title: Detection and cellular localisation of the synthetic soluble macromolecular drug carrier pHPMA.
abstract: Synthetic macromolecules such as copolymers of N-(2-hydroxypropyl)methacrylamide (pHPMA) are potential carriers for the delivery of drugs owing to their ability to passively accumulate in solid tumours [enhanced permeation and retention (EPR) effect]. To gain further knowledge about the biodistribution and the cellular localisation, poly(HPMA) was prepared for labelling by introducing biotin molecules. Biotinylated pHPMA (5 mol%) was intravenously injected into tumour-bearing rats and the accumulation of biotin-pHPMA was visualised using a streptavidin-alkaline phosphatase technique at day 7 post injection. In spite of the high solubility of pHPMA copolymers and the lack of attachment to cell structures, the biotinylated polymer could be easily detected in tissues fixed in 10% paraformaldehyde-phosphate buffer at 4 degrees C for 48 h. While biotin-pHPMA could be detected intracytoplasmically in liver and spleen, a predominantly interstitial localisation was observed within the anaplastic prostate carcinoma (Dunning R3327-AT1). How biotin as a label influences the biodistribution of poly(HPMA) was assessed by scintigraphy, autoradiography and histology comparing homopolymer poly(HPMA) with biotin-pHPMA. The organ distribution patterns of the two polymers correlated well, except with respect to kidney. It is assumed that the accumulation of biotin-pHPMA in the distal tubuli is due to a biotin transporter in the brush border membrane. The technique presented is useful for a more comprehensive understanding of the biodistribution of soluble macromolecules.
authors.affiliation: Department of Radiation Oncology, E0505, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. kissel@dkfz.de
authors.forename: Maria
authors.initials: M
authors.lastname: Kissel
authors.forename: Peter
authors.initials: P
authors.lastname: Peschke
authors.forename: Vladimir
authors.initials: V
authors.lastname: Subr
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Anke M
authors.initials: AM
authors.lastname: Strunz
authors.forename: Rainer
authors.initials: R
authors.lastname: Kühnlein
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Eckhard
authors.initials: E
authors.lastname: Friedrich
mesh_terms: D000178:Acrylamides / Q000493:pharmacokinetics; D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001710:Biotin / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000493:pharmacokinetics*; D004952:Esters / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D046911:Macromolecular Substances; D008297:Male; D008689:Methacrylates / Q000493:pharmacokinetics*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D012016:Reference Values; D012995:Solubility; D013848:Thigh / Q000000981:diagnostic imaging / Q000473:pathology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014915:Whole-Body Counting
chemical_list: D000178:Acrylamides; D004337:Drug Carriers; D004952:Esters; D007457:Iodine Radioisotopes; D046911:Macromolecular Substances; D008689:Methacrylates; D019275:Radiopharmaceuticals; C447720:methacryloylglycylglycine-4-nitrophenyl ester; D001710:Biotin; C032976:N-(2-hydroxypropyl)methacrylamide