Developing drugs for treating glioblastoma has been a significant challenge. Herein, a series of arene ruthenium(II) complexes have been synthesized and investigated as potential candidates to suppress the proliferation and metastasis of glioblastoma. It is found that para-substituent-modified molecules, especially 6, exhibit higher antitumor activity than ortho-substituents. Further studies show that 6 can trigger tumor cell autophagy by regulating the PI3K/AKT/mTOR pathway. Moreover, it is also found that 6 can induce DNA damage in glioblastoma cells through binding and stabilizing VEGF G-quadruplex DNA. Furthermore, it is confirmed that 6 can inhibit the proliferation and metastasis of U87-MG glioblastoma cell in situ xenograft in the zebrafish model. Hence, arene ruthenium(II) complexes can be developed as promising therapeutic agents for glioblastoma treatment in the future.
Meng Zhang,Yumei Wang,Jiayi Wang,Jiayi Zuo,Feng Jiang,Feng Cao
Neovascular ocular diseases are a leading cause of irreversible vision loss. Although intravitreal anti-VEGF therapy is the standard treatment, its invasive delivery and limited efficacy in some patients emphasize the need for non-invasive strategies targeting multiple angiogenic pathways. In this study, we developed a novel hybrid nanoplatform for the non-invasive co-delivery of axitinib (Axi) and telmisartan (Tel) to synergistically inhibit both VEGF and Ang-2 signaling pathways. Poorly soluble drugs were incorporated into layered double hydroxides (LDHs) via a micelle-assisted intercalation strategy and subsequently modified with hyaluronic acid (HA) conjugated to Gly-Val-Sar (GVS), a novel PepT1-targeted tripeptide. The Zn-containing LDH provided controlled drug release, and exhibited anti-inflammatory properties. HA modification prolonged ocular retention, and GVS enhanced transmembrane transport. The resulting Axi/Tel-D@LDH-HA-GVS nanocomposites demonstrated favorable physicochemical properties, efficient uptake by human conjunctival and retinal pigment epithelial cells, and potent inhibition of hypoxia-induced angiogenesis in vitro. In vivo, the formulations exhibited prolonged ocular retention, effective posterior tissue distribution, and good biosafety. In a diabetic retinopathy model, Axi/Tel-D@LDH-HA-GVS nanocomposites restored retinal structure and markedly reduced the expression of VEGF, Ang-2, TNF-α, and IL-6. Collectively, this study provides a promising non-invasive and synergistic strategy for targeted treatment of ocular neovascular diseases.
Background Angiogenesis and inflammation exhibit a mutually reinforcing relationship in many human diseases. Vascular endothelial growth factor (VEGF) is one of the most important proangiogenic mediators. Conbercept is a novel VEGF inhibitor.Method Type II collagen-induced rat rheumatoid arthritis (CIA) model was established to evaluate the anti-chronic inflammation activities of Conbercept. ELISA was used to measure the concentrations of immune factors in the blood of arthritis rats. The xylene-induced ear edema was conducted to evaluate the effect of Conbercept on acute inflammation.Result and discussion Our results showed that Conbercept significantly reduced the paw edema volume and the arthritis index in CIA rats. Furthermore, we found that Conbercept decreased the serum levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in CIA rats. Xylene-induced ear edema is a widely used method to study acute inflammation. Conbercept significantly inhibited xylene-induced ear edema.Conclusion All results indicate that Conbercept exhibits significant inhibition of acute and chronic inflammation.
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