Aminofullerenes as targeted inhibitors of EGFR: from pancreatic cancer inhibitors to <i>Drosophila m</i>. Toxicology

Pancreatic ductal adenocarcinoma (PDAC) is recognized as one of the most formidable cancers, largely due to its distinct microenvironment characterized predominantly by extensive desmoplastic stroma. In this study, we synthesized three novel water-soluble fullerene-based nanomaterials targeting EGFR protein. The direct amination of fullerene carbon atoms, was followed by conjugation with a modified derivative of the EGFR inhibitor-erlotinib, resulting in the formation of novel water-soluble fullerene derivatives. Further investigation into PAN02 and AsPC-1 cell lines revealed that these fullerene nanomaterials could induce cell cycle arrest in the G0/G1 phase, corroborated by alterations in the expression levels of the p27 and cyclin E1 proteins. Additionally, mechanisms of cell death were identified as autophagy for C₆₀BUT and C₇₀BUT-ERL, and apoptosis for Gd@C₈₂EDA-ERL nanomaterials. Crucially, the study uncovered the efficacy of synthesized aminofullerenes in inhibiting the EGFR signaling pathway. The further toxicological studies of Gd@C₈₂EDA-ERL fullerene on <i>Drosophila melanogaster</i>, underscored its potential for theranostic applications.胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）被认为是最为凶险的恶性肿瘤之一，其核心致病特征在于独特的肿瘤微环境，以广泛的促结缔组织增生基质为主要表现。本研究成功合成了三种靶向表皮生长因子受体（EGFR）蛋白的新型水溶性富勒烯基纳米材料：首先对富勒烯碳原子进行直接氨基化修饰，随后将其与表皮生长因子受体抑制剂厄洛替尼（erlotinib）的改性衍生物进行偶联，最终得到系列新型水溶性富勒烯衍生物。针对PAN02与AsPC-1细胞系的体外实验显示，此类富勒烯纳米材料可诱导细胞周期阻滞于G0/G1期，该效应得到了p27与细胞周期蛋白E1（cyclin E1）蛋白表达水平变化的佐证。此外，研究明确了三种纳米材料的细胞死亡机制：C₆₀BUT与C₇₀BUT-ERL通过自噬途径诱导细胞死亡，而Gd@C₈₂EDA-ERL则通过凋亡途径发挥细胞杀伤作用。尤为关键的是，本研究证实合成的氨基富勒烯可有效抑制表皮生长因子受体信号通路。针对Gd@C₈₂EDA-ERL富勒烯在黑腹果蝇（Drosophila melanogaster）体内开展的进一步毒理学研究，进一步凸显了其在诊疗一体化领域的应用潜力。