Paclitaxel (taxol) is in routine clinical use for treatment of a variety of cancers. Because of its low aqueous solubility, it requires Cremophur EL (polyethoxylated castor oil) and ethanol as a vehicle (Diluent 12). These agents cause severe allergic reactions upon intravenous administration. In this study paclitaxel was covalently attached to human serum albumin. The 2'-hydroxyl group of the drug was esterefied with succinic anhydride and then derivatized to give the N-hydroxy-3-sulfosuccinimide active ester, highly reactive to lysyl amino groups of the protein, Two different conjugate populations (with 6 or 30 average molecules of drug linked to each albumin molecule) were prepared, purified and characterized. The conjugates were stable in physiological solution 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. The conjugates maintained high cytotoxicity with efficient cell binding and internalization followed by release of the drug inside the cell. The pharmacokinetics of the conjugate (after iv administration) was evaluated and compared to that of the free drug, Both followed a bicompartmental model but elimination of the conjugate from the plasma was much slower than the free drug, giving a relevant rise in AUC and MRT values. The conjugate also released of parent drug continuously to the plasma over prolonged periods, thus providing a depot effect. The acute toxicity noted with the standard formulation of taxol was strongly reduced in our albumin-conjugated preparation. (
Preparation, characterization and properties in vitro and in vivo of a paclitaxel-albumin conjugate
DOSIO, Franco;BRUSA, Paola;ARPICCO, Silvia Maria;CATTEL, Luigi
1997-01-01
Abstract
Paclitaxel (taxol) is in routine clinical use for treatment of a variety of cancers. Because of its low aqueous solubility, it requires Cremophur EL (polyethoxylated castor oil) and ethanol as a vehicle (Diluent 12). These agents cause severe allergic reactions upon intravenous administration. In this study paclitaxel was covalently attached to human serum albumin. The 2'-hydroxyl group of the drug was esterefied with succinic anhydride and then derivatized to give the N-hydroxy-3-sulfosuccinimide active ester, highly reactive to lysyl amino groups of the protein, Two different conjugate populations (with 6 or 30 average molecules of drug linked to each albumin molecule) were prepared, purified and characterized. The conjugates were stable in physiological solution 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. The conjugates maintained high cytotoxicity with efficient cell binding and internalization followed by release of the drug inside the cell. The pharmacokinetics of the conjugate (after iv administration) was evaluated and compared to that of the free drug, Both followed a bicompartmental model but elimination of the conjugate from the plasma was much slower than the free drug, giving a relevant rise in AUC and MRT values. The conjugate also released of parent drug continuously to the plasma over prolonged periods, thus providing a depot effect. The acute toxicity noted with the standard formulation of taxol was strongly reduced in our albumin-conjugated preparation. (
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