Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery.
Liposomes labeled with various markers were subjected to local-regional administration with either direct injection or convection-enhanced delivery (CED) into rodent brains and brain tumor models. Direct injection of liposomes containing attached or encapsulated fluorochromes and/or encapsulated gold particles indicated that tissue localization of liposomes could be sensitively and specifically detected in the central nervous system (CNS). When CED was applied, liposomes achieved extensive and efficient distribution within normal mouse brains. Co-infusion of mannitol further increased tissue penetration of liposomes. Liposomes were also loaded with gadodiamide to monitor their CNS distribution in rats by magnetic resonance imaging (MRI). CED-infused liposomes were readily seen on MRI scans as large regions of intense signal at 2 h, and more diffuse regions at 24 h. Finally, labeled liposomes were infused via CED into tumor tissue in glioma xenograft models in rodent hosts. In intracranial U-87 glioma xenografts, CED-infused liposomes had distributed throughout tumor tissue, including extension into surrounding normal tissue. Greater penetration was observed using 40 versus 90 nm liposomes, as well as with mannitol co-infusion. To our knowledge, this is the first report of CED infusion of liposomes into the CNS. We conclude that CED of liposomes in the CNS is a feasible approach, and offers a promising strategy for targeting therapeutic agents to brain tumors.
Mamot
Christoph
C
Division of Hematology-Oncology, University of California at San Francisco, San Francisco, CA, USA.
Nguyen
John B
JB
Pourdehnad
Micheal
M
Hadaczek
Piotr
P
Saito
Ryuta
R
Bringas
John R
JR
Drummond
Daryl C
DC
Hong
Keelung
K
Kirpotin
Dmitri B
DB
McKnight
Tracy
T
Berger
Mitchel S
MS
Park
John W
JW
Bankiewicz
Krys S
KS
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D018481:Convection; D016503:Drug Delivery Systems; D005682:Gadolinium / Q000008:administration & dosage / Q000493:pharmacokinetics; D005910:Glioma / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging; D008353:Mannitol / Q000008:administration & dosage; D051379:Mice; D051381:Rats; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous
D008081:Liposomes; D008353:Mannitol; D005682:Gadolinium