Hydrogel matrix presence and composition influence drug responses of encapsulated glioblastoma spheroids
Hydrogel matrix presence and composition influence drug responses of encapsulated glioblastoma spheroids
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DOI：
10.1016/j.actbio.2021.05.005
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发表时间：
2021-09-06
影响因子：
9.7
通讯作者：
Zustiak, Silviya P.
中科院分区：
文献类型：
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作者：
Hill, L.;Bruns, J.;Zustiak, Silviya P.
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤，患者的中位生存期为12-15个月。为了促进治疗开发，需要充分概括体内肿瘤微环境的生物工程GBM模型。基质包封的多细胞球体代表这样的模型，因为它们概括了实体瘤的特征，例如维度、细胞-细胞和细胞基质相互作用。然而，对于哪些基质性质是提高基于球体的药物筛选平台的预测能力的关键，还没有达成共识。我们使用了水凝胶封装的GBM球体模型，其中基质性质被独立地改变，以研究它们对GBM球体特征和药物反应性的影响。我们专注于水凝胶的降解性，通过酶促降解交联剂调整，和水凝胶的可降解性，通过整联蛋白配体调整。我们观察到GBM球状体的细胞浸润增加，并且与不可降解的非粘附性水凝胶中的球状体或自由漂浮的球状体相比，可降解的粘附性水凝胶中对替莫唑胺的抗性增加。此外，与非粘性可降解水凝胶相比，粘合剂中的球状体的渗透指数更高。对于可降解水凝胶中的球状体，我们确定浸润细胞比球状体核心中的细胞对替莫唑胺更敏感。浸润细胞的替莫唑胺敏感性独立于整合素粘附。我们不能将差异药物反应归因于差异细胞增殖或有限的药物渗透到水凝胶基质中。我们的研究结果表明，细胞-基质相互作用指导GBM球体药物反应性，进一步阐明这些相互作用可以使工程更预测药物筛选平台。多形性胶质母细胞瘤（GBM）多细胞球体有望用于药物筛选和开发，因为与单层培养物相比，它们更好地模拟了体内细胞对治疗剂的反应。传统的球体模型缺乏外部细胞外基质（ECM），无法模拟GBM微环境中的机械，物理和生化线索。虽然在水凝胶基质中嵌入球状体已被证明可以更好地概括肿瘤微环境，但对控制球状体对药物反应性的关键基质性质的理解仍然有限。在这里，我们解耦和独立改变基质性质，如降解性，通过酶可降解的肽交联剂，和细胞粘附，通过粘合剂配体，进一步了解什么样的基质性质有助于GBM耐药性。(c)2021 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Glioblastoma multiforme (GBM) is the most aggressive brain tumor with median patient survival of 12-15 months. To facilitate treatment development, bioengineered GBM models that adequately recapitulate the in vivo tumor microenvironment are needed. Matrix-encapsulated multicellular spheroids represent such model because they recapitulate solid tumor characteristics, such as dimensionality, cell-cell, and cell matrix interactions. Yet, there is no consensus as to which matrix properties are key to improving the predictive capacity of spheroid-based drug screening platforms. We used a hydrogel-encapsulated GBM spheroid model, where matrix properties were independently altered to investigate their effect on GBM spheroid characteristics and drug responsiveness. We focused on hydrogel degradability, tuned via enzymatically degradable crosslinkers, and hydrogel adhesiveness, tuned via integrin ligands. We observed increased cellular infiltration of GBM spheroids and increased resistance to temozolomide in degradable, adhesive hydrogels compared to spheroids in non-degradable, non-adhesive hydrogels or to free-floating spheroids. Further, a higher infiltration index was noted for spheroids in adhesive compared to nonadhesive degradable hydrogels. For spheroids in degradable hydrogels, we determined that infiltrating cells were more susceptible to temozolomide compared to cells in the spheroid core. The temozolomide susceptibility of the infiltrating cells was independent of integrin adhesion. We could not attribute differential drug responses to differential cellular proliferation or to limited drug penetration into the hydrogel matrix. Our results suggest that cell-matrix interactions guide GBM spheroid drug responsiveness and that further elucidation of these interactions could enable the engineering of more predictive drug screening platforms. Statement of significance Glioblastoma multiforme (GBM) multicellular spheroids hold promise for drug screening and development as they better mimic in vivo cellular responses to therapeutics compared to monolayer cultures. Traditional spheroid models lack an external extracellular matrix (ECM) and fail to mimic the mechanical, physical, and biochemical cues seen in the GBM microenvironment. While embedding spheroids in hydrogel matrices has been shown to better recapitulate the tumor microenvironment, there is still limited understanding as to the key matrix properties that govern spheroid responsiveness to drugs. Here we decoupled and independently altered matrix properties such as degradability, via an enzymatically degradable peptide crosslinker, and cell adhesion, via an adhesive ligand, giving further insight into what matrix properties contribute to GBM chemoresistance. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.