Multicellular Ovarian Cancer Model for Evaluation of Nanovector Delivery in Ascites and Metastatic Environments.
Multicellular Ovarian Cancer Model for Evaluation of Nanovector Delivery in Ascites and Metastatic Environments.
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DOI：
10.3390/pharmaceutics13111891
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发表时间：
2021-11-08
期刊：
影响因子：
5.4
通讯作者：
Steinbach-Rankins JM
中科院分区：
文献类型：
--
作者：
Winter SJ;Miller HA;Steinbach-Rankins JM
开发了一种由上皮性卵巢癌和成纤维细胞组成的新型多细胞模型，作为评估纳米载体递送的体外平台，并最终帮助开发靶向治疗。我们假设在球状体基质中包含基于肽的支架（PuraMatrix）以代表体内肿瘤微环境改变沿着转移部位条件，将增强球状体细胞生长和迁移并改变纳米载体转运。通过比较暴露于基质细胞活化和组织缺氧的卵巢癌细胞的生长和迁移来评估该模型。成纤维细胞活化通过TGF-β1介导的途径实现，组织缺氧通过缺氧中孵育的3D球体实现。通过荧光和共聚焦显微镜评估表面修饰的纳米载体转运。与先前在腹水和远端转移瘤中的体内观察结果一致，暴露于活化基质微环境的球状体比未活化的对应物更致密、更收缩且具有更多的迁移细胞。缺氧条件下导致负径向球体生长超过5天相比，在常氧的径向增加。由于密度更大的环境，纳米载体渗透在PuraMatrix中减弱，无论表面改性如何。该平台可用于评估基于卵巢腹水和转移性环境的纳米载体转运，并且从长远来看，它提供了评估纳米载体功效的手段。
A novel multicellular model composed of epithelial ovarian cancer and fibroblast cells was developed as an in vitro platform to evaluate nanovector delivery and ultimately aid the development of targeted therapies. We hypothesized that the inclusion of peptide-based scaffold (PuraMatrix) in the spheroid matrix, to represent in vivo tumor microenvironment alterations along with metastatic site conditions, would enhance spheroid cell growth and migration and alter nanovector transport. The model was evaluated by comparing the growth and migration of ovarian cancer cells exposed to stromal cell activation and tissue hypoxia. Fibroblast activation was achieved via the TGF-β1 mediated pathway and tissue hypoxia via 3D spheroids incubated in hypoxia. Surface-modified nanovector transport was assessed via fluorescence and confocal microscopy. Consistent with previous in vivo observations in ascites and at distal metastases, spheroids exposed to activated stromal microenvironment were denser, more contractile and with more migratory cells than nonactivated counterparts. The hypoxic conditions resulted in negative radial spheroid growth over 5 d compared to a radial increase in normoxia. Nanovector penetration attenuated in PuraMatrix regardless of surface modification due to a denser environment. This platform may serve to evaluate nanovector transport based on ovarian ascites and metastatic environments, and longer term, it provide a means to evaluate nanotherapeutic efficacy.
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