Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Nanoscale. 2023 Jun 8;15(22):9801-9812. doi: 10.1039/d3nr00196b.
With its lack of commonly targeted receptors, triple negative breast cancer (TNBC) is aggressive and difficult to treat. To address this problem, nanotubes self-assembled from single stranded DNA (ssDNA)-amphiphiles were used as a delivery vehicle for doxorubicin (DOX) to target TNBC cells. Since DOX and other standard of care treatments such as radiation have been documented to induce senescence, the ability of the nanotubes to deliver the senolytic ABT-263 was also investigated. The ssDNA-amphiphiles were synthesized from a 10 nucleotide sequence attached to a dialkyl, (C), tail a C alkyl spacer, and have been previously shown to self-assemble into hollow nanotubes and spherical micelles. Here, we demontrate that these ssDNA spherical micelles could transition into long nanotubes in the presence of excess tails. The nanotubes could then be shortened probe sonication. The ssDNA nanotubes internalized into three different TNBC cell lines: Sum159, MDA-MB-231, and BT549, with minimal internalization in healthy Hs578Bst cells, suggesting an inherent targeting ability. Inhibition of different internalization mechanisms showed that the nanotubes internalized in the TNBC cells primarily through macropinocytosis and scavenger receptor-mediated endocytosis, both of which are upregulated pathways in TNBC. DOX was intercalated into the ssDNA nanotubes and delivered to TNBC cells. Compared to free DOX, DOX-intercalated nanotubes proved equally cytotoxic to TNBC cells. In order to demonstrate the potential for delivery of different therapeutics, ABT-263 was incorporated into the hydrophobic bilayer wall of the nanotubes and was delivered to a DOX-induced model of senescence. The ABT-263 encapsulating nanotubes demonstrated cytotoxicity to senescent TNBC cells as well as sensitization to further DOX treatment. Thus, our ssDNA nanotubes are a promising delivery vehicle that could be used for targeted delivery of therapeutics to TNBC cells.
由于缺乏常见的靶向受体，三阴性乳腺癌（TNBC）具有侵袭性且难以治疗。为了解决这个问题，我们使用由单链 DNA（ssDNA）两亲体自组装而成的纳米管作为阿霉素（DOX）的递送载体，以靶向 TNBC 细胞。由于 DOX 和其他标准治疗方法（如放射治疗）已被证明能诱导衰老，因此还研究了纳米管递送衰老选择性药物 ABT-263 的能力。ssDNA 两亲体由附着在二烷基（C）尾上的 10 个核苷酸序列合成，C 烷基间隔物，并已被证明能自组装成中空纳米管和球形胶束。在这里，我们证明这些 ssDNA 球形胶束在存在过量尾部时可以转变为长纳米管。然后可以通过探针超声缩短纳米管。ssDNA 纳米管内化到三种不同的 TNBC 细胞系中：Sum159、MDA-MB-231 和 BT549，而在健康的 Hs578Bst 细胞中几乎没有内化，这表明存在固有靶向能力。抑制不同的内化机制表明，纳米管主要通过巨胞饮作用和清道夫受体介导的内吞作用内化到 TNBC 细胞中，这两种途径在 TNBC 中都是上调的途径。DOX 被插入到 ssDNA 纳米管中并递送到 TNBC 细胞中。与游离 DOX 相比，DOX 插入的纳米管对 TNBC 细胞同样具有细胞毒性。为了证明递送不同治疗药物的潜力，将 ABT-263 掺入纳米管的疏水双层壁中，并递送到 DOX 诱导的衰老模型中。包封 ABT-263 的纳米管对衰老的 TNBC 细胞具有细胞毒性，并对进一步的 DOX 治疗敏感。因此，我们的 ssDNA 纳米管是一种很有前途的递送载体，可用于将治疗药物靶向递送到 TNBC 细胞。
