Preclinical evaluation of the cardiotoxicity of PK2: a novel HPMA copolymer-doxorubicin-galactosamine conjugate antitumour agent.
PK2 is a polymeric anticancer conjugate composed of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone and pendant doxorubicin (DOX) linked via a Gly-Phe-Leu-Gly peptide spacer. Additionally galactose residues are present to facilitate liver targeting. To justify clinical evaluation of PK2 it was necessary to determine its late cardiotoxicity compared to that of free DOX. A well standardised Sprague-Dawley rat model was used with either intravenous (i.v.) administration (4, 8 and 12 mg/kg DOX equivalent) or intraperitoneal (i.p.) administration (12, 18, 24 and 36 mg/kg DOX equivalent) of PK2. This variation in the route was due to the limited solubility of PK2 at higher doses. PK2 showed two to three times less acute toxicity (assessed by the maximum reduction in body weight in the first 2 weeks) than free DOX, and both compounds were less toxic when given i.p.. No animals given PK2 i.v. showed clinical signs of cardiotoxicity, the only toxicity seen was abnormal tooth growth (approximately 50% of the animals receiving 12 mg/kg, DOX equivalent). In contrast, several animals receiving free DOX (1-4 mg/kg) i.v. died due to cardiotoxicity in an approximately dose-related manner. All animals receiving free DOX (4 mg/kg) died by 12 weeks. Following i.p. administration of PKZ there were only two late deaths related to cardiotoxicity and these were in the 24 mg/kg DOX equivalent group. All animals receiving PK2 at the highest dose (36 mg/kg DOX equivalent) died within 4 weeks, cardiotoxicity was not the main contributing factor. In this study, PK2 displayed a approximately 5-fold reduction in cardiotoxicity relative to free DOX and this supported the progression of PK2 into early clinical investigation.
Hopewel
J W
JW
Normal Tissue Radiobiology Group, Research Institute (University of Oxford), The Churchill Hospital, UK.
Duncan
R
R
Wilding
D
D
Chakrabarti
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D005688:Galactosamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000633:toxicity*; D011109:Polymethacrylic Acids / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023382:Toxicity Tests, Acute
D000970:Antineoplastic Agents; D009842:Oligopeptides; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; C450921:doxorubicin-N-(2-hydroxypropyl)methacrylamide galactosamine conjugate; D005688:Galactosamine; D004317:Doxorubicin