Liposomal encapsulation enhances the antitumour efficacy of the vascular disrupting agent ZD6126 in murine B16.F10 melanoma

摘要: Vascular disrupting agents (VDAs) are able to affect selectively tumour endothelial cell morphology resulting in vessel occlusion and widespread necrosis. However, single-agent antitumour activity of VDAs is typically limited, as regrowth occurs rapidly following drug treatment. To improve the therapeutic effectiveness VDAs, we investigated liposomal targeting using ZD6126 a model VDA. phosphate-prodrug tubulin-binding vascular agent phenol. was encapsulated into long circulating PEG-liposomes for passive conjugated with peptide ligands containing RGD-motif active αv-integrins on cells. could be stably encapsulated, liposomes displayed minimal leakage vitro (<10% 3 weeks). In vivo, upon intravenous injection, free converted phenol, which cleared from circulation within minutes. contrast, either RGD-targeted or PEG showed prolonged blood times (t1/2=10 h), phenol exposure also (t1/2=8 h). Both formulations accumulation plus hepatosplenic uptake by local macrophages. The altered pharmacokinetics tissue distribution profiles both resulted single-dose multiple-dose regimes, improved efficacy established murine B16.F10 melanomas compared ZD6126. passively actively targeted equal efficacy, indicating that delivery may suffice disrupt vessels without need specific endothelium.