Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging.
Although liposomes have been used as a vehicle for delivery of therapeutic agents in oncology, their efficacy in targeting brain tumors has been limited due to poor penetration through the blood-brain barrier. Because convection-enhanced delivery (CED) of liposomes may improve the therapeutic index for targeting brain tumors, we conducted a three-stage study: stage 1 established the feasibility of using in vivo magnetic resonance imaging (MRI) to confirm adequate liposomal distribution within targeted regions in normal rat brain. Liposomes colabeled with gadolinium (Gd) and a fluorescent indicator, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-5,5'-disulfonic acid [DiI-DS; formally DiIC(18)(3)-DS], were administered by CED into striatal regions. The minimum concentration of Gd needed for monitoring, correlation of infused volume with distribution volume, clearance of infused liposome containing Gd and DiI-DS (Lip/Gd/DiI-DS), and potential local toxicity were evaluated. After determination of adequate conditions for MRI detection in normal brain, stage 2 evaluated the feasibility of in vivo MRI monitoring of liposomal distribution in C6 and 9L-2 rat glioma models. In both models, the distribution of Lip/Gd/DiI-DS covering the tumor mass was well defined and monitored with MRI. Stage 3 was designed to develop a clinically relevant treatment strategy in the 9L-2 model by infusing liposome containing Gd (Lip/Gd), prepared in the same size as Lip/Gd/DiI-DS, with Doxil, a liposomal drug of similar size used to treat several cancers. MRI detection of Lip/Gd coadministered with Doxil provided optimum CED parameters for complete coverage of 9L-2 tumors. By permitting in vivo monitoring of therapeutic distribution in brain tumors, this technique optimizes local drug delivery and may provide a basis for clinical applications in the treatment of malignant glioma.
Saito
Ryuta
R
Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, San Francisco, California 94103, USA.
Bringas
John R
JR
McKnight
Tracy R
TR
Wendland
Michael F
MF
Mamot
Christoph
C
Drummond
Daryl C
DC
Kirpotin
Dmitri B
DB
Park
John W
JW
Berger
Mitchel S
MS
Bankiewicz
Krys S
KS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D002232:Carbocyanines / Q000008:administration & dosage / Q000494:pharmacology; D018481:Convection; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D005682:Gadolinium / Q000008:administration & dosage / Q000493:pharmacokinetics; D005910:Glioma / Q000378:metabolism; D018316:Gliosarcoma / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D009927:Tissue and Organ Procurement
D000903:Antibiotics, Antineoplastic; D002232:Carbocyanines; D005456:Fluorescent Dyes; D008081:Liposomes; C024286:3,3'-dioctadecylindocarbocyanine; D004317:Doxorubicin; D005682:Gadolinium