate extracellular matrix (ECM) support
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