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Polypeptide-engineered DNA tetrahedrons for targeting treatment of colorectal cancer via apoptosis and autophagy.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-07-10 , DOI: 10.1016/j.jconrel.2019.07.012
Nan Zhang 1 , Yanan Yang 2 , Ziyi Wang 2 , Jing Yang 2 , Xiao Chu 2 , Jin Liu 3 , Yongxing Zhao 1
Affiliation  

Smart delivery of therapeutic peptides that target cellular signaling pathways holds high specificity and great promise for cancer therapy. Here, DNA tetrahedrons (TDs) are designed to carry two therapeutic peptides-FAS peptide and FK-16 peptide. DNA TDs are designed with varied numbers and spatial placement of FAS peptides and FK-16 peptides, and tested for their anti-cancer efficacy. Trimerization of FAS receptors using TDs that are assembled with three FAS peptides enhances FAS-induced cell apoptosis. FK-16 peptides are conjugated to TDs via a peptide sequence sensitive to MMP-2/9 in tumor microenvironment. Therefore, FK-16 peptides are expected to detach from TDs once arrived the tumor microenvironment. A cell penetrating peptide (TAT) is also conjugated to the FK-16 peptide to facilitate its intracellular delivery, which increases the FK-16 peptide-induced cell apoptosis and autophagy. TD-3(TFM)3(FAS) (TFM: TAT + FK-16 + MMP-2/9) exhibits the highest HT-29 inhibition in vitro and in vivo among all therapies. In addition to the high anti-cancer efficacy, TD-3(TFM)3(FAS) shows a high specificity to HT-29 cells in vitro and in vivo. Low cell inhibition rates and cellular uptake are observed in normal cells. In sum, the multifunctional TD-3(TFM)3(FAS) provides a new platform for the smart delivery of anti-cancer peptides to achieve enhanced efficacy and high specificity.

中文翻译:

多肽工程化的DNA四面体可通过凋亡和自噬靶向治疗结直肠癌。

靶向细胞信号传导途径的治疗性肽的智能传递具有高度特异性,对癌症治疗具有广阔的前景。在这里,DNA四面体(TDs)被设计为携带两个治疗性肽-FAS肽和FK-16肽。设计了具有不同数量和空间位置的FAS肽和FK-16肽的DNA TD,并对其抗癌功效进行了测试。使用与三种FAS肽组装的TD对FAS受体进行三聚化可增强FAS诱导的细胞凋亡。FK-16肽通过对肿瘤微环境中MMP-2 / 9敏感的肽序列与TD偶联。因此,一旦到达肿瘤微环境,FK-16肽有望与TD分离。细胞穿透肽(TAT)也与FK-16肽缀合,以促进其细胞内递送,这会增加FK-16肽诱导的细胞凋亡和自噬。在所有疗法中,TD-3(TFM)3(FAS)(TFM:TAT + FK-16 + MMP-2 / 9)在体外和体内均表现出最高的HT-29抑制作用。TD-3(TFM)3(FAS)除具有很高的抗癌功效外,在体外和体内均对HT-29细胞具有高度特异性。在正常细胞中观察到低的细胞抑制率和细胞摄取。总之,多功能TD-3(TFM)3(FAS)为智能递送抗癌肽提供了一个新平台,以实现增强的功效和高特异性。在正常细胞中观察到低的细胞抑制率和细胞摄取。总之,多功能TD-3(TFM)3(FAS)为智能递送抗癌肽提供了一个新平台,以实现增强的功效和高特异性。在正常细胞中观察到低的细胞抑制率和细胞摄取。总之,多功能TD-3(TFM)3(FAS)为智能递送抗癌肽提供了一个新平台,以实现增强的功效和高特异性。
更新日期:2019-07-10
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