Purpose

To investigate the effectiveness of targeted ECO/miR-200c in modulating tumor microenvironment and treating triple negative breast cancer (TNBC) using non-invasive magnetic resonance molecular imaging (MRMI) of extradomain B fibronectin (EDB-FN) with a targeted MRI contrast agent.

Methods

MDA-MB-231 and Hs578T TNBC cells were transfected with RGD-PEG-ECO/miR-200c. Invasive and migratory potential was evaluated using transwell, scratch wound, and spheroid formation assays. Athymic nude mice bearing orthotopic MDA-MB-231 and Hs578T xenografts were treated with weekly i.v. injection of RGD-PEG-ECO/miR-200c nanoparticles at 1.0 mg/kg/week RNA for 6 weeks. MRMI of EDB-FN was performed using a targeted contrast agent MT218 [ZD2-N₃-Gd(DO3A)] on a 3 T MRS 3000 scanner. T₁-weighted images were acquired following intravenous injection of MT218 at dose of 0.1 mmol/kg using a fast spin echo axial sequence with respiratory gating.

Results

Systemic administration of RGD-PEG-ECO/miR-200c nanoparticles in mice bearing orthotopic TNBC xenografts significantly suppressed tumor progression without toxic side-effects. MRMI with MT218 revealed that the treatment significantly suppressed tumor proliferation as compared to the control. MRMI also showed that the miR-200c treatment altered tumor microenvironment by reducing EDB-FN expression, as evidenced by decreased contrast enhancement in both MDA-MB-231 and Hs578T tumors. The reduction of EDB-FN was confirmed by immunohistochemistry.

Conclusions

Targeted delivery of miR-200c with RGD-PEG-ECO/miR-200c nanoparticles effectively modulates tumor microenvironment and suppresses TNBC proliferation in animal models. MRMI of tumor EDB-FN expression is effective to non-invasively monitor tumor response and therapeutic efficacy of RGD-PEG-ECO/miR-200c nanoparticles in TNBC.

中文翻译：

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靶向 ECO/miR-200c 纳米粒子在调节肿瘤微环境和治疗三阴性乳腺癌方面的疗效，通过 MR 分子成像进行无创监测

目的

研究靶向 ECO/miR-200c 在调节肿瘤微环境和治疗三阴性乳腺癌 (TNBC) 中的有效性，使用域外 B 纤连蛋白 (EDB-FN) 的非侵入性磁共振分子成像 (MRMI) 和靶向 MRI 造影剂.

方法

用 RGD-PEG-ECO/miR-200c 转染 MDA-MB-231 和 Hs578T TNBC 细胞。使用 transwell、划伤和球体形成测定法评估了侵入和迁移潜力。接受原位 MDA-MB-231 和 Hs578T 异种移植物的无胸腺裸鼠每周静脉注射 1.0 mg/kg/周 RNA 的 RGD-PEG-ECO/miR-200c 纳米颗粒，持续 6 周。EDB-FN 的 MRMI 使用靶向造影剂 MT218 [ZD2-N ₃ -Gd(DO3A)] 在 3 T MRS 3000 扫描仪上进行。在以 0.1 mmol/kg 的剂量静脉注射 MT218 后，使用带有呼吸门控的快速自旋回波轴向序列获得T _{1加权图像。}

结果

在携带原位 TNBC 异种移植物的小鼠中全身施用 RGD-PEG-ECO/miR-200c 纳米颗粒可显着抑制肿瘤进展，而无毒副作用。与对照相比，带有 MT218 的 MRMI 显示该治疗显着抑制了肿瘤增殖。MRMI 还表明，miR-200c 治疗通过降低 EDB-FN 表达来改变肿瘤微环境，这可以通过 MDA-MB-231 和 Hs578T 肿瘤的对比度增强降低来证明。免疫组织化学证实了 EDB-FN 的减少。

结论

用 RGD-PEG-ECO/miR-200c 纳米粒子靶向递送 miR-200c 可有效调节动物模型中的肿瘤微环境并抑制 TNBC 增殖。肿瘤 EDB-FN 表达的 MRMI 可有效地无创监测 RGD-PEG-ECO/miR-200c 纳米颗粒在 TNBC 中的肿瘤反应和治疗效果。