EVALUATION OF METHODS FOR COMPLEXING PREDNIMUSTINE TO LOW-DENSITY-LIPOPROTEIN

Many cancer cells express a higher receptor-mediated uptake of low-density lipoprotein (LDL) than normal cells. LDL has been proposed as a carrier for anticancer agents in order to improve the selectivity of cancer chemotherapeutics. In this study two reassembly and one transfer method for preparation of prednimustine-LDL complex were evaluated. All three methods gave stable complexes between drug and lipoprotein, but only the reassembly methods gave satisfactory incorporation of drug. The binding, uptake, and metabolism of the drug-LDL conjugates by T-47D breast cancer cells and GM 2000 LDL-receptor negative fibroblasts showed similar values for all three types of complexes and native LDL Native LDL was able to compete for the cellular uptake of I-125-labelled drug-LDL complexes as well as for the I-125-labelled native LDL, strongly suggesting a LDL-receptor mediated uptake. The cytotoxicity of the complexes prepared by the reassembly methods was tested on cultured T-47D cells. The preparations showed high and similar activities with ID50 values near 2 mug/ml while the free drug gave a value of 5.1 mug/ml under the same incubation conditions. The results are discussed in terms of important factors for the successful conjugation of drugs with LDL.