Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.
OBJECTIVE
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.


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 (i.v.) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m(2) (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.


CONCLUSIONS
The recommended PK2 dose is 120 mg/m(2), 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.
Seymour
Leonard W
LW
Cancer Research UK Institute for Cancer Studies, University of Birmingham, United Kingdom.
Ferry
David R
DR
Anderson
David
D
Hesslewood
Stuart
S
Julyan
Peter J
PJ
Poyner
Richard
R
Doran
Jayne
J
Young
Annie M
AM
Burtles
Sally
S
Kerr
David J
DJ
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005260:Female; D005688:Galactosamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D015902:Gamma Cameras; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D011109:Polymethacrylic Acids / Q000737:chemistry; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D005688:Galactosamine; D004317:Doxorubicin