Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: Laboratory investigation

Peter J Dickinson, Richard A Lecouteur, Robert Higgins, John R. Bringas, Byron Roberts, Richard F. Larson, Yoji Yamashita, Michal Krauze, Charles O. Noble, Daryl Drummond, Dmitri B. Kirpotin, John W. Park, Mitchel S. Berger, Krystof S. Bankiewicz

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Object. 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.

Original languageEnglish (US)
Pages (from-to)989-998
Number of pages10
JournalJournal of Neurosurgery
Volume108
Issue number5
DOIs
StatePublished - May 2008

Fingerprint

irinotecan
Convection
Liposomes
Canidae
Magnetic Resonance Imaging
Animal Models
Dogs
Subarachnoid Space
Rhodamines
Encephalitis
Glioma
Nanoparticles

Keywords

  • Brain
  • Convection-enhanced delivery
  • Dog
  • Irinotecan
  • Magnetic resonance imaging

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging : Laboratory investigation. / Dickinson, Peter J; Lecouteur, Richard A; Higgins, Robert; Bringas, John R.; Roberts, Byron; Larson, Richard F.; Yamashita, Yoji; Krauze, Michal; Noble, Charles O.; Drummond, Daryl; Kirpotin, Dmitri B.; Park, John W.; Berger, Mitchel S.; Bankiewicz, Krystof S.

In: Journal of Neurosurgery, Vol. 108, No. 5, 05.2008, p. 989-998.

Research output: Contribution to journalArticle

Dickinson, PJ, Lecouteur, RA, Higgins, R, Bringas, JR, Roberts, B, Larson, RF, Yamashita, Y, Krauze, M, Noble, CO, Drummond, D, Kirpotin, DB, Park, JW, Berger, MS & Bankiewicz, KS 2008, 'Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: Laboratory investigation', Journal of Neurosurgery, vol. 108, no. 5, pp. 989-998. https://doi.org/10.3171/JNS/2008/108/5/0989
Dickinson, Peter J ; Lecouteur, Richard A ; Higgins, Robert ; Bringas, John R. ; Roberts, Byron ; Larson, Richard F. ; Yamashita, Yoji ; Krauze, Michal ; Noble, Charles O. ; Drummond, Daryl ; Kirpotin, Dmitri B. ; Park, John W. ; Berger, Mitchel S. ; Bankiewicz, Krystof S. / Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging : Laboratory investigation. In: Journal of Neurosurgery. 2008 ; Vol. 108, No. 5. pp. 989-998.
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abstract = "Object. 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.",
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T1 - Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging

T2 - Laboratory investigation

AU - Dickinson, Peter J

AU - Lecouteur, Richard A

AU - Higgins, Robert

AU - Bringas, John R.

AU - Roberts, Byron

AU - Larson, Richard F.

AU - Yamashita, Yoji

AU - Krauze, Michal

AU - Noble, Charles O.

AU - Drummond, Daryl

AU - Kirpotin, Dmitri B.

AU - Park, John W.

AU - Berger, Mitchel S.

AU - Bankiewicz, Krystof S.

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N2 - Object. 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.

AB - Object. 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.

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