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Kaneo, Yoshiharu; Tanaka, Tetsuro; Higashi, Kazuto; Furutani, Yoshitsugu
Drug Delivery System, 1997/09/10, Letnik: 12, Številka: 5Journal Article
Transferrin receptor (TFR) levels in proliferating malignant cells have often been found to be far higher than in the corresponding normal cells. Cisplatin(cis-diamminedichloroplatinum (II) : CDDP) was complexed via an intermediate carboxymethyl dextran (CMD) to transferrin (TF) which recognizes TFR on the cell surface. CMD was first conjugated to TF by a modified water-soluble carbodiimide method in which N-hydroxysuccinimide was used to enhance the coupling reaction. Conjugates of TF and CMD of differing molar ratios (TF/CMD 1 : 0.4, 1 : 1.4 and 1 : 1.6) were prepared by this method. Spectrophotometric titration of the conjugates with Fe3+ showed that the ferric ion binding activity of apo-TF-CMD was reduced as the molar ratio of CMD to TF increased. CDDP was complexed to the TF-CMD resulting in complexes (TF-CMD-CDDP) carrying up to 8 w/w % of the drug which was reversibly released from the carrier conjugate. Diferric-TF-CMD-CDDP consisted of 0.4 mol of CMD per 1 mol of TF and 3.6 w/w % of CDDP retained cytotoxic activity against human leukemia cell lines, HL60 and K562. The LD50 values of the diferric-TF-CMD-CDDP and CMD-CDDP were 21.0 μM and 29.5 μM in HL60, and were 40.0 μM and 62.0 μM in K562, respectively, suggesting that the specific complex showed preferential cytotoxicity for the tumor cells in comparison to the nonspecific CMD-CDDP.
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