Effective delivery of an angiogenesis inhibitor by neovessel-targeted liposomes.

Angiogenesis is critical for tumor growth and metastasis, and several angiogenesis inhibitors have been developed for the treatment of cancer. Previously, we identified angiogenic vessel-homing peptide, Ala-Pro-Arg-Pro-Gly (APRPG), by use of a phage-displayed peptide library. APRPG peptide-modified liposomes have been revealed to be useful for the delivery of encapsulated drugs to angiogenic vasculature in tumor-bearing animals. In the present study, to assess the usefulness of APRPG-PEG-modified liposomes as a carrier of angiogenesis inhibitors in vitro and in vivo, we designed and validated APRPG-PEG-modified liposomal angiogenesis inhibitor. SU1498, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, was successfully encapsulated into the liposomes. APRPG-PEG-modified liposomal SU1498 inhibited VEGF-stimulated endothelial cell proliferation in vitro. Moreover, APRPG-PEG-modified liposomal SU1498 significantly decreased tumor microvessel density in Colon26 NL-17 cell-bearing mice and prolonged the survival time of the mice. These findings suggest that APRPG-PEG-modified liposomes effectively deliver SU1498 to angiogenic endothelial cells in tumors and thus inhibit tumor-induced angiogenesis.