Multicellular tumor spheroids as a model for assessing delivery of oligonucleotides in three dimensions.
Multicellular tumor spheroids as a model for assessing delivery of oligonucleotides in three dimensions.
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DOI：
10.1038/mtna.2014.5
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发表时间：
2014-03-11
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寡核苷酸在体外选择性操纵基因表达方面显示出了希望，但这种成功尚未转化为临床癌症治疗。一个潜在的原因是细胞在单层中的行为与在三维肿瘤中的行为不同，导致寡核苷酸在肿瘤中的渗透和分布有限。当寡核苷酸与纳米载体如脂质复合物和聚合复合物（通常用于寡核苷酸的递送载体）缔合时，这可能尤其如此。多细胞肿瘤球体（MCTS），一个三维模型，非常类似于小无血管肿瘤和微转移，已被用作单层培养和体内研究之间的中间体，用于筛选小分子药物。然而，球状体很少用于各种寡核苷酸递送制剂的研究。在这里，我们已经评估了剪接转换反义寡核苷酸的摄取和功效，使用各种交付方式在二维和三维文化模型。我们发现，递送剂的大小显著影响到球体的渗透，从而影响寡核苷酸的生物学效应。我们假设，MCTS模型将被证明是一个有用的工具，在未来的发展寡核苷酸递送制剂。
Oligonucleotides have shown promise in selectively manipulating gene expression in vitro, but that success has not translated to the clinic for cancer therapy. A potential reason for this is that cells behave differently in monolayer than in the three-dimensional tumor, resulting in limited penetration and distribution of oligonucleotides in the tumor. This may be especially true when oligonucleotides are associated with nanocarriers such as lipoplexes and polyplexes, commonly used delivery vehicles for oligonucleotides. The multicellular tumor spheroid (MCTS), a three-dimensional model that closely resembles small avascular tumors and micrometastases, has been utilized as an intermediate between monolayer culture and in vivo studies for the screening of small-molecule drugs. However, spheroids have been little used for the study of various oligonucleotide delivery formulations. Here, we have evaluated the uptake and efficacy of splice-switching antisense oligonucleotides using various delivery modalities in two- and three-dimensional culture models. We find that the size of the delivery agent dramatically influences penetration into the spheroid and thus the biological effect of the oligonucleotides. We hypothesize that the MCTS model will prove to be a useful tool in the future development of oligonucleotide delivery formulations.
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