Abstract
In order to provide a new macromolecular prodrug of cisplatin (CDDP, antitumor platinum complex) having high water-solubility, reduced side-effects and excellent antitumor activity, poly(ethylene glycol) (PEG) derivative having terminal dicarboxylic acid group was coupled with CDDP through chelate-type coordination bonds to give conjugates of monomethoxy-poly(ethylene glycol) and CDDP (MPEG-DA/CDDP conjugates). The in vitro release behavior of platinum complex from the MPEG-DA/CDDP conjugate having various length of PEG was investigated and compared with the control conjugate having non-chelate-type coordination bonds. Sustained release was observed for the MPEG-DA/CDDP conjugate having the longest PEG chain. The in vitro cytotoxic activity of the conjugates was investigated against p388D1 lymphocytic leukemia cells. The MPEG-DA/CDDP conjugate showed slightly lower cytotoxic activity than free CDDP. Although the cytotoxic activity of free CDDP and control conjugate was decreased by incubation in medium with serum, the MPEG-DA/CDDP conjugate kept their cytotoxic activity in higher level after incubation in medium with serum. The stability of the cytotoxic activity was dependent on molecular weight of PEG. These results suggest that the stability of CDDP moiety against serum proteins in the medium was increased by excluded volume effect of PEG chain and fixation through stable chelate-type coordination bonds. The MPEG-DA/CDDP conjugate thus has potential as macromolecular prodrug of CDDP with higher solubility and stability in blood for tumor treatment. Copyright © 2000 John Wiley & Sons, Ltd.
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