title: Synthesis and in vitro evaluation of macromolecular antitumour derivatives based on phenylenediamine mustard.
abstract: Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) and poly(ethylene glycol) (PEG)-grafted PHEG conjugates of N,N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were synthetised. A collagenase-sensitive oligopeptide spacer was selected to link the cytotoxic agent PDM onto the polymeric carrier. First, the oligopeptide-drug conjugate, L-pro-L-leu-gly-L-pro-gly-PDM, was prepared. In a second step, the low molecular weight PDM derivative and PEG-NH(2) were coupled to a N,N-disuccinimidylcarbonate activated PHEG. Dynamic laser light scattering measurements indicated the formation of aggregates. The presence of human serum albumin had no significant effect on the diameter of the conjugates. The hydrolytic stability of the conjugates was investigated in buffer solutions. The conjugates showed an improved stability compared to the parent nitrogen mustard. The enzymatic degradation studies of the polymeric conjugates were performed in the presence of collagenase type IV (Clostridiopeptidase A; EC 3.4.24.3), cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5) and tritosomes. Only the bacterial collagenase type IV was able to cleave the spacer releasing free PDM and its peptidyl derivative, gly-L-pro-gly-PDM. The in vitro cytotoxicity of the conjugates was evaluated against HT1080 fibrosarcoma cells and MDA adenocarcinoma cells. All conjugates showed low toxicity towards these cell lines.
authors.affiliation: Polymer Materials Research Group, Ghent University, Krijgslaan 281 S4-bis, 9000 Ghent, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Winne
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Seymour
authors.forename: Etienne H
authors.initials: EH
authors.lastname: Schacht
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D046911:Macromolecular Substances / Q000138:chemical synthesis / Q000493:pharmacokinetics; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D046911:Macromolecular Substances; D009588:Nitrogen Mustard Compounds; C038005:phenylenediamine mustard