Monajati Maryam, Tavakoli Shirin, Abolmaali Samira Sadat, Yousefi Gholamhossein, Tamaddon AliMohammad
Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71345, Iran.
Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Bioimpacts. 2018;8(4):241-252. doi: 10.15171/bi.2018.27. Epub 2018 Apr 18.
Sorafenib (SFB) is an FDA-approved chemotherapeutic agent with a high partition coefficient (log P = 4.34) for monotherapy of hepatocellular carcinoma (HCC). The oral bioavailability is low and variable, so it was aimed to study the application of the polymeric nanoassembly of cholesterol conjugates of branched polyethyleneimine (PEI) for micellar solubilization of SFB and to investigate the impact of the polymer PEGylation on the physicochemical and cellular characteristics of the lipopolymeric dispersions. Successful synthesis of cholesterol-PEI lipopolymers, either native or PEGylated, was confirmed by FTIR, H-NMR, pyrene assay methods. The nanoassemblies were also characterized in terms of morphology, particle size distribution and zeta-potential by TEM and dynamic light scattering (DLS). The SFB loading was optimized using general factorial design. Finally, the effect of particle characteristics on cellular uptake and specific cytotoxicity was investigated by flow cytometry and MTT assay in HepG2 cells. Transmission electron microscopy (TEM) showed that PEGylation of the lipopolymers reduces the size and changes the morphology of the nanoassembly from rod-like to spherical shape. However, PEGylation of the lipopolymer increased critical micelle concentration (CMC) and reduced the drug loading. Moreover, the particle shape changes from large rods to small spheres promoted the cellular uptake and SFB-related cytotoxicity. The combinatory effects of enhanced cellular uptake and reduced general cytotoxicity can present PEGylated PEI-cholesterol conjugates as a potential carrier for delivery of poorly soluble chemotherapeutic agents such as SFB in HCC that certainly requires further investigations and .
索拉非尼（SFB）是一种经美国食品药品监督管理局（FDA）批准的化疗药物，具有较高的分配系数（log P = 4.34），用于肝细胞癌（HCC）的单药治疗。其口服生物利用度低且变化较大，因此旨在研究支链聚乙烯亚胺（PEI）胆固醇共轭物的聚合物纳米组装体对SFB的胶束增溶作用，并研究聚合物聚乙二醇化对脂聚合物分散体的物理化学和细胞特性的影响。通过傅里叶变换红外光谱（FTIR）、氢核磁共振（H-NMR）、芘测定法证实了天然或聚乙二醇化的胆固醇-PEI脂聚合物的成功合成。还通过透射电子显微镜（TEM）和动态光散射（DLS）对纳米组装体的形态、粒径分布和zeta电位进行了表征。使用通用析因设计优化了SFB的负载量。最后，通过流式细胞术和MTT法在HepG2细胞中研究了颗粒特性对细胞摄取和特异性细胞毒性的影响。透射电子显微镜（TEM）显示，脂聚合物的聚乙二醇化减小了尺寸，并使纳米组装体的形态从棒状变为球形。然而，脂聚合物的聚乙二醇化增加了临界胶束浓度（CMC）并降低了药物负载量。此外，颗粒形状从大棒状变为小球形促进了细胞摄取和与SFB相关的细胞毒性。增强细胞摄取和降低一般细胞毒性的联合作用可使聚乙二醇化的PEI-胆固醇共轭物成为在HCC中递送难溶性化疗药物（如SFB）的潜在载体，这当然需要进一步研究。
