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Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance

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Abstract

Current therapy for glioblastoma multiforme (GBM) is largely ineffective, with nearly universal tumor recurrence. The failure of current therapy is primarily due to the lack of approaches for the efficient delivery of therapeutics to diffuse tumors in the brain. In our prior study, we developed brain-penetrating nanoparticles that are capable of penetrating brain tissue and distribute over clinically relevant volumes when administered via convection-enhanced delivery (CED). We demonstrated that these particles are capable of efficient delivery of chemotherapeutics to diffuse tumors in the brain, indicating that they may serve as a groundbreaking approach for the treatment of GBM. In the original study, nanoparticles in the brain were imaged using positron emission tomography (PET). However, clinical translation of this delivery platform can be enabled by engineering a non-invasive detection modality using magnetic resonance imaging (MRI). For this purpose, we developed chemistry to incorporate superparamagnetic iron oxide (SPIO) into the brain-penetrating nanoparticles. We demonstrated that SPIO-loaded nanoparticles, which retain the same morphology as nanoparticles without SPIO, have an excellent transverse (T2) relaxivity. After CED, the distribution of nanoparticles in the brain (i.e., in the vicinity of injection site) can be detected using MRI and the long-lasting signal attenuation of SPIO-loaded brain-penetrating nanoparticles lasted over a one-month timecourse. Development of these nanoparticles is significant as, in future clinical applications, co-administration of SPIO-loaded nanoparticles will allow for intraoperative monitoring of particle distribution in the brain to ensure drug-loaded nanoparticles reach tumors as well as for monitoring the therapeutic benefit with time and to evaluate tumor relapse patterns.

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Acknowledgments

This work was supported by a T-TARE award from the Yale Cancer Center (WMS & JP), grants from the US National Institutes of Health to WMS (CA149128) and FH (CA-140102, EB-011968, NS-052519),VABC Foundation (WMS, JP & JZ), Yale Center for Clinical Investigation (CTSA UL1 TR000142, JZ), American Cancer Society (IRG 58-012-55, JZ), and Matthew Larson Foundation (JZ).

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA

    Garth Strohbehn, Ragy R. T. Ragheb, Tarek M. Fahmy, Fahmeed Hyder, W. Mark Saltzman & Jiangbing Zhou

  2. Department of Diagnostic Radiology, Yale University, New Haven, CT, 06510, USA

    Daniel Coman & Fahmeed Hyder

  3. Department of Pathology, Yale University, New Haven, CT, 06510, USA

    Anita J. Huttner

  4. Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA

    Liang Han, Joseph M. Piepmeier & Jiangbing Zhou

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  1. Garth Strohbehn
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  2. Daniel Coman
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  3. Liang Han
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  4. Ragy R. T. Ragheb
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  5. Tarek M. Fahmy
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  7. Fahmeed Hyder
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  8. Joseph M. Piepmeier
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  9. W. Mark Saltzman
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  10. Jiangbing Zhou
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Correspondence to Jiangbing Zhou.

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G. Strohbehn and D. Coman have contributed equally to this work.

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Strohbehn, G., Coman, D., Han, L. et al. Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance. J Neurooncol 121, 441–449 (2015). https://doi.org/10.1007/s11060-014-1658-0

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