LECTIN-MEDIATED DRUG TARGETING - PREPARATION, BINDING CHARACTERISTICS, AND ANTIPROLIFERATIVE ACTIVITY OF WHEAT-GERM-AGGLUTININ CONJUGATED DOXORUBICIN ON CACO-2 CELLS

Purpose. To investigate the usefulness of wheat germ agglutinin as a t argeting carrier protein for an acid-labile chemotherapeutic prodrug d irected against colon carcinoma cells in vitro. Methods. Cis-aconityl- linked doxorubicin-wheat germ agglutinin was prepared by a two step pr ocedure and the conjugate-binding capacity of target-and non-target ce lls was assayed by flow cytometry. The antiproliferative activity of t he prodrug on Caco-2 and MOLT-4 cells was determined by the XTT- and B rdU-test and compared with that of the parent drug and the lectin alon e. Results. At pH 4.0, about 50% of the conjugated doxorubicin were re leased within 24 h from the water soluble prodrug exhibiting a conjuga tion number of 24 (mol doxorubicin/mol WGA). The prodrug-binding capac ity of colon carcinoma cells exceeded that of human colonocytes and ly mphoblastic MOLT-4 cells 4.5-fold. Additionally, the antiproliferative effect of the conjugate on Caco-2 cells was 39% as opposed to 5% in c ase of MOLT-4 cells. As the unmodified carrier protein inhibited or st imulated Caco-2 cell growth in a concentration-dependent manner, the c ytostatic activity of the conjugate was determined at WGA concentratio ns without an effect on cell-proliferation. Considering 50% release of conjugated drug at the most, the prodrug yielded 160% of the cytostat ic activity of free doxorubicin. Conclusions. WGA-prodrug targeting of fers new perspectives For site-specific, cytoinvading drug delivery in colon cancer chemotherapy.