Synthesis and biological characterization of a VEGFR targeting liposomal drug in a tumor-bearing animal model

1336 Objectives VEGF dependent signal transduction pathways have been demonstrated as important targets for anti-angiogenesis therapy in cancer treatment. This study developed a VEGFR-targeted doxorubicin-encapsulated liposomal drug (VEGF-LipoDox) and performed the biological characterizations in mice bearing human epithelial carcinoma A431 xenograft. Methods His6-tagged recombinant human VEGF was expressed in yeast, purified, characterized, and conjugated to the native liposomal doxorubicin (LipoDox) to give VEGF-LipoDox (19.5 μg VEGF/μmole lipid). Both liposomes were labeled with 111In in high radiochemical purities (both > 98%). In vitro cellular uptake in BAEC cells (a bovine aortic endothelial cell) and In vivo pharmacokinetics studies and animal SPECT/CT imaging of A431 tumor-bearing mice after intravenous administration of 111In-LipoDox and 111In-VEGF-LipoDox were performed. Results The uptake of VEGF-LipoDox in BAEC cells was 8-folds higher than that of LipoDox after a 24-h incubation. The uptakes of 111In-VEGF-LipoDox in hematopoietic tissues (e.g., spleen and bone marrow) of A431 tumor-bearing mice were higher than those of 111In-LipoDox at 48 h p.i., while the liver uptakes were similar. The more rapid blood clearance of VEGF-LipoDox (1.91 mL/h) compared with LipoDox (0.18 mL/h) may account for the lower radioactivity accumulation in tumor and the less tumor-to-muscle ratio post injection of VEGF-LipoDox in A431 tumor mice. The results were consistent with the findings in animal SPECT/CT imaging. Conclusions The results of this study suggested that, though VEGF conjugation may promote the in vitro cellular uptake in VEGF receptor-expression cells, it may also enhance the excretion of VEGF-conjugated liposomes by hematopoietic tissues.