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Synergistic Suppression of Tumor Angiogenesis by the Co-delivering of Vascular Endothelial Growth Factor Targeted siRNA and Candesartan Mediated by Functionalized Carbon Nanovectors

Xuefang Ding,Yujie Su,Cheng Wang,Fangrong Zhang,Kerong Chen,Yu Wang,Min Li,Wei Wang

Single-walled carbon nanotubes (SWNTs) with unique physicochemical properties have exhibited promising biomedical applications as drug and gene carriers. In this study, polyethylenimine (PEI)-modified SWNT conjugates linked with candesartan (CD) were developed to deliver vascular endothelial growth factor (VEGF)-targeted siRNA (siVEGF) for the synergistic and targeted treatment of tumor angiogenesis. The characterization results revealed that SWNT–PEI–CD conjugates were successfully synthesized and exhibited desirable dispersibility and superior stability. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that SWNT–PEI–CD/siVEGF complexes could achieve high cellular uptake and specific intracellular distribution of siRNA in AT1R overexpressed PANC-1 cells. Strong down-regulation of VEGF was also verified by qualitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot in complex-treated PANC-1 cells. The in vitro angiogenesis assay showed that SWNT–PEI–CD/siVEGF complexes highly inhibited tube formation of human umbilical vein endothelial cells. Furthermore, in vivo observation in PANC-1 xenografted nude mice demonstrated that SWNT–PEI–CD/siVEGF complexes exhibited significant distribution at tumor sites and caused obvious inhibition of tumor growth and tumor-associated angiogenesis repression induced by the drug combination of CD and siVEGF. Finally, a WST-1 assay indicated that SWNT–PEI–CD possessed low cytotoxicity, and a hemolysis test showed good biocompatibility of SWNT–PEI–CD. Hematological and histological analyses confirmed that SWNT–PEI–CD/siVEGF complexes did not cause any obvious toxic effects to blood and major organs. These findings suggested that the SWNT–PEI–CD/siVEGF co-delivery system with tumor-targeting specificity, improved endosomal escaping properties, and collaboration of angiogenesis inhibition could be a prospective method for efficient tumor antiangiogenic therapy.