Self-anti-angiogenesis nanoparticles enhance anti-metastatic-tumor efficacy of chemotherapeutics

Beyond traditional endothelium-dependent vessel(EDV),vascular mimicry(VM)is another critical tumor angiogenesis that further forms in many malignant metastatic tumors.However,the existing anti-angiogenesis combined chemotherapeutics strategies are only efficient for the treatment of EDV-based subcutaneous tumors,but remain a great challenge for the treatment of in situ malignant metastatic tumor associated with EDV and VM.Here,we demonstrate a self-assembled nanoparticle(VE-DDP-Pro)featuring self-anti-EDV and-VM capacity enables to significantly enhance the treatment efficacy of cisplatin(DDP)against the growth and metastasis of ovarian cancer.The VE-DDP-Pro is constructed by patching DDP loaded cRGD-folate-heparin nanoparticles(VE)onto the surface of protamine(Pro)nanoparticle.We demonstrated the self-anti-angiogenesis capacity of VE-DDP-Pro was attributed to VE,which could significantly inhibit the formation of EDV and VM by regulating signaling pathway of MMP-2/VEGF,AKT/mTOR/MMP-2/Laminin and AKT/mTOR/EMT,facilitating chemotherapeutics to effectively suppress the development and metastasis of ovarian cancer.Thus,combing with the chemotherapeutics effectiveness of DDP,the VE-DDP-Pro can significantly enhance treatment efficacy and prolong median survival of mice with metastatic ovarian cancer.We believe our self-assembled nanoparticles integrating the anti-EDV and anti-VM capacity provide a new preclinical sight to enhance the efficacy of chemotherapeutics for the treatment malignant metastasis tumor.