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

TLDR

Preclinical studies show that targeting a galactosamine‑modified doxorubicin polymer (PK2) to the liver yields strong anticancer activity. The study aimed to evaluate the toxicity, pharmacokinetics, and liver‑targeting of PK2, a doxorubicin polymer linked via a lysosome‑degradable tetrapeptide to a galactosamine‑bearing copolymer. Thirty‑one liver‑cancer patients received PK2 by 1‑hour IV infusion every 3 weeks, with body distribution monitored by gamma‑camera imaging and SPECT to assess targeting, toxicity, and efficacy. Dose escalation to 160 mg/m² (MTD) caused severe fatigue, grade 4 neutropenia, and grade 3 mucositis, while 16.9 % ± 3.9 % of the doxorubicin dose accumulated in liver and 3.3 % ± 5.6 % in tumor, with no targeting seen without galactosamine; three hepatoma patients achieved partial responses, one remaining in remission 47 months, supporting liver‑specific delivery at a recommended 120 mg/m² every 3 weeks.

Abstract

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.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.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.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.