Real-time visualization and characterization of liposomal delivery into the monkey brain by magnetic resonance imaging.

Liposomes loaded with Gadoteridol, in combination with convection-enhanced delivery (CED), offer an excellent option to monitor CNS delivery of therapeutic compounds with MRI. In previous studies, we investigated possible clinical applications of liposomes to the treatment of brain tumors. In this study, up to 700 microl of Gadoteridol/rhodamine-loaded liposomes were distributed in putamen, corona radiata and brainstem of non-human primates. Distribution was monitored by real-time MRI throughout infusion procedures and allowed accurate calculation of volume of distribution within anatomical structures. We found that different regions of the brain gave various volumes of distribution when infused with the same volume of liposome. Based on these findings, distinct distribution pathways within infused structures can be predicted. This work underlines the importance of monitoring drug delivery to CNS and enables accurate delivery of drug-loaded liposomes to specific brain regions with a standard MRI procedure. Findings presented in this manuscript may allow for modeling of parameters used for direct delivery of therapeutics into various regions of the brain.

[1]  P. Colosi,et al.  Distribution of AAV-TK following Intracranial Convection-Enhanced Delivery into Rats , 2000, Cell transplantation.

[2]  J P Johnson,et al.  Intracerebral clysis in a rat glioma model. , 2000, Neurosurgery.

[3]  P F Morrison,et al.  Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. , 1999, Journal of neurosurgery.

[4]  Ryuta Saito,et al.  Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain , 2005, Experimental Neurology.

[5]  F. Szoka,et al.  Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating , 2005, Brain Research.

[6]  P F Morrison,et al.  Convection-enhanced delivery of macromolecules in the brain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Mackay,et al.  In vivo measurement of T2 distributions and water contents in normal human brain , 1997, Magnetic resonance in medicine.

[8]  D. Groothuis,et al.  Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion. , 1999, Journal of neurosurgery.

[9]  John A Butman,et al.  Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. , 2002, Journal of neurosurgery.

[10]  R. Sánchez-Pernaute,et al.  Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain , 2001, Neuroreport.

[11]  Denis Le Bihan,et al.  Looking into the functional architecture of the brain with diffusion MRI , 2003, Nature Reviews Neuroscience.

[12]  M. Berger,et al.  Extensive Distribution of Liposomes in Rodent Brains and Brain Tumors Following Convection-Enhanced Delivery , 2004, Journal of Neuro-Oncology.

[13]  Heidi Phillips,et al.  Heparin Coinfusion during Convection-Enhanced Delivery (CED) Increases the Distribution of the Glial-Derived Neurotrophic Factor (GDNF) Ligand Family in Rat Striatum and Enhances the Pharmacological Activity of Neurturin , 2001, Experimental Neurology.

[14]  M. Berger,et al.  Distribution of Liposomes into Brain and Rat Brain Tumor Models by Convection-Enhanced Delivery Monitored with Magnetic Resonance Imaging , 2004, Cancer Research.

[15]  A. Olivi,et al.  New Approach to Tumor Therapy for Inoperable Areas of the Brain: Chronic Intraparenchymal Drug Delivery , 2002, Journal of Neuro-Oncology.

[16]  E. Oldfield,et al.  Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates. , 1999, Journal of neurosurgery.

[17]  J. Bruce,et al.  Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model. , 2000 .

[18]  P. V. van Zijl,et al.  Three‐dimensional tracking of axonal projections in the brain by magnetic resonance imaging , 1999, Annals of neurology.

[19]  V. Torchilin Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

[20]  D. Brooks,et al.  Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease , 2003, Nature Medicine.

[21]  G. Gillies,et al.  A realistic brain tissue phantom for intraparenchymal infusion studies. , 2004, Journal of neurosurgery.

[22]  E. Neuwelt,et al.  Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. , 1996, Neurosurgery.

[23]  A. MacKay,et al.  In vivo visualization of myelin water in brain by magnetic resonance , 1994, Magnetic resonance in medicine.

[24]  William Jagust,et al.  Convection-Enhanced Delivery of AAV Vector in Parkinsonian Monkeys; In Vivo Detection of Gene Expression and Restoration of Dopaminergic Function Using Pro-drug Approach , 2000, Experimental Neurology.