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Radiolabeling and PET–MRI microdosing of the experimental cancer therapeutic, MN-anti-miR10b, demonstrates delivery to metastatic lesions in a murine model of metastatic breast cancer
Cancer Nanotechnology ( IF 4.5 ) Pub Date : 2021-07-08 , DOI: 10.1186/s12645-021-00089-5
Mariane Le Fur 1, 2 , Alana Ross 1 , Pamela Pantazopoulos 1 , Nicholas Rotile 1, 2 , Iris Zhou 1, 2 , Peter Caravan 1, 2 , Zdravka Medarova 1 , Byunghee Yoo 1
Affiliation  

In 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. In 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. Our 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.

中文翻译:

实验性癌症治疗剂 MN-anti-miR10b 的放射性标记和 PET-MRI 微剂量显示在转移性乳腺癌小鼠模型中可递送至转移性病灶

在我们早期的工作中,我们确定 microRNA-10b (miR10b) 是转移性肿瘤细胞活力的主要调节因子。这些知识使我们能够设计一种 miR10b 靶向疗法,由与超小型氧化铁纳米颗粒 (MN) 缀合的抗 miR10b antagomir 组成,称为 MN-抗 miR10b。在乳腺癌小鼠模型中,我们证明 MN-anti-miR10b 可使已形成的转移灶持久消退,且没有全身毒性的证据。作为将 MN-anti-miR10b 用于治疗转移性乳腺癌的第一步,我们需要确定在小鼠中如此有效的 MN-anti-miR10b 是否也会在人类转移中积累。在本研究中,我们设计了一种用 Cu-64 (64Cu) 有效放射性标记 MN-anti-miR10b 的方法,并评估了两种不同剂量的放射性标记产品的药代动力学和生物分布:治疗剂量,称为大剂量,对应于 64Cu -MN-抗-miR10b与未标记的MN-抗-miR10b共同注射,以及示踪剂水平剂量的64Cu-MN-抗-miR10b,称为微剂量。此外,我们使用体内和离体正电子发射断层扫描-磁共振成像(PET-MRI)评估了转移性病灶对 64Cu-MN-anti-miR10b 的摄取。在施用微剂量或大剂量后观察到治疗剂的可比分布。PET-MRI 还证明了转移性淋巴结、肺和骨对治疗剂的吸收,其 PET 信号明显高于没有转移性病变的相同器官。我们的结果表明,微剂量注射药物后的 PET-MRI 将准确反映治疗剂的固有生物分布。本研究开发的工具为 MN-anti-miR10b 和其他类似疗法在癌症患者中的临床测试奠定了基础。
更新日期:2021-07-09
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