Vascular disrupting agents (VDAs) are able to affect selectively tumour endothelial cell morphology resulting in vessel occlusion and widespread tumour cell
necrosis. However, single-agent antitumour activity of VDAs is typically limited, as tumour regrowth occurs rapidly following
drug treatment. To improve the therapeutic effectiveness of VDAs, we investigated liposomal targeting using
ZD6126 as a model VDA.
ZD6126 is a
phosphate-
prodrug of the
tubulin-binding vascular disrupting agent
ZD6126 phenol.
ZD6126 was encapsulated into long circulating PEG-
liposomes for passive targeting and PEG-
liposomes conjugated with
peptide ligands containing the RGD-motif for active targeting to alpha(v)-
integrins on tumour endothelial cells.
ZD6126 could be stably encapsulated, and
liposomes displayed minimal leakage in vitro (<10% in 3 weeks). In vivo, upon
intravenous injection, free
ZD6126 was rapidly converted into
ZD6126 phenol, which was cleared from the circulation within minutes. In contrast,
ZD6126 encapsulated into either RGD-targeted or PEG
liposomes showed prolonged blood circulation times (t(1/2)=10 h), and
ZD6126 phenol exposure was also prolonged (t(1/2)=8 h). Both liposomal formulations displayed tumour accumulation plus hepatosplenic uptake by local macrophages. The altered pharmacokinetics and tissue distribution profiles of both liposomal
ZD6126 formulations resulted both in single-dose and multiple-dose regimes, in improved therapeutic efficacy in established murine B16.F10
melanomas compared with free
ZD6126. The passively and actively targeted
liposomes showed equal antitumour efficacy, indicating that delivery of
ZD6126 to the tumour tissue may suffice to disrupt tumour blood vessels without the need for specific targeting to the tumour endothelium.