Anticancer double lipid prodrugs: liposomal preparation and characterization

Abstract

The escape of encapsulated anticancer drugs from liposomes by passive diffusion often leads to suboptimal drug concentrations in the cancer tissue, therefore calling for effective trigger mechanisms to release the drug at the target. We investigated mixtures of lipid components that not only form stable liposomes, but also can be turned into active drugs by secretory phospholipase A₂ (sPLA₂), an enzyme that is upregulated in various cancer cells, without the necessity for conventional liposome drug loading. The liposomes are composed of a novel lipid-based retinoid prodrug premixed with saturated phospholipids. The prodrug is found to be miscible with phospholipids, and the lipid mixtures are shown to form liposomes with the desired size distribution. The preparation procedure, phase behavior, and physicochemical properties of the formed liposomes are described as a function of lipid composition. We show that the premixing of the prodrug with phospholipids can be used to modify the physicochemical properties of liposomal formulations. The results should prove useful for further exploration of the potential for using these novel lipid prodrugs in liposomal formulations for cancer treatment.

Keywords::

• Secretory phospholipase A₂ (sPLA₂)
• anticancer prodrug
• triggered drug release
• lipid mixture
• NBD–dithionite interaction

Acknowledgments

Palle J. Pedersen and Prof. Mads H. Clausen (Department of Chemistry, Technical University of Denmark) are gratefully acknowledged for providing the C6-RAR compound and the prodrug.

Declaration of interest

The authors thank the Danish Council for Strategic Research (NABIIT Program) for financial support. MEMPHYS–Center for Biomembrane Physics is supported by the Danish National Research Foundation.