Design of 18 nm Doxorubicin-Loaded 3-Helix Micelles: Cellular Uptake and Cytotoxicity in Patient-Derived GBM6 Cells,ACS Biomaterials Science & Engineering

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Design of 18 nm Doxorubicin-Loaded 3-Helix Micelles: Cellular Uptake and Cytotoxicity in Patient-Derived GBM6 Cells
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-12-18 , DOI: 10.1021/acsbiomaterials.0c01639
Benson T. Jung ₁ , Katherine Jung ₂ , Marc Lim ₃ , Michael Li ₂ , Raquel Santos ₄ , Tomoko Ozawa ₄ , Ting Xu _{1,

2,

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Affiliation

The fate of nanocarrier materials at the cellular level constitutes a critical checkpoint in the development of effective nanomedicines, determining whether tissue level accumulation results in therapeutic benefit. The cytotoxicity and cell internalization of ∼18 nm 3-helix micelle (3HM) loaded with doxorubicin (DOX) were analyzed in patient-derived glioblastoma (GBM) cells in vitro. The half-maximal inhibitory concentration (IC₅₀) of 3HM-DOX increased to 6.2 μg/mL from <0.5 μg/mL for free DOX in patient-derived GBM6 cells, to 15.0 μg/mL from 6.5 μg/mL in U87MG cells, and to 21.5 μg/mL from ∼0.5 μg/mL in LN229 cells. Modeling analysis of previous 3HM biodistribution results predicts that these cytotoxic concentrations are achievable with intravenous injection in rodent GBM models. 3HM-DOX formulations were internalized intact and underwent intracellular trafficking distinct from free DOX. 3HM was quantified to have an internalization half-life of 12.6 h in GBM6 cells, significantly longer than that reported for some liposome and polymer systems. 3HM was found to traffic through active endocytic processes, with clathrin-mediated endocytosis being the most involved of the pathways studied. Inhibition studies suggest substantial involvement of receptor recognition in 3HM uptake. As the 3HM surface is PEG-ylated with no targeting functionalities, protein corona–cell surface interactions, such as the apolipoprotein-low-density lipoprotein receptor, are expected to initiate internalization. The present work gives insights into the cytotoxicity, pharmacodynamics, and cellular interactions of 3HM and 3HM-DOX relevant for ongoing preclinical studies. This work also contributes to efforts to develop predictive mathematical models tracking the accumulation and biodistribution kinetics at a systemic level.

中文翻译：

18 nm阿霉素负载的3-螺旋胶束的设计：患者来源的GBM6细胞的细胞摄取和细胞毒性。

纳米载体材料在细胞水平上的命运构成了有效纳米药物开发中的关键检查点，决定了组织水平的积累是否会带来治疗益处。体外分析了患者来源的胶质母细胞瘤（GBM）细胞中负载阿霉素（DOX）的〜18 nm 3-螺旋胶束（3HM）的细胞毒性和细胞内在化。最大抑制浓度的一半（IC ₅₀）3HM-DOX从患者来源的GBM6细胞中的游离DOX从<0.5μg/ mL增加到6.2μg/ mL，在U87MG细胞中从6.5μg/ mL增加到15.0μg/ mL，从约0.5增加到21.5μg/ mL LN229细胞中的微克/毫升。先前3HM生物分布结果的模型分析预测，在啮齿动物GBM模型中通过静脉注射可以达到这些细胞毒性浓度。3HM-DOX制剂完整内在化，并经历了与游离DOX不同的细胞内运输。量化3HM在GBM6细胞中的内在半衰期为12.6小时，明显长于某些脂质体和聚合物系统的报道。发现3HM通过活跃的内吞过程进行运输，网格蛋白介导的内吞作用是所研究途径中最参与的过程。抑制研究表明受体识别与3HM摄取有关。由于3HM表面是PEG化的，没有靶向功能，因此蛋白质电晕-细胞表面相互作用（如载脂蛋白-低密度脂蛋白受体）有望引发内在化。本工作提供了有关正在进行的临床前研究的3HM和3HM-DOX的细胞毒性，药效学和细胞相互作用的见解。这项工作还有助于开发预测性数学模型，以在系统水平上跟踪累积和生物分布动力学。本工作提供了有关正在进行的临床前研究的3HM和3HM-DOX的细胞毒性，药效学和细胞相互作用的见解。这项工作还有助于开发预测性数学模型，以在系统水平上跟踪累积和生物分布动力学。本工作提供了有关正在进行的临床前研究的3HM和3HM-DOX的细胞毒性，药效学和细胞相互作用的见解。这项工作还有助于开发预测性数学模型，以在系统水平上跟踪累积和生物分布动力学。

更新日期：2021-01-11

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