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

Jichao Kang, Vijay Kumar, Dong Yang, Priyanka Roy Chowdhury, Raymond Hohl

Research output: Contribution to journalArticle

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Abstract

The solubility of camptothecin (CPT), a highly potent antineoplastic agent, as a function of different concentrations of cyclodextrins (α-cyclodextrin, α-CD; β-cyclodextrin, β-CD; and γ-cyclodextrin, γ-CD; hydroxypropyl-β-cyclodextrin, HP-β-CD; and randomly substituted dimethyl-β-cyclodextrin, RDM-β-CD, and dimethyl-γ-cyclodextrin, RDM-β-CD) in 0.02 N HCl solution at 25°C was investigated. The results showed a linear increase in the solubility of CPT with increasing concentration of CDs. The apparent stability constants (Kc) for the CPT complexes with α-CD, β-CD, γ-CD, HP-β-CD, RDM-β-CD, and RDM-γ-CD were 188, 266, 73, 160, 910, and 40.6 M-1, respectively, suggesting that RDM-β-CD afforded the most stable complex. At a 25% w/v concentration of RDM-β-CD, the solubility of CPT was 228.45±8.45 μg/ml, about 171 times higher than that in 0.02 N HCl. The stability of CPT in pH 7.4 buffer at 25°C also increased linearly with an increase in the concentration of RDM-β-CD. The observed pseudo-first-order hydrolysis rate constants (kobs) for the free and complexed CPT were 11.8×10-3 and 1.18×10-3 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-β-CD/CPT and HP-β-CD/CPT complexes to be about two-fold more active than free CPT. In conclusion, the results showed that CDs, in general, and RDM-β-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.

Original languageEnglish (US)
Pages (from-to)163-170
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume15
Issue number2
DOIs
StatePublished - Feb 27 2002

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Camptothecin
Cyclodextrins
Antineoplastic Agents
Solubility
Half-Life
Buffers
Leukemia
Hydrolysis

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

@article{333b8216ea1b4c73a34d2786193e2296,
title = "Cyclodextrin complexation: Influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent",
abstract = "The solubility of camptothecin (CPT), a highly potent antineoplastic agent, as a function of different concentrations of cyclodextrins (α-cyclodextrin, α-CD; β-cyclodextrin, β-CD; and γ-cyclodextrin, γ-CD; hydroxypropyl-β-cyclodextrin, HP-β-CD; and randomly substituted dimethyl-β-cyclodextrin, RDM-β-CD, and dimethyl-γ-cyclodextrin, RDM-β-CD) in 0.02 N HCl solution at 25°C was investigated. The results showed a linear increase in the solubility of CPT with increasing concentration of CDs. The apparent stability constants (Kc) for the CPT complexes with α-CD, β-CD, γ-CD, HP-β-CD, RDM-β-CD, and RDM-γ-CD were 188, 266, 73, 160, 910, and 40.6 M-1, respectively, suggesting that RDM-β-CD afforded the most stable complex. At a 25{\%} w/v concentration of RDM-β-CD, the solubility of CPT was 228.45±8.45 μg/ml, about 171 times higher than that in 0.02 N HCl. The stability of CPT in pH 7.4 buffer at 25°C also increased linearly with an increase in the concentration of RDM-β-CD. The observed pseudo-first-order hydrolysis rate constants (kobs) for the free and complexed CPT were 11.8×10-3 and 1.18×10-3 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-β-CD/CPT and HP-β-CD/CPT complexes to be about two-fold more active than free CPT. In conclusion, the results showed that CDs, in general, and RDM-β-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.",
author = "Jichao Kang and Vijay Kumar and Dong Yang and Chowdhury, {Priyanka Roy} and Raymond Hohl",
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Cyclodextrin complexation : Influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent. / Kang, Jichao; Kumar, Vijay; Yang, Dong; Chowdhury, Priyanka Roy; Hohl, Raymond.

In: European Journal of Pharmaceutical Sciences, Vol. 15, No. 2, 27.02.2002, p. 163-170.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cyclodextrin complexation

T2 - Influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent

AU - Kang, Jichao

AU - Kumar, Vijay

AU - Yang, Dong

AU - Chowdhury, Priyanka Roy

AU - Hohl, Raymond

PY - 2002/2/27

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N2 - The solubility of camptothecin (CPT), a highly potent antineoplastic agent, as a function of different concentrations of cyclodextrins (α-cyclodextrin, α-CD; β-cyclodextrin, β-CD; and γ-cyclodextrin, γ-CD; hydroxypropyl-β-cyclodextrin, HP-β-CD; and randomly substituted dimethyl-β-cyclodextrin, RDM-β-CD, and dimethyl-γ-cyclodextrin, RDM-β-CD) in 0.02 N HCl solution at 25°C was investigated. The results showed a linear increase in the solubility of CPT with increasing concentration of CDs. The apparent stability constants (Kc) for the CPT complexes with α-CD, β-CD, γ-CD, HP-β-CD, RDM-β-CD, and RDM-γ-CD were 188, 266, 73, 160, 910, and 40.6 M-1, respectively, suggesting that RDM-β-CD afforded the most stable complex. At a 25% w/v concentration of RDM-β-CD, the solubility of CPT was 228.45±8.45 μg/ml, about 171 times higher than that in 0.02 N HCl. The stability of CPT in pH 7.4 buffer at 25°C also increased linearly with an increase in the concentration of RDM-β-CD. The observed pseudo-first-order hydrolysis rate constants (kobs) for the free and complexed CPT were 11.8×10-3 and 1.18×10-3 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-β-CD/CPT and HP-β-CD/CPT complexes to be about two-fold more active than free CPT. In conclusion, the results showed that CDs, in general, and RDM-β-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.

AB - The solubility of camptothecin (CPT), a highly potent antineoplastic agent, as a function of different concentrations of cyclodextrins (α-cyclodextrin, α-CD; β-cyclodextrin, β-CD; and γ-cyclodextrin, γ-CD; hydroxypropyl-β-cyclodextrin, HP-β-CD; and randomly substituted dimethyl-β-cyclodextrin, RDM-β-CD, and dimethyl-γ-cyclodextrin, RDM-β-CD) in 0.02 N HCl solution at 25°C was investigated. The results showed a linear increase in the solubility of CPT with increasing concentration of CDs. The apparent stability constants (Kc) for the CPT complexes with α-CD, β-CD, γ-CD, HP-β-CD, RDM-β-CD, and RDM-γ-CD were 188, 266, 73, 160, 910, and 40.6 M-1, respectively, suggesting that RDM-β-CD afforded the most stable complex. At a 25% w/v concentration of RDM-β-CD, the solubility of CPT was 228.45±8.45 μg/ml, about 171 times higher than that in 0.02 N HCl. The stability of CPT in pH 7.4 buffer at 25°C also increased linearly with an increase in the concentration of RDM-β-CD. The observed pseudo-first-order hydrolysis rate constants (kobs) for the free and complexed CPT were 11.8×10-3 and 1.18×10-3 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-β-CD/CPT and HP-β-CD/CPT complexes to be about two-fold more active than free CPT. In conclusion, the results showed that CDs, in general, and RDM-β-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.

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