anti-miR-10b Nanodrug for Treatment of Breast Cancer Metastasis: Study in Companion Animals

用于治疗乳腺癌转移的抗 miR-10b 纳米药物：伴侣动物研究

• 批准号: 10659027
• 负责人: ANNA MOORE
• 金额: $ 55.69万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-13 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659027
• 关键词: 4T1; Anatomy; Animal Model; Animals; Apoptosis; Area; Biodistribution; Biomedical Research; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; Cell Proliferation; Cell Survival; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Companions; Cytostatics; Dextrans; Dose; Drug Delivery Systems; Drug Kinetics; Family Felidae; Goals; Growth; Human; Human Development; Immunocompetent; Location; Lung; MDA MB 231; Magnetic Resonance Imaging; Magnetic nanoparticles; Magnetism; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Lung; Metastatic breast cancer; MicroRNAs; Modeling; Monitor; Mus; Neoplasm Metastasis; Organ; Pharmacotherapy; Phenotype; Physiological; Pilot Projects; Property; Site; Technology; Testing; Therapeutic; Therapeutic Studies; Time; Toxic effect; arm; bone; cancer therapy; cell killing; chemotherapy; clinical implementation; clinical translation; companion animal; delivery vehicle; design; first-in-human; human disease; human model; imaging capabilities; in vitro testing; in vivo; in vivo imaging; intravenous injection; lymph nodes; mortality; mouse model; nanodrug; nanomedicine; nanoparticle; nanotoxicity; neoplastic cell; novel; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; systemic toxicity; theranostics; triple-negative invasive breast carcinoma; uptake

ABSTRACT Nanoparticle-based technologies including theranostic nanomedicine are fast developing areas of biomedical research offering unprecedented potential for cancer treatment. This application is designed to bring this potential to translational level and investigate the application of our novel image-capable nanodrug for treatment of metastatic breast cancer in a large animal model. Breast cancer metastasis is the main cause of mortality among breast cancer patients, and for that reason the specific aims of this application respond to an unmet clinical need. This proposed strategy is based on our discovery that the survival of metastatic cells crucially depends on the high expression of microRNA-10b (miR-10b) and that miR-10b is responsible for metastatic cell viability. With this discovery it became possible to kill these cells at metastatic sites by inhibiting miR-10b. This is achieved using a nanodrug composed of anti-miR-10b antagomirs conjugated to dextran-coated magnetic nanoparticles (termed MN-anti-miR10b). These nanoparticles serve as delivery vehicles for the antagomirs. Also, the magnetic properties of these nanoparticles allow for monitoring of their delivery in vivo using magnetic resonance imaging (MRI), which is an added value for clinical implementation of this therapeutic approach. In pre-clinical studies in mice, we showed delivery of MN-anti-miR-10b to established metastases in the lymph nodes, lungs, bone and brain. Pilot studies in companion cats showed the delivery of the nanodrug to the metastatic lesions after intravenous injection. Therapeutic studies in the murine model of human MDA-MB-231 TNBC showed that delivery of MN-anti-miR10b to lymph nodes with established metastases resulted in arrest of metastatic growth by halting tumor cell proliferation and triggering apoptosis. When combined with a low-dose chemotherapy, MN-anti-miR10b caused complete elimination of lymph node metastases with no evidence of systemic toxicity after just four weekly treatments. Next, we showed the utility of the nanodrug in combination with low-dose chemotherapy for treatment of established lung metastases corresponding to Stage IV of human disease in immunocompetent murine model (4T1). We found that six weekly treatments were sufficient to cause complete regression of pre-existing lung metastases with no further dissemination to other organs in the remaining animals. With an outlook to clinical translation of our studies, in this application we propose to test our nanodrug strategy in large animals with spontaneous metastatic breast cancer (companion cats). Studies proposed here will serve as a necessary step towards first-in-human trials, because they will prove successful delivery of the nanodrug in large animals, which are anatomically and physiologically distinct from the murine models tested to date. Furthermore, these studies will provide us with additional information on PK/PD parameters in a large animal model. Finally, therapeutic studies in spontaneous models will mimic those in humans where development of metastases is largely unpredicted in terms of time and location. We expect that these studies will serve as the final step in the pre-clinical stage of this project, which will next move to the pre-IND stage.

抽象的 包括治疗诊断纳米医学在内的基于纳米颗粒的技术是生物医学快速发展的领域 研究为癌症治疗提供了前所未有的潜力。这个应用程序旨在带来这个 转化水平的潜力并研究我们的新型具有成像功能的纳米药物在治疗中的应用 大型动物模型中转移性乳腺癌的研究。乳腺癌转移是导致死亡的主要原因 在乳腺癌患者中，因此该应用程序的具体目标响应了未满足的问题 临床需要。这一提出的策略是基于我们的发现，即转移细胞的存活至关重要 取决于 microRNA-10b (miR-10b) 的高表达，并且 miR-10b 负责转移细胞 生存能力。有了这一发现，就有可能通过抑制 miR-10b 来杀死转移部位的这些细胞。这 使用由抗 miR-10b antagomir 与葡聚糖包被的磁性物质缀合组成的纳米药物来实现 纳米颗粒（称为 MN-抗-miR10b）。这些纳米颗粒充当 antagomir 的递送载体。还， 这些纳米粒子的磁性允许使用磁性来监测它们在体内的递送 磁共振成像（MRI），这对于临床实施这种治疗方法具有附加价值。在 在小鼠的临床前研究中，我们展示了 MN-抗 miR-10b 递送至淋巴中已建立的转移灶 淋巴结、肺、骨和脑。对伴侣猫的初步研究表明，纳米药物可以传递到 静脉注射后出现转移灶。人 MDA-MB-231 小鼠模型的治疗研究 TNBC 表明，将 MN-anti-miR10b 递送至已发生转移的淋巴结可导致肿瘤细胞停滞 通过阻止肿瘤细胞增殖并引发细胞凋亡来促进转移生长。当与低剂量联合使用时 化疗后，MN-抗 miR10b 导致淋巴结转移完全消除，且无证据表明 仅四周治疗后的全身毒性。接下来，我们展示了纳米药物组合的效用 用低剂量化疗治疗已形成的相当于人类 IV 期的肺转移 免疫功能正常的小鼠模型（4T1）中的疾病。我们发现每周六次治疗足以引起 先前存在的肺转移完全消退，不会进一步扩散到其他器官 剩下的动物。 展望我们的研究的临床转化，在本次应用中，我们建议测试我们的纳米药物策略 患有自发性转移性乳腺癌的大型动物（伴侣猫）。这里提出的研究将服务于 作为迈向首次人体试验的必要步骤，因为他们将证明纳米药物在 大型动物，在解剖学和生理学上与迄今为止测试的小鼠模型不同。 此外，这些研究将为我们提供有关大型动物 PK/PD 参数的更多信息 模型。最后，自发模型中的治疗研究将模仿人类的治疗研究，其中 转移在时间和地点方面很大程度上是不可预测的。我们期望这些研究将作为 该项目临床前阶段的最后一步，接下来将进入 IND 前阶段。

项目成果

Omniparticle Contrast Agent for Multimodal Imaging: Synthesis and Characterization in an Animal Model.

用于多模态成像的全粒子造影剂：动物模型中的合成和表征。

• 发表时间: 2023-04
• 影响因子: 3.1
• 作者: Robertson, Neil;Sempere, Lorenzo;Kenyon, Elizabeth;Mallet, Christiane;Smith, Kylie;Hix, Jeremy;Halim, Alan;Fan, Jinda;Moore, Anna
• 通讯作者: Moore, Anna

Case report: MicroRNA-10b as a therapeutic target in feline metastatic mammary carcinoma and its implications for human clinical trials.

病例报告：MicroRNA-10b 作为猫转移性乳腺癌的治疗靶点及其对人类临床试验的影响。

• 发表时间: 2022
• 作者: Savan, N Anna;Saavedra, Paulo Vilar;Halim, Alan;Yuzbasiyan;Wang, Ping;Yoo, Byunghee;Kiupel, Matti;Sempere, Lorenzo;Medarova, Zdravka;Moore, Anna
• 通讯作者: Moore, Anna