title: Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: laboratory investigation.
abstract: OBJECTIVE
  Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging-compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery.
  
  
  METHODS
  Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution.
  
  
  RESULTS
  Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in 1 dog, and focal, mild perivascular, nonsuppurative encephalitis in 1 dog.
  
  
  CONCLUSIONS
  Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies.
authors.affiliation: Department of Surgical and Radiological Sciences, Tupper Hall, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. pjdickinson@ucdavis.edu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dickinson
authors.forename: Richard A
authors.initials: RA
authors.lastname: LeCouteur
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Higgins
authors.forename: John R
authors.initials: JR
authors.lastname: Bringas
authors.forename: Byron
authors.initials: B
authors.lastname: Roberts
authors.forename: Richard F
authors.initials: RF
authors.lastname: Larson
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Michal
authors.initials: M
authors.lastname: Krauze
authors.forename: Charles O
authors.initials: CO
authors.lastname: Noble
authors.forename: Daryl
authors.initials: D
authors.lastname: Drummond
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D004784:Environmental Monitoring; D005260:Female; D005453:Fluorescence; D005682:Gadolinium; D000077146:Irinotecan; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D053758:Nanoparticles
chemical_list: D008081:Liposomes; D000077146:Irinotecan; D005682:Gadolinium; D002166:Camptothecin