Higher liposomal membrane fluidity enhances the in vitro antitumor activity of folate-targeted liposomal mitoxantrone.

The efficacy of folate-targeted liposomal drug delivery has not been fully achieved in part because of the slow release of the encapsulated drugs following uptake of the liposomes by target cells. Since liposomal mitoxantrone (MXN) composed of lipids with high fluidity was reported to achieve strong anticancer effects in vivo, we hypothesized that folate-targeted liposomal MXN uptake via folate receptor (FR)-mediated endocytosis could effectively release drugs into the endosomal compartment. Folate-targeted liposomal MXN was prepared using two lipids with different fluidities. MXN was released slowly from all types of liposome into PBS, indicating that the cellular uptake of MXN was considered to be in the liposomal form. Folate-targeted liposomes with high fluidity exhibited lower cellular uptake of loaded FITC-labeled dextran into FR (+) KB cells, but, when MXN was loaded, higher cytotoxicity than liposomes with lower fluidity. On the other hand, the cellular uptake of non-folate liposomes was not affected by the membrane fluidity, but higher cytotoxicity was observed in liposomal MXN with high fluidity, which suggested a higher rate of release of the drug from the liposomes. High levels of cytotoxic activity were achieved with folate-targeted liposomal MXN though the cellular uptake rate was restricted by selecting liposomes with higher lipid membrane fluidity. This finding provides a new insight into folate-targeted carrier drug delivery.