查找使用阿拉丁产品的科研文献

Co-delivery of p53 and MDM2 inhibitor RG7388 using a hydroxyl terminal PAMAM dendrimer derivative for synergistic cancer therapy

Kang Chen,Xiu Xin,Lipeng Qiu,Wenpan Li,Guannan Guan,Gang Li,Mingxi Qiao,Xiuli Zhao,Haiyang Hu,Dawei Chen

P53 inactivation is often achieved through gene mutation and the excessive activity of its major negative regulator, murine double minute 2 protein (MDM2). In the present study we utilized a PAMAM-OH derivative (PAMSPF) to co-deliver p53 plasmid and MDM2 inhibitor (RG7388) to the tumor site and evaluated the synergistic anti-tumor effect of p53 plasmid and RG7388. PAMSPF was able to condense DNA and encapsulate RG7388 to form spherical nanoparticles (PAMSPF/p53/RG) with particle sizes of around 200 nm, and remain stable in the presence of heparin and nuclease . The drug loading capacity and encapsulation efficiency of RG7388 in PAMSPF/p53/RG were 0.5% and 92.5%, respectively. The p53 expressions in MDA-MB-435, p53-wild type MCF-7 cells (MCF-7/WT) and p53-silenced MCF-7 cells (MCF-7/S) treated with PAMSPF/p53/RG were promoted significantly. As a result, PAMSPF/p53/RG was able to inhibit cell proliferation , arrest cell cycle , and induce cell apoptosis of MDA-MB-435, MCF-7/WT and MCF-7/S cells. PAMSPF/p53/RG suppressed human umbilical vascular endothelial cells (HUVECs) migration, invasion and tube formation through decreasing the VEGF expression. And the biological activities described above of PAMSPF/p53/RG were significantly higher than those of PAMSPF/53 and PAMSPF/RG, exhibiting the synergistic actions of p53 plasmid and RG7388. In addition, intravenous administration of PAMPSF/p53/RG inhibited tumor growth of MDA-MB-435 and MCF-7/WT xenograft mice models, and induced no substantial weight loss. PAMSPF/p53/RG also reduced cell proliferation, and induced cell apoptosis in vivo based on the immunohistochemistry results. Collectively, PAMSPF/p53/RG is an excellent system for gene and drug co-delivery, and the combined treatment of p53 plasmid and RG7388 possesses a synergistic antitumor activity both in vitro and in vivo . Statement of significance In the present study we utilized a PAMAM-OH derivative (PAMSPF) to co-deliver p53 plasmid and RG7388 (MDM2 inhibitor) and evaluated their synergistic anti-tumor effect. PAMSPF could condense p53 plasmid and encapsulate RG7388 to form nanoparticles (PAMSPF/p53/RG). The p53 expressions in MDA-MB-435, p53-wild type MCF-7 cells (MCF-7/WT) and p53-silenced MCF-7 cells (MCF-7/S) treated with PAMSPF/p53/RG were promoted significantly. As a result, PAMSPF/p53/RG could inhibit cell proliferation, arrest cell cycle, and induce cell apoptosis of three kinds of cells. In addition, intravenous administration of PAMPSF/p53/RG inhibited tumor growth of MDA-MB-435 and MCF-7/WT xenograft mice models. Collectively, PAMSPF/p53/RG is an excellent system for gene and drug co-delivery, and the combined treatment of p53 plasmid and RG7388 possesses a synergistic antitumor activity.