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首页> 外文期刊>Journal of biomedical materials research. Part B, Applied biomaterials. >EngineeringHepG2spheroids with injectable fiber fragments as predictable models for drug metabolism and tumor infiltration
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EngineeringHepG2spheroids with injectable fiber fragments as predictable models for drug metabolism and tumor infiltration

机译：用注射纤维片段的工程Hepg2股骨片作为药物代谢和肿瘤渗透的可预测模型

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In vitro cell and tissue models are playing essential roles in the identification of active pharmaceutical ingredients. Though HepG2 cells have attractive profiles over primary hepatocytes in the availability and viability retention, the expression of metabolizing enzymes is quite low. In the current study, three-dimensional (3D) HepG2 spheroids with smaller sizes of 150 mu m (3Ds) and bigger sizes of 300 mu m (3Db) are engineered using injectable fiber fragments as the substrate. In contrast to two-dimensional (2D) culture, the enzyme activities for drug metabolisms are restored in 3Ds and the pathophysiological profiles of tumor tissues are rebuilt in 3Db spheroids. Compared with spheroid culture without fiber fragments, 3Ds spheroids show higher activities of metabolizing enzymes (CYP3A4, CYP2A9, and phase II) and higher sensitivities to enzyme inducers (rifampicin and glutathione) and inhibitors (ketoconazole and probenecid). The drug clearance and toxicity to 3Ds spheroids predict better the clinical observations and drug-drug interactions. In addition, compared to scaffold-free spheroid culture, stronger expressions of E-cadherin and hypoxia-inducible factor-1 alpha (HIF-1 alpha) and higher fibronectin secretions are determined in 3Db spheroids, displaying apparent hypoxic and apoptotic regions similar to those found in solid tumors. In contrast to the overestimated drug toxicity in other systems, the infiltrations of free drug and drug-loaded micelles are apparently restricted in 3Db spheroids, exhibiting drug resistance just like in tumor tissues. Thus, this study demonstrates HepG2 spheroids with different sizes as predictable and physiologically relevant models for high-throughput screening of drug metabolism and tumor infiltration.
机译：体外细胞和组织模型在药物活性成分的鉴定中发挥着重要作用。尽管HepG2细胞在可利用性和生存能力保留方面比原代肝细胞有吸引力，但代谢酶的表达相当低。在目前的研究中，使用可注射纤维碎片作为基质，设计了尺寸较小的150μm（3Ds）和尺寸较大的300μm（3Db）的三维（3D）HepG2球体。与二维（2D）培养相比，药物代谢的酶活性在3Ds中恢复，肿瘤组织的病理生理学轮廓在3Db球体中重建。与不含纤维片段的球体培养相比，3Ds球体显示出更高的代谢酶活性（CYP3A4、CYP2A9和II期），以及对酶诱导剂（利福平和谷胱甘肽）和抑制剂（酮康唑和丙磺舒）更高的敏感性。药物清除率和对3Ds球体的毒性可以更好地预测临床观察和药物相互作用。此外，与无支架球体培养相比，3Db球体中E-钙粘蛋白和缺氧诱导因子-1α（HIF-1α）的表达更强，纤维连接蛋白分泌更高，显示出与实体瘤相似的明显缺氧和凋亡区域。与其他系统中高估的药物毒性不同，游离药物和载药胶束的渗透明显受限于3Db球体，表现出与肿瘤组织一样的耐药性。因此，本研究证明，不同大小的HepG2球体是高通量筛选药物代谢和肿瘤浸润的可预测和生理相关模型。

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