Cyclodextrin complexation: influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent

The solubility of camptothecin (CPT), a highly potent antineoplastic agent, as a function of different concentrations of cyclodextrins (alpha-cyclodextrin, alpha-CD; beta-cyclodextrin, beta-CD; and gamma-cyclodextrin, gamma-CD; hydroxypropyl-beta-cyclodextrin, HP-beta-CD; and randomly substituted dimethyl-beta-cyclodextrin, RDM-beta-CD, and dimethyl-gamma-cyclodextrin, RDM-beta-CD) in 0.02 N HCl solution at 25degreesC was investigated. The results showed a linear increase in the solubility of CPT with increasing concentration of CDs. The apparent stability constants (K-c) for the CPT complexes with alpha-CD, beta-CD, gamma-CD, HP-beta-CD, RDM-beta-CD, and RDM-gamma-CD were 188, 266, 73, 160, 910, and 40.6 M-1, respectively, suggesting that RDM-beta-CD afforded the most stable complex. At a 25% w/v concentration of RDM-beta-CD, the solubility of CPT was 228.45+/-8.45 mug/ml, about 171 times higher than that in 0.02 N HCl. The stability of CPT in pH 7.4 buffer at 25degreesC also increased linearly with an increase in the concentration of RDM-beta-CD. The observed pseudo-first-order hydrolysis rate constants (k(obs)) for the free and complexed CPT were 11.8 X 10(-3) and 1.18 X 10(-3) min(-1), corresponding to an increase in half-life of CPT from 58.7 to 587.3 min, respectively. The preliminary cytotoxicity study against the human-derived myeloid THP-1 leukemia cell line showed RDM-beta-CD/CPT and HP-beta-CD/CPT complexes to be about two-fold more active than free CPT. In conclusion, the results showed that CDs, in general, and RDM-beta-CD, in particular, are effective complexing agents and can be used to improve the solubility and stability of CPT. The increase in cytotoxicity of CPT in the presence of CD is likely due to an increase in its stability. (C) 2002 Elsevier Science B.V. All rights reserved.