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.
Katanasaka
Y
Y
Department of Medical Biochemistry, School of Pharmaceutical Sciences and Global COE, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Ida
T
T
Asai
T
T
Maeda
N
N
Oku
N
N
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis
D020533:Angiogenesis Inhibitors; D002934:Cinnamates; D008081:Liposomes; C483044:SU 1498; D040262:Receptors, Vascular Endothelial Growth Factor