title: Effect of physicochemical modification on the biodistribution and tumor accumulation of HPMA copolymers.
abstract: Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that are being broadly implemented in the delivery of anticancer therapeutics. To better predict the in vivo potential of the copolymers and to describe the biodistributional consequences of functionalization, 13 physicochemically different HPMA copolymers were synthesized, varying in molecular weight and in the nature and amount of functional groups introduced. Upon radiolabeling, the copolymers were injected i.v., and their circulation kinetics, tissue distribution and tumor accumulation were monitored in rats bearing subcutaneous Dunning AT1 tumors. It was found that increasing the average molecular weight of HPMA copolymers resulted in prolonged circulation times and in increased tumor concentrations. Conjugation of carboxyl and hydrazide groups, as well as introduction of spacer, drug and peptide moieties reduced the long-circulating properties of the copolymers and as a result, lower levels were found in tumors and in all organs other than kidney. Interestingly, however, in spite of the reduced (absolute) tumor concentrations, hardly any reduction in the relative levels localizing to tumors was found. Tumor-to-organ ratios were comparable to unmodified control for the majority of chemically modified copolymers, indicating that functionalization does not necessarily affect the tumor targeting ability of the copolymers and suggesting that HPMA copolymer-based drug delivery systems may prove to be attractive tools for more effectively treating various forms of advanced solid malignancy.
authors.affiliation: Department of Innovative Cancer Diagnosis and Therapy, Clinical Cooperation Unit Radiotherapeutic Oncology, German Cancer Research Center, Heidelberg. T.Lammers@dkfz.de
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.forename: Rainer
authors.initials: R
authors.lastname: Kühnlein
authors.forename: Maria
authors.initials: M
authors.lastname: Kissel
authors.forename: Vladimir
authors.initials: V
authors.lastname: Subr
authors.forename: Tomas
authors.initials: T
authors.lastname: Etrych
authors.forename: Robert
authors.initials: R
authors.lastname: Pola
authors.forename: Michal
authors.initials: M
authors.lastname: Pechar
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Peter
authors.initials: P
authors.lastname: Huber
authors.forename: Peter
authors.initials: P
authors.lastname: Peschke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008689:Methacrylates / Q000737:chemistry / Q000493:pharmacokinetics*; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D011109:Polymethacrylic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008689:Methacrylates; D009842:Oligopeptides; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide