Abstract
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.
Highlights
Following the observation that soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing anthracyclines display anti-tumour activity in vivo (Duncan et al, 1989; Cassidy et al, 1989) we have explored the potential of this polymer-based system for targeted delivery of doxorubicin (DOX) to the hepatocyte galactose receptor
The galactose-targeted polymer is associated with hepatocytes rather than nonparenchymal cells, and it is transferred into lysosomes within 1 h of intravenous administration (Duncan et al, 1986)
All HPLC solvents were from Fisons plc (Loughborough, UK), Hanks buffered salts solutions (HBSS) and donor horse serum were purchased from Flow Laboratories (Rickmansworth, UK), and disposable Sephadex G-25 chromatography columns (PDI0) were from Pharmacia Ltd (Milton Keynes, UK)
Summary
Following the observation that soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing anthracyclines display anti-tumour activity in vivo (Duncan et al, 1989; Cassidy et al, 1989) we have explored the potential of this polymer-based system for targeted delivery of doxorubicin (DOX) to the hepatocyte galactose receptor. HPMA Copolymers have previously been synthesised containing galactose (Duncan et al, 1983a; Duncan et al, 1986; O'Hare et al, 1989) and are known to associate with human hepatoma cell lines in vitro (O'Hare et al, 1989) and show livertargeting in vivo (Chytry et al, 1987). The galactose-targeted polymer is associated with hepatocytes rather than nonparenchymal cells, and it is transferred into lysosomes within 1 h of intravenous administration (Duncan et al, 1986)
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