Pharmacokinetics and pharmacodynamics of chlorambucil delivered in long-circulating nanoemulsion

Abstract

Chlorambucil was incorporated into a nanoemulsion modified with poly(ethylene glycol) to improve its pharmacokinetics and tissue distribution, and thus enhance its therapeutic efficacy. A long-circulating nanoemulsion (LNE) was prepared using soybean oil, egg lecithin, cholesterol and PEG₂₀₀₀DSPE. The LNE had an oil droplet size <200 nm with a surface charge of −32.2 to −35.6 mV. Approximately, 97% of the chlorambucil was encapsulated in the LNE. Intravenous (i.v.) administration of the chlorambucil LNE to C57 B/6 mice showed improved pharmacokinetic parameters with 1.4-fold higher area under the plasma concentration–time curve (AUC) and 1.3-fold longer half-life compared to a non-PEG-modified nanoemulsion, and 2.7-fold higher AUC and 7.6-fold longer half-life compared to chlorambucil solution. Tissue distribution studies after i.v. administration with LNE showed a considerable decrease in drug uptake in the reticulo-endothelial system containing organs compared to non-PEG-modified nanoemulsion. Additionally, the chlorambucil delivered in LNE significantly enhanced therapeutic efficacy in the subcutaneous colon-38 adenocarcinoma tumor mouse model with no apparent increase in toxicity. This study suggests that LNE could produce remarkably improved pharmacokinetic profile and therapeutic efficacy of chlorambucil compared to non-PEG-modified nanoemulsion and solution.

Keywords::

• Chlorambucil
• nanoemulsion
• PEG-DSPE
• pharmacokinetics
• antitumor activity
• colon-38 adenocarcinoma

Acknowledgments

This work was supported by a UniServices Drug Delivery Grant, The University of Auckland, New Zealand.

Declaration of interest: The author reports no conflicts of interest.