Effective Permeation of Anticancer Drugs into Glioblastoma Spheroids via Conjugation with a Sulfobetaine Copolymer,Biomacromolecules

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Effective Permeation of Anticancer Drugs into Glioblastoma Spheroids via Conjugation with a Sulfobetaine Copolymer
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-10-23 , DOI: 10.1021/acs.biomac.0c01200
Nobuyuki Morimoto ₁ , Masaya Yamamoto _{1,

2}

Affiliation

Three-dimensional cell aggregates (spheroids) are becoming a research focus because their construction is similar to that in vivo microenvironments, enabling the acceleration of drug discovery and reducing the need for animal tests, and other advantages. However, the delivery of drugs to the inside of spheroids is time-consuming and has low efficiency. In this study, we selected a sulfobetaine copolymer that translocates to the cell membrane in monolayer cultured cells as a nanocarrier of anticancer drugs. Doxorubicin (Dox) and 17-demethoxy-17-allylamino geldanamycin (17AAG) were modified to the copolymer of sulfobetaine methacrylate and poly(ethylene glycol) methacrylate, P(SB-PEG), and added to glioblastoma A-172 cell spheroids. Dox-P(SB-PEG) showed fast permeation into A-172 spheroids, and the fluorescence in cells was observed in the center area of the spheroids within 1 h of polymer addition. Conversely, only the outer one to two cell layers of spheroids were observed when Dox was added to the spheroids. Dox-P(SB-PEG) in A-172 spheroids was localized in the mitochondria of each cell and exhibited comparable drug efficacy to that of Dox in growth inhibition assays of A-172 spheroids. Moreover, approximately 10-fold higher drug efficacy in growth inhibition and invasion of A-172 spheroids was found using 17AAG-P(SB-PEG). Conjugating anticancer drugs with P(SB-PEG) is a promising strategy to enhance drug permeation and efficacy against spheroid cells.

中文翻译：

通过与磺基甜菜碱共聚物的缀合，有效地将抗癌药物渗透到胶质母细胞瘤球体中

三维细胞聚集体（球体）正成为研究重点，因为它们的结构与体内微环境相似，从而加速了药物发现并减少了对动物测试的需求，以及其他优势。然而，将药物递送到球体内部是费时的并且效率低下。在这项研究中，我们选择了一种磺基甜菜碱共聚物，该共聚物可转移到单层培养细胞的细胞膜中，作为抗癌药物的纳米载体。将阿霉素（Dox）和17-去甲氧基-17-烯丙胺格尔德霉素（17AAG）改性为磺基甜菜碱甲基丙烯酸酯和聚（甲基）乙二醇乙二醇酯P（SB-PEG），并添加至胶质母细胞瘤A-172细胞球体中。Dox-P（SB-PEG）迅速渗透到A-172球体中，加入聚合物后1小时内，在球体的中心区域观察到细胞中的荧光。相反，当将Dox添加到球体时，仅观察到球体的外部一到两个细胞层。A-172球体中的Dox-P（SB-PEG）定位于每个细胞的线粒体中，并且在A-172球体的生长抑制试验中显示出与Dox相当的药物功效。此外，使用17AAG-P（SB-PEG）发现在抑制A-172球状体的生长和侵袭方面，药物功效提高了约10倍。将抗癌药物与P（SB-PEG）结合使用是提高药物渗透性和对抗球状细胞功效的有前途的策略。A-172球体中的Dox-P（SB-PEG）定位于每个细胞的线粒体中，并且在A-172球体的生长抑制试验中显示出与Dox相当的药物功效。此外，使用17AAG-P（SB-PEG）发现在抑制A-172球状体的生长和侵袭方面，药物功效提高了约10倍。将抗癌药物与P（SB-PEG）结合使用是提高药物渗透性和对抗球状细胞功效的有前途的策略。A-172球体中的Dox-P（SB-PEG）定位于每个细胞的线粒体中，并且在A-172球体的生长抑制试验中显示出与Dox相当的药物功效。此外，使用17AAG-P（SB-PEG）发现在抑制A-172球状体的生长和侵袭方面，药物功效提高了约10倍。将抗癌药物与P（SB-PEG）结合使用是提高药物渗透性和对抗球状细胞功效的有前途的策略。

更新日期：2020-12-14

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