Drug-eluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model.
OBJECTIVE
To evaluate the local tissue concentrations of the antineoplastic agent doxorubicin and the amount of drug still present inside drug delivery embolization beads at different time points after embolization and to compare doxorubicin levels with histologic modifications around the beads in a pig liver model. It was hypothesized that doxorubicin-eluting beads maintain cytotoxic concentrations of drug locally over a period of several weeks, as suggested by in vitro elution tests.


METHODS
Left lobe hepatic artery embolization was performed in 10 pigs with 100-300-microm or 700-900-microm beads loaded with 37.5 mg doxorubicin/mL. Control unloaded 100-300-microm beads were injected in five pigs. Livers were sampled 28 days or 90 days after embolization. The amount of drug retained inside the beads was assessed with infrared microspectroscopy. Doxorubicin concentration and distribution in the tissue around the beads were determined with microspectrofluorimetry and compared with tissue modifications on hematein eosin saffron-stained sections.


RESULTS
Doxorubicin-eluting beads eluted 43% of their initial drug load after 28 days and 89% after 90 days. Doxorubicin was present in tissues around the beads at both time points, with a significant decrease over time (P = .0004). The drug was detected at distances as far as 600 microm from the bead edge. Doxorubicin tissue concentrations ranged from 0.55 microM to 6.80 microM, [corrected] which are cytotoxic levels in hepatocyte cell cultures. High concentrations of drug were associated with coagulative necrosis of liver parenchyma. Doxorubicin-eluting beads 100-300 microm in size induced more necrosis than 700-900-microm beads (P = .0036).


CONCLUSIONS
Doxorubicin-eluting beads deliver high concentrations of the drug over a period of at least 3 months at several hundred micrometers from the bead, leading to significant cytotoxic effects.
Namur
Julien
J
Unité MéDIAN, MEDyC, CNRS UMR 6237, Université de Reims Champagne Ardennes, Reims, France. namurjul@hotmail.fr
Wassef
Michel
M
Millot
Jean-Marc
JM
Lewis
Andrew L
AL
Manfait
Michel
M
Laurent
Alexandre
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D016461:Chemoembolization, Therapeutic; D003692:Delayed-Action Preparations; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004337:Drug Carriers; D006499:Hepatic Artery; D007269:Injections, Intra-Arterial; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology; D008297:Male; D015591:Microspectrophotometry; D023421:Models, Animal; D009336:Necrosis; D010316:Particle Size; D013050:Spectrometry, Fluorescence; D013055:Spectrophotometry, Infrared; D013552:Swine; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004317:Doxorubicin