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Identification of endogenous angiogenesis inhibitors has led to development of an increasingly attractive strategy for cancer therapy and other angiogenesis-driven diseases. Vascular endothelial growth inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis inhibitor, has been intensively studied, and this work shed new light on developing promising anti-angiogenic strategies. It is well-documented that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to integrin α(v)β(3), which is abundantly expressed in cancer cells and specifically associated with angiogenesis on tumors. Here, we designed a fusion protein containing the special RGD-4C motif sequence and VEGI-192, aimed at offering more effective multiple targeting to tumor cells and tumor vasculature, and higher anti-angiogenic and antitumor efficacy. Functional tests demonstrated that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192) potently inhibited endothelial growth in vitro and suppressed neovascularization in chicken chorioallantoic membrane in vivo, to a higher degree as compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192, but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast tumor cells, significantly inhibiting growth of MDA-MB-435 cells in vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8 as well as caspase-3, which was mediated by activating the JNK signaling associated with upregulation of pro-apoptotic protein Puma, and consequently led to the observed significant antitumor effect in vivo against a human breast cancer xenograft. Our study indicated that the RGD-VEGI-192 fusion protein might represent a novel anti-angiogenic and antitumor strategy.

The enhancement of DNA affinity of small molecules usually ensures their high nuclease activities, and may also open a new scope of their applications in biology and medicine. In this work, we demonstrate that the nuclease activity and cytotoxicity of the small DNA intercalators can be dramatically enhanced by single atomic-layered graphene oxide (GO) sheets. Through π–π stacking interaction mainly between GO and the aromatic ligands of intercalators, the conjugates of GO and a small intercalator could be formed. Because of the large planar structure of the GO sheets, the coupling of GO with the small intercalators increased their affinity to DNA. Owing to the formation of conjugates with GO, the binding site of small intercalators to DNA was also changed from a minor groove to a major groove. Notably, GO and small intercalator conjugates exhibited higher cytotoxicity than that of the small intercalator alone. The results open up potential applications of GO for new chemotherapeutic agents that work through DNA intercalation.

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