TY - JOUR
T1 - Time-resolved MRI assessment of convection-enhanced delivery by targeted and nontargeted nanoparticles in a human glioblastoma mouse model
AU - Stephen, Zachary R.
AU - Chiarelli, Peter A.
AU - Revia, Richard A.
AU - Wang, Kui
AU - Kievit, Forrest
AU - Dayringer, Chris
AU - Jeon, Mike
AU - Ellenbogen, Richard
AU - Zhang, Miqin
N1 - Funding Information:
This work is supported by NIH grant R01CA161953 and the Biomedical Research Support Shared Instrumentation Grant (S10RR029021 to 14T HRIM Facility). P.A. Chiarelli, Z.R. Stephen, and M. Jeon were supported by a training grant (T32CA138312) from the NCI of the NIH. R.A. Revia is supported by the NIH under Award Number F31CA232546.We acknowledge lab assistance from D. Kahn and M. Halbert, as well as the use of facilities at Nanoengineering and Science Institute, the Molecular Engineering and Science Institute (supported by NSF grant NNCI-1542101), and resources at UW Medicine Pathology laboratory and flow cytometry core facility
Funding Information:
This work is supported by NIH grant R01CA161953 and the Biomedical Research Support Shared Instrumentation Grant (S10RR029021 to 14T HRIM Facility). P.A. Chiarelli, Z.R. Stephen, and M. Jeon were supported by a training grant (T32CA138312) from the NCI of the NIH. R.A. Revia is supported by the NIH under Award Number F31CA232546. We acknowledge lab assistance from
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/15
Y1 - 2019/9/15
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85072233967&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072233967&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-2998
DO - 10.1158/0008-5472.CAN-18-2998
M3 - Article
C2 - 31331912
AN - SCOPUS:85072233967
SN - 0008-5472
VL - 79
SP - 4776
EP - 4786
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -