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Abstract：
Cytotoxic activity has been reported for the xanthone α-mangostin (AMN) against Glioblastoma multiforme (GBM), an aggressive malignant brain cancer with a poor prognosis. Recognizing that AMN\'s high degree of hydrophobicity is likely to limit its systemic administration, we formulated AMN using reconstituted high-density lipoprotein (rHDL) nanoparticles. The photophysical characteristics of the formulation, including fluorescence lifetime and steady-state anisotropy, indicated that AMN was successfully incorporated into the rHDL nanoparticles. To our knowledge, this is the first report on the fluorescent characteristics of AMN with an HDL-based drug carrier. Cytotoxicity studies in a 2D culture and 3D spheroid model of LN-229 GBM cells and normal human astrocytes showed an enhanced therapeutic index with the rHDL-AMN formulation compared to the unincorporated AMN and Temozolomide, a standard GBM chemotherapy agent. Furthermore, treatment with the rHDL-AMN facilitated a dose-dependent upregulation of autophagy and reactive oxygen species generation to a greater extent in LN-229 cells compared to astrocytes, indicating the reduced off-target toxicity of this novel formulation. These studies indicate the potential therapeutic benefits to GBM patients via selective targeting using the rHDL-AMN formulation.
摘要：
据报道，黄原酮α-芒果苷（AMN）对多形性胶质母细胞瘤（GBM）的细胞毒性活性，预后不良的侵袭性恶性脑癌。认识到AMN的高度疏水性可能会限制其全身给药，我们使用重组高密度脂蛋白(rHDL)纳米颗粒配制AMN.配方的光物理特性，包括荧光寿命和稳态各向异性，表明AMN已成功掺入rHDL纳米颗粒中。据我们所知,这是关于基于HDL的药物载体的AMN的荧光特性的首次报道。LN-229GBM细胞和正常人星形胶质细胞的2D培养和3D球体模型中的细胞毒性研究显示，与未掺入的AMN和替莫唑胺相比，rHDL-AMN制剂的治疗指数提高。标准GBM化疗药物。此外，与星形胶质细胞相比，用rHDL-AMN治疗更大程度地促进了LN-229细胞中自噬和活性氧的剂量依赖性上调，表明该新型制剂的脱靶毒性降低。这些研究表明通过使用rHDL-AMN制剂的选择性靶向对GBM患者的潜在治疗益处。
