MINT, UNIV Angers, INSERM 1066, CNRS 6021, Angers, France.
Nanoscale. 2018 Jul 19;10(28):13485-13501. doi: 10.1039/c8nr02132e.
Increasing intracellular drug concentration using nanocarriers can be a potential strategy to improve efficacy against glioblastoma (GBM). Here, the fluorescent-labelled NFL-TBS·40-63 peptide (fluoNFL) concentration on a lipid nanocapsule (LNC) was studied to enhance nanovector internalization into human GBM cells. LNC surface-functionalization with various fluoNFL concentrations was performed by adsorption. LNC size and surface charge altered gradually with increasing peptide concentration, but their complement protein consumption remained low. Desorption of fluoNFL from the LNC surface was found to be slow. Furthermore, it was observed that the rate and extent of LNC internalization in the U87MG human glioblastoma cells were dependent on the surface-functionalizing fluoNFL concentration. In addition, we showed that the uptake of fluoNFL-functionalized LNCs was preferential towards U87MG cells compared to healthy human astrocytes. The fluoNFL-functionalized LNC internalization into the U87MG cells was energy-dependent and occurred possibly by macropinocytosis and clathrin-mediated and caveolin-mediated endocytosis. A new ferrocifen-type molecule (FcTriOH), as a potent anticancer candidate, was then encapsulated in the LNCs and the functionalization improved its in vitro efficacy compared to other tested formulations against U87MG cells. In the preliminary study, on subcutaneous human GBM tumor model in nude mice, a significant reduction of relative tumor volume was observed at one week after the second intravenous injection with FcTriOH-loaded LNCs. These results showed that enhancing NFL peptide concentration on the LNC surface is a promising approach for increased and preferential nanocarrier internalization into human GBM cells, and the FcTriOH-loaded LNCs are a promising therapy approach for GBM.
使用纳米载体增加细胞内药物浓度可能是提高胶质母细胞瘤（GBM）疗效的一种潜在策略。在这里，研究了荧光标记的 NFL-TBS·40-63 肽（fluoNFL）在脂质纳米胶囊（LNC）上的浓度，以增强纳米载体进入人 GBM 细胞的内化。通过吸附作用，用不同浓度的 fluoNFL 对 LNC 表面进行功能化。随着肽浓度的增加，LNC 的大小和表面电荷逐渐改变，但它们的补体蛋白消耗仍然很低。发现 fluoNFL 从 LNC 表面的解吸速度较慢。此外，观察到 U87MG 人胶质母细胞瘤细胞中 LNC 的内化速率和程度取决于表面功能化 fluoNFL 浓度。此外，我们表明，与健康的人星形胶质细胞相比，U87MG 细胞对 fluoNFL 功能化 LNC 的摄取具有偏好性。fluoNFL 功能化的 LNC 内化到 U87MG 细胞中是能量依赖性的，可能通过巨胞饮作用、网格蛋白介导的内吞作用和小窝蛋白介导的内吞作用发生。然后，将一种新的二茂铁型分子（FcTriOH）作为一种有效的抗癌候选药物封装在 LNC 中，与其他测试制剂相比，其功能化提高了对 U87MG 细胞的体外疗效。在初步研究中，在裸鼠皮下人 GBM 肿瘤模型中，在第二次静脉注射 FcTriOH 载药 LNC 后一周，观察到相对肿瘤体积显著减少。这些结果表明，增加 LNC 表面上的 NFL 肽浓度是一种有前途的方法，可以增加和优先内化纳米载体进入人 GBM 细胞，并且 FcTriOH 载药 LNC 是 GBM 的一种有前途的治疗方法。
