PREPARATION, CHARACTERIZATION AND PROPERTIES IN-VITRO AND IN-VIVO OF A PACLITAXEL-ALBUMIN CONJUGATE

Paclitaxel (taxol) is in routine clinical use for treatment of a varie ty of cancers. Because of its low aqueous solubility, it requires Crem ophur EL (polyethoxylated castor oil) and ethanol as a vehicle (Diluen t 12). These agents cause severe allergic reactions upon intravenous a dministration. In this study paclitaxel was covalently attached to hum an serum albumin. The 2'-hydroxyl group of the drug was esterefied wit h succinic anhydride and then derivatized to give the N-hydroxy-3-sulf osuccinimide active ester, highly reactive to lysyl amino groups of th e protein, Two different conjugate populations (with 6 or 30 average m olecules of drug linked to each albumin molecule) were prepared, purif ied and characterized. The conjugates were stable in physiological sol ution and in serum whereas the presence of proteases or liver extract released the drug in a linear fashion. The antitumor activity of free drug and conjugates was tested on three different tumor cell lines. Th e conjugates maintained high cytotoxicity with efficient cell binding and internalization followed by release of the drug inside the cell. T he pharmacokinetics of the conjugate (after iv administration) was eva luated and compared to that of the free drug, Both followed a bicompar tmental model but elimination of the conjugate from the plasma was muc h slower than the free drug, giving a relevant rise in AUC and MRT val ues. The conjugate also released of parent drug continuously to the pl asma over prolonged periods, thus providing a depot effect. The acute toxicity noted with the standard formulation of taxol was strongly red uced in our albumin-conjugated preparation. (C) 1997 Elsevier Science Ireland Ltd.