Fate of N-(2-hydroxypropyl)methacrylamide copolymers with pendent galactosamine residues after intravenous administration to rats

Comparison of the liver subcellular distribution of free daunomycin and that bound to galactosamine targeted N-(2-hydroxypropyl)methacrylamide copolymers, following intravenous administration in the rat

“…Pendant galactosamine residues have been shown to elevate deposition of HPMA-DOX in liver, via an interaction with hepatocyte cell surface receptor (Duncan et al, 1986;Seymour et al, 1990); one such formulation being recently accepted for phase I/II clinical trial as a potential treatment for hepatocellular carcinoma and metastatic disease residing in the liver. The pharmacokinetics of galactose targeted HPMA-DOX have been studied in detail (Seymour et al, 1990), but the intracellular pharmacokinetics of these conjugates are of considerable importance, both to elucidate their mechanisms of action and to understand whether such materials may be useful for the circumvention of multidrug resistance (MDR), a clinical phenomenon to which free anthracyclines are particularly susceptible (Kaye & Merry, 1985).…”

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

“…These copolymers can be tailor-made to include oligopeptide drugpolymer linkages that are stable in the circulation , but readily degraded intracellularly by the lysosomal thiol-dependent (cysteine-) proteinases (Duncan et al, 1983;Rejmanova et al, 1983). HPMA copolymers can also be synthesized to include potentially useful targeting residues, such as galactose, which target the polymer efficiently to hepatocytes (Duncan et al, 1983a;Duncan et al, 1986) or immunoglobulins (rat IgG) and anti 0 antibodies (1iAhovai & Iklhova ' et al, 1986).…”

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

“…Both conventional chemotherapeutics and drugs designed to interact with novel targets can be polymerbound. In theory, the construct can also incorporate ligands to facilitate receptor-mediated tumour targeting (Duncan and Kopecek, 1984;Duncan et al, 1986;Duncan, 1992;Duncan and Spreafico, 1994;Brocchini and Duncan, 1999). The original model proposed by Ringsdorf (1975) envisaged a hydrophilic polymer backbone chosen to aid drug solubilisation, a biodegradable polymer -drug linker designed to ensure stability in the circulation, and a targeting ligand to promote tumour-specific delivery.…”

“…Although a vast array of putative tumour targeting residues have been investigated, so far the only 'targeted' conjugate to enter clinical testing is an HPMA copolymer -doxorubicin conjugate containing, additionally, galactosamine (XVII, PK2 (FCE28069)). This conjugate was designed (Duncan et al, 1983(Duncan et al, , 1986 to target the asialoglycoprotein receptor present on normal hepatocytes and hepatocellular carcinoma with the hope of improving treatment of primary and secondary liver cancer. Liver targeting of this conjugate has been verified by clinical gamma camera imaging (Seymour et al, 2002).…”