Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model.
OBJECTIVE
The combination of embolic beads with a multitargeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres and evaluates the in vitro biologic efficacy on cell cultures and the resulting in vivo pharmacokinetics profiles in an animal model.


METHODS
DC Bead microspheres, 70-150 µm and 100-300 µm (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New Zealand white rabbits received sunitinib either by intraarterial injection of 100-300 µm sized beads or per os. Plasma and liver tissue drug concentrations were assessed by liquid chromatography-tandem mass spectroscopy.


RESULTS
Sunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast-release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/mL), but high concentrations at 6 hours (14.9 µg/g) and 24 hours (3.4 µg/g) were found in the liver tissue.


CONCLUSIONS
DC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization.
School of Pharmaceutical Sciences, University of Geneva, 30, quai Ernest Ansermet, 1211 Geneva.
Katrin
K
Fuchs
Department of Radiology and Interventional Radiology, CHUV University of Lausanne, Lausanne, Switzerland.
Pierre E
PE
Bize
Department of Visceral Surgery, CHUV University of Lausanne, Lausanne, Switzerland.
Olivier
O
Dormond
Department of Radiology and Interventional Radiology, CHUV University of Lausanne, Lausanne, Switzerland.
Alban
A
Denys
School of Pharmaceutical Sciences, University of Geneva, 30, quai Ernest Ansermet, 1211 Geneva.
Eric
E
Doelker
School of Pharmaceutical Sciences, University of Geneva, 30, quai Ernest Ansermet, 1211 Geneva.
Gerrit
G
Borchard
School of Pharmaceutical Sciences, University of Geneva, 30, quai Ernest Ansermet, 1211 Geneva. Electronic address: Olivier.jordan@unige.ch.
Olivier
O
Jordan
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D054855:Drug-Eluting Stents; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008863:Microspheres; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011817:Rabbits; D000077210:Sunitinib; D014018:Tissue Distribution
D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib