New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer.
BACKGROUND
In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2).


OBJECTIVE
The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB.


RESULTS
Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 micromol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal.


CONCLUSIONS
Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.
Hong
Kelvin
K
Division of Vascular and Interventional Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Khwaja
Afsheen
A
Liapi
Eleni
E
Torbenson
Michael S
MS
Georgiades
Cristos S
CS
Geschwind
Jean-Francois H
JF
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D007269:Injections, Intra-Arterial; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008863:Microspheres; D011817:Rabbits
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C010013:adriamycinol