Time-resolved MRI assessment of convection-enhanced delivery by targeted and nontargeted nanoparticles in a human glioblastoma mouse model

Zachary R. Stephen, Peter A. Chiarelli, Richard A. Revia, Kui Wang, Forrest Kievit, Chris Dayringer, Mike Jeon, Richard Ellenbogen, Miqin Zhang

Research output: Contribution to journalArticle

Abstract

Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. Highresolution T2-weighted, T2∗-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTXmediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. Significance: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.

Original languageEnglish (US)
Pages (from-to)4776-4786
Number of pages11
JournalCancer Research
Volume79
Issue number18
DOIs
StatePublished - Sep 15 2019

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Convection
Glioblastoma
Nanoparticles
Glioma
Neoplasms
Active Biological Transport
Cell Nucleus
Brain Neoplasms
Contrast Media
Flow Cytometry
Erythrocytes
Chlorotoxin
Ligands
Technology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Time-resolved MRI assessment of convection-enhanced delivery by targeted and nontargeted nanoparticles in a human glioblastoma mouse model. / Stephen, Zachary R.; Chiarelli, Peter A.; Revia, Richard A.; Wang, Kui; Kievit, Forrest; Dayringer, Chris; Jeon, Mike; Ellenbogen, Richard; Zhang, Miqin.

In: Cancer Research, Vol. 79, No. 18, 15.09.2019, p. 4776-4786.

Research output: Contribution to journalArticle

Stephen, ZR, Chiarelli, PA, Revia, RA, Wang, K, Kievit, F, Dayringer, C, Jeon, M, Ellenbogen, R & Zhang, M 2019, 'Time-resolved MRI assessment of convection-enhanced delivery by targeted and nontargeted nanoparticles in a human glioblastoma mouse model', Cancer Research, vol. 79, no. 18, pp. 4776-4786. https://doi.org/10.1158/0008-5472.CAN-18-2998
Stephen, Zachary R. ; Chiarelli, Peter A. ; Revia, Richard A. ; Wang, Kui ; Kievit, Forrest ; Dayringer, Chris ; Jeon, Mike ; Ellenbogen, Richard ; Zhang, Miqin. / Time-resolved MRI assessment of convection-enhanced delivery by targeted and nontargeted nanoparticles in a human glioblastoma mouse model. In: Cancer Research. 2019 ; Vol. 79, No. 18. pp. 4776-4786.
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AU - Dayringer, Chris

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AB - Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. Highresolution T2-weighted, T2∗-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTXmediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. Significance: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.

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