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Efficacy of Targeted ECO/miR-200c Nanoparticles for Modulating Tumor Microenvironment and Treating Triple Negative Breast Cancer as Non-invasively Monitored by MR Molecular Imaging

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Abstract

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.

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Author notes

  1. Andrew L. Schilb and Nadia R. Ayat contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Wickenden 427, Mail Stop 7207, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    Andrew L. Schilb, Nadia R. Ayat, Amita M. Vaidya, Laura M. Hertz, Ryan C. Hall, Josef H. Scheidt, Da Sun, Zhanhu Sun & Zheng-Rong Lu

  2. Department of Radiology, Case Western Reserve University, Cleveland, OH, 44106, USA

    Ramamurthy Gopalakrishnan

  3. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA

    Zheng-Rong Lu

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  1. Andrew L. Schilb
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  2. Nadia R. Ayat
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  3. Amita M. Vaidya
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Correspondence to Zheng-Rong Lu.

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Schilb, A.L., Ayat, N.R., Vaidya, A.M. et al. Efficacy of Targeted ECO/miR-200c Nanoparticles for Modulating Tumor Microenvironment and Treating Triple Negative Breast Cancer as Non-invasively Monitored by MR Molecular Imaging. Pharm Res 38, 1405–1418 (2021). https://doi.org/10.1007/s11095-021-03083-z

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