Abstract

Polymer materials encapsulating drugs have broad prospects for drug delivery. We evaluated the effectiveness of polyethylene glycol-poly (lactic-co-glycolic acid) (PLGA-PEG) encapsulation and release characteristics of PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235). We proposed a strategy for targeting radiosensitization of liver cancer cells. The biocompatibility, cell interaction, and internalization of Glypican-3 (GPC3) antibody-modified, BEZ235-loaded PLGA-PEG nanoparticles (NP-BEZ235-Ab) in hepatoma cells in vitro were studied. Also, the cell killing effect of NP-BEZ235-Ab combined with γ-ray cell was evaluated. We used confocal microscopy to monitor nanoparticle-cell interactions and cellular uptake, conducted focus-formation experiments to analyze the synergistic biological effects of NP-BEZ235-Ab and priming, and studied synergy in liver cancer cells using molecular biological methods such as western blotting. We found that PLGA-PEG has good loading efficiency for BEZ235 and high selectivity to GPC3-positive HepG2 liver cancer cells, thus documenting that NP-BEZ235-Ab acts as a small-molecule drug delivery nanocarrier. At the nominal concentration, the NP-BEZ235-Ab nanoformulation synergistically kills liver cancer cells with significantly higher efficiency than does the free drug. Thus, NP-BEZ235-Ab is a potential radiosensitizer.

Graphical Abstract

摘要

包封药物的高分子材料在药物递送方面具有广阔的前景。我们评估了聚乙二醇-聚（乳酸-共-乙醇酸）（PLGA-PEG）包封的有效性和 PI3K/mTOR 抑制剂 NVP-BEZ235（BEZ235）的释放特性。我们提出了一种靶向肝癌细胞放射增敏的策略。研究了 Glypican-3 (GPC3) 抗体修饰的、负载有 BEZ235 的 PLGA-PEG 纳米颗粒 (NP-BEZ235-Ab) 在体外肝癌细胞中的生物相容性、细胞相互作用和内化。此外，还评估了 NP-BEZ235-Ab 与 γ 射线细胞组合的细胞杀伤效果。我们使用共聚焦显微镜监测纳米颗粒-细胞相互作用和细胞摄取，进行焦点形成实验以分析 NP-BEZ235-Ab 和引发的协同生物效应，并使用蛋白质印迹等分子生物学方法研究了肝癌细胞的协同作用。我们发现 PLGA-PEG 对 BEZ235 具有良好的负载效率和对 GPC3 阳性 HepG2 肝癌细胞的高选择性，从而证明 NP-BEZ235-Ab 可作为小分子药物递送纳米载体。在标称浓度下，NP-BEZ235-Ab 纳米制剂协同杀死肝癌细胞的效率明显高于游离药物。因此，NP-BEZ235-Ab 是一种潜在的放射增敏剂。NP-BEZ235-Ab 纳米制剂协同杀死肝癌细胞的效率明显高于游离药物。因此，NP-BEZ235-Ab 是一种潜在的放射增敏剂。NP-BEZ235-Ab 纳米制剂协同杀死肝癌细胞的效率明显高于游离药物。因此，NP-BEZ235-Ab 是一种潜在的放射增敏剂。

图形概要