Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.
The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.
Lee
Kwang-Hun
KH
Division of Vascular and Interventional Radiology, The Russell H Morgan Department of Radiology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Liapi
Eleni A
EA
Cornell
Curt
C
Reb
Philippe
P
Buijs
Manon
M
Vossen
Josephina A
JA
Ventura
Veronica Prieto
VP
Geschwind
Jean-Francois H
JF
D000180:Acrylic Resins; D015901:Angiography, Digital Subtraction; D000818:Animals; D016461:Chemoembolization, Therapeutic / Q000295:instrumentation*; D003287:Contrast Media; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006499:Hepatic Artery; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008863:Microspheres; D011108:Polymers; D011145:Polyvinyls; D011817:Rabbits
D000180:Acrylic Resins; D003287:Contrast Media; D011108:Polymers; D011145:Polyvinyls; D004317:Doxorubicin