Independently Tuning the Biochemical and Mechanical Properties of 3D Hyaluronan-Based Hydrogels with Oxime and Diels-Alder Chemistry to Culture Breast Cancer Spheroids
Independently Tuning the Biochemical and Mechanical Properties of 3D Hyaluronan-Based Hydrogels with Oxime and Diels-Alder Chemistry to Culture Breast Cancer Spheroids
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DOI：
10.1021/acs.biomac.7b01422
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发表时间：
2017-12-01
影响因子：
6.2
通讯作者：
Shoichet, Molly S.
中科院分区：
文献类型：
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作者：
Baker, Alexander E. G.;Tam, Roger Y.;Shoichet, Molly S.
为了在体外将天然乳腺癌细胞的生长模拟为球体，需要一个定义良好的基质来模拟肿瘤微环境。寻找一种用于3D细胞培养的仿生材料而不是Matrigel，这对该领域提出了挑战。由于透明质酸在肿瘤微环境中含量丰富，并且可以进行化学修饰，我们合成了一种机械和化学特性独立可调的透明质酸(HA)水凝胶，用于乳腺癌细胞的3D培养。通过将羟基磷灰石修饰成不同的生物正交官能团，其力学性能受化学交联控制，其生化性能受Diels-Alder化学接枝生物活性多肽的控制。从硬度和多肽组成两个方面对一系列水凝胶进行筛选，以形成癌症球体。在优化的水凝胶配方中，3D乳腺癌球体显示出药物向其核心的扩散减少，细胞多药耐药外排泵上调，这与在耐药肿瘤中观察到的情况类似。我们的结果突出了这些可调和定义良好的凝胶在药物筛选分析中的潜力。
For native breast cancer cell growth to be mimicked in vitro as spheroids, a well-defined matrix that mimics the tumor microenvironment is required. Finding a biomimetic material for 3D cell culture other than Matrigel has challenged the field. Because hyaluronan is naturally abundant in the tumor microenvironment and can be chemically modified, we synthesized a hyaluronan (HA) hydrogel with independently tunable mechanical and chemical properties for 3D culture of breast cancer cells. By modifying HA with distinct bioorthogonal functional groups, its mechanical properties are controlled by chemical cross linking via oxime ligation, and its biochemical properties are controlled by grafting bioactive peptides via Diels-Alder chemistry. A series of hydrogels were screened in terms of stiffness and peptide composition for cancer spheroid formation. In the optimal hydrogel formulation, the 3D breast cancer spheroids showed decreased drug diffusion into their core and upregulation of cellular multidrug-resistant efflux pumps similar to what is observed in drug-resistant tumors. Our results highlight the potential of these tunable and well-defined gels in drug screening assays.