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Hepatic Drug Targeting: Phase I Evaluation of Polymer-Bound Doxorubicin

From the Cancer Research UK Institute for Cancer Studies, University of Birmingham, Department of Physics and Nuclear Medicine, City Hospital National Health Service Trust, and Department of Nuclear Medicine, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Trust, Birmingham; Department of Nuclear Medicine, Christie Hospital, Withington, Manchester; and Cancer Research UK, London, United Kingdom.

In memory of Professor Tom Connors.Address reprint requests to D.J. Kerr, MD, University of Oxford, Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Rd, Oxford OX2 6HE, United Kingdom; email: david.kerr{at}clinpharm .ox.ac.uk.

PURPOSE: Preclinical studies have shown good anticancer activity following targeting of a polymer bearing doxorubicin with galactosamine (PK2) to the liver. The present phase I study was devised to determine the toxicity, pharmacokinetic profile, and targeting capability of PK2.

PATIENTS AND METHODS: Doxorubicin was linked via a lysosomally degradable tetrapeptide sequence to N-(2-hydroxypropyl)methacrylamide copolymers bearing galactosamine. Targeting, toxicity, and efficacy were evaluated in 31 patients with primary (n = 25) or metastatic (n = 6) liver cancer. Body distribution of the radiolabelled polymer conjugate was assessed using gamma-camera imaging and single-photon emission computed tomography.

RESULTS: The polymer was administered by intravenous (IV) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m² (doxorubicin equivalents), the maximum-tolerated dose, which was associated with severe fatigue, grade 4 neutropenia, and grade 3 mucositis. Twenty-four hours after administration, 16.9% ± 3.9% of the administered dose of doxorubicin targeted to the liver and 3.3% ± 5.6% of dose was delivered to tumor. Doxorubicin-polymer conjugate without galactosamine showed no targeting. Three hepatoma patients showed partial responses, with one in continuing partial remission 47 months after therapy.

CONCLUSION: The recommended PK2 dose is 120 mg/m², administered every 3 weeks by IV infusion. Liver-specific doxorubicin delivery is achievable using galactosamine-modified polymers, and targeting is also seen in primary hepatocellular tumors.

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