N-(2-Hydroxypropyl)methacrylamide (
HPMA) copolymers containing
doxorubicin (DOX) and
galactosamine can be targeted to the hepatocyte
galactose receptor for organ-specific
chemotherapy of primary and metastatic
liver cancer. Here we report the dose-dependent pharmacokinetics of this macromolecular conjugate. Following
intravenous administration to mice most efficient liver targeting was seen at low dose (0.05 mg DOX kg-1), with receptor saturation observed using higher bolus doses. Repeated low dose bolus
injections did not cause down-regulation of the
galactose receptor and targeted
drug delivery rates of greater than or equal to 2 micrograms DOX g-1 liver h-1 were achieved. DOX is released from such conjugates intracellularly via action of lysosomal
proteinases. It was shown that isolated rat liver lysosomal
enzymes (Tritosomes) can release unmodified DOX from the peptidyl side chain
Gly-Phe-Leu-Gly at a rate greater than or equal to 3 micrograms DOX g-1 liver h-1 i.e. the hydrolytic capacity is greater than the observed rate of
drug delivery to the liver lysosomes in vivo. Although most conjugate would be captured by normal hepatocytes following
intravenous administration, it was shown that the human
hepatoma cell line HepG2 retains the
galactose receptor, accumulating and processing the conjugate efficiently. Potential dose limiting toxicities of such
drug conjugates could include cardio- or hepatotoxicity. Administration of conjugate reduced the 15 min heart level of DOX approximately 100-fold compared with that observed for an equivalent dose of free
drug. Preliminary experiments showed that plasma levels of
alkaline phosphatase,
alanine transaminase and asparate
transaminase did not change following administration of
HPMA copolymer-
daunorubicin (DNR) (10 mg DNR kg-1) indicating no significant heptatoxicity.