title: Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine.
abstract: Galactose-targeted delivery of macromolecules and drug conjugates to asialoglycoprotein receptor (ASGPR) positive cells has been widely documented in animals, although targeting in humans has never been demonstrated. In this study we report the pharmacokinetics and imaging determined in the first patient enrolled in a phase I clinical study of the poly[N-(2-hydroxypropyl)methacrylamide] copolymer bearing doxorubicin and galactosamine, known as PK2. Gradient high performance liquid chromatography (HPLC) evaluation of plasma and urine has been combined with 123I-based imaging to show biphasic clearance of the drug from the plasma (half-lives of 78+/-1 and 990+/-15), and approximately 30% delivery of the drug to the hepatic region, as determined by planar whole body imaging at 24 h. This patient has a multifocal hepatoma, and single photon emission computed tomography (SPECT) analysis showed a ratio of tumour tissue to normal liver uptake of approximately 1:3, at 24 h. On the basis of this patient, effective hepatic targeting can be achieved following an intravenous dose of 20 mg/m2 doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established.
authors.affiliation: Department of Nuclear Medicine, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Julyan
authors.forename: L W
authors.initials: LW
authors.lastname: Seymour
authors.forename: D R
authors.initials: DR
authors.lastname: Ferry
authors.forename: S
authors.initials: S
authors.lastname: Daryani
authors.forename: C M
authors.initials: CM
authors.lastname: Boivin
authors.forename: J
authors.initials: J
authors.lastname: Doran
authors.forename: M
authors.initials: M
authors.lastname: David
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: C
authors.initials: C
authors.lastname: Christodoulou
authors.forename: A M
authors.initials: AM
authors.lastname: Young
authors.forename: S
authors.initials: S
authors.lastname: Hesslewood
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001711:Biotransformation; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005688:Galactosamine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007457:Iodine Radioisotopes; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D011109:Polymethacrylic Acids / Q000493:pharmacokinetics*; D015899:Tomography, Emission-Computed, Single-Photon; D014915:Whole-Body Counting
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D007457:Iodine Radioisotopes; D011109:Polymethacrylic Acids; C055174:daunomycin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D005688:Galactosamine; D003630:Daunorubicin