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

Abstract

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 ATR 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.

Topical Triamcinolone Acetonide-Loaded Liposomes as Primary Therapy for Macular Edema Secondary to Branch Retinal Vein Occlusion: A Pilot Study

“…Interestingly, these groups of drugs have been related to VEGF-A downregulation (the main cytokine involved in the pathophysiology of ME secondary to BRVO). Although candesartan reduced the expression of VEGF-A and its intracellular signaling, 75,76 and limits VEGF receptor-2 expression, 77 the evidence was collected in cell cultures or in animal models using high doses and parenteral administration. Nonselective beta blockers, such as propranolol, have been reported to inhibit retinal neovascularization and reducing VEGF expression in oxygen-induced retinopathy of premature animal models 78,79 ; however, these findings have not been consistent.…”

Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect via Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment

“…Targeted angiogenesis therapy through blocking the VEGF signaling pathway has shown considerable promise in advanced NSCLC treatment 13. VEGF small interference RNA (siRNA) can precisely and efficiently silence VEGF expression and block VEGF signal pathway, leading to a significant decrease in tumor blood vessels and suppression of tumor growth and metastasis 14-16. However, siRNA with an inherent negative charge, high hydrophilicity and macromolecular size, is susceptible to ribonuclease (RNase) degradation and suffers from poor stability and low targeted tumor accumulation during the delivery process 17.…”

Targeted delivery of HES5-siRNA with novel polypeptide-modified nanoparticles for hepatocellular carcinoma therapy

“…The cell cycle distribution of the HepG2 cells aer treatment with different formulations of siRNA for 24 h was analyzed by ow cytometry. 28 As shown in Fig. 5A, obviously reduced populations at the S and G2/M phases were detected, and meanwhile a prominent cell cycle arrest at G0/G1 phase occurred aer the cells were incubated with siRNA in different formulations.…”