Correlation of the acid-sensitivity of polyethylene glycol daunorubicin conjugates with their in vitro antiproliferative activity.
Polyethylene glycol conjugates with linkers of varying acid-sensitivity were prepared by reacting five maleimide derivatives of daunorubicin containing an amide bond (1) or acid-sensitive carboxylic hydrazone bonds (2-5) with alpha-methoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 20000) or alpha,omega-bis-thiopropionic acid amide poly(ethylene glycol) (MW 20000). The polymer drug derivatives were designed to release daunorubicin inside the tumor cell by acid-cleavage of the hydrazone bond after uptake of the conjugate by endocytosis. In subsequent cell culture experiments, the order of antitumor activity of the PEG daunorubicin conjugates correlated with their acid-sensitivity as determined by HPLC (cell lines: BXF T24 bladder carcinoma and LXFL 529L lung cancer cell line; assay: propidium iodide fluorescence assay). The acid-sensitivity of the link between PEG and daunorubicin is therefore an important parameter for in vitro efficacy.
Tumor Biology Center, Department of Medical Oncology, Clinical Research, Breisacher Strasse 117, D-79106 Freiburg, Germany.
Paula C A
PC
Rodrigues
Thomas
T
Roth
Heinz H
HH
Fiebig
Clemens
C
Unger
Rolf
R
Mülhaupt
Felix
F
Kratz
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008968:Molecular Conformation; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D003630:Daunorubicin