Canine Model of Convection-Enhanced Delivery of Cetuximab Conjugated Iron-Oxide Nanoparticles Monitored with Magnetic Resonance Imaging

• Authors: Simon Platt, University of Georgia; Edjah Nduom, Emory University; Marc Kent, University of Georgia; Courtenay Freeman, University of Georgia; Revaz Machaidze, Emory University; Milota Kaluzova, Emory University; Liya Wang, Emory University; Hui Mao, Emory University; Constantinos G Hadjipanayis, Emory University
• Journal Title: Clinical Neurosurgery
• Volume: Volume 59
• Publisher: Lippincott, Williams & Wilkins | 2012, Pages 107-113
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1227/NEU.0b013e31826989ef
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Glioblastoma; Magnetic Nanoparticles; Convection-Enhanced Delivery; MRI; EGFR; Cetuximab; Canine

Abstract

Introduction Visualizing distribution of infused therapeutic agents into the brain by convection-enhanced delivery (CED) is necessary to ensure accurate delivery into target sites. Recently, bioconjugated magnetic iron-oxide nanoparticles (IONPs) have been shown to produce a magnetic resonance imaging (MRI) contrast in the rodent brain after CED permitting direct visualization of nanoparticle distribution and dispersion over time. We have now studied the CED of IONPs in the larger, more clinically relevant, canine brain for assessment of distribution, dispersion, toxicity, and clearance. Methods Eight healthy laboratory dogs were infused with either free IONPs (n=4) or cetuximab-conjugated IONPs (cetuximab-IONPs; n=4) at different infusion rates (0.5, 1.0, 3.0, and 5.0 microliters/min) and volumes (180, 300, 360, and 720 microliters). IONP CED was monitored by sequential MRIs (pre-operative, within 12 h, 5 d, 7 d, and 30 d post-operative) and volumes of distribution and dispersion were calculated from the MR images. Toxicity assessment was based on MRI, clinical examination, hematologic/cerebrospinal fluid (CSF) analysis, and brain histopathological evaluation. Results Robust delivery and monitoring of IONP distribution in the grey and white matter of the canine brain was achieved by CED and MRI. Quantitative measurements of IONP distribution volumes was achieved by MRI. Distribution volumes were linearly proportional to infusion volumes and dispersion of IONPs occurred 5 d after CED. Use of the slower infusion rates allowed for more uniform initial distribution of IONPs and low infusate leakback of IONPs along the catheter track. No signs of toxicity were found in any animals that underwent IONP or cetuximab-conjugated IONP CED based on physical examination and hematologic/CSF analysis. MRI and histopathologic analysis of brains 30 d after CED revealed near complete clearance of IONPs. Uptake of IONPs by astrocytes and microglia was found adjacent to the catheter sites. Conclusions CED of either free or cetuximab-conjugated IONPs in the canine brain is safe and represents an effective delivery method in a larger animal model. MRI monitoring of distribution and dispersion of IONPs is possible and quantitative after CED. Future studies involving CED of bioconjugated IONPs in canines with spontaneous gliomas may provide a unique and more clinical relevant animal model for targeting infiltrative cancer cells responsible for tumor recurrence.