Designed Antitumor Peptide for Targeted siRNA Delivery into Cancer Spheroids
Designed Antitumor Peptide for Targeted siRNA Delivery into Cancer Spheroids
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DOI：
10.1021/acsami.1c14761
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发表时间：
2021-10-18
影响因子：
9.5
通讯作者：
Zhao, Xiubo
中科院分区：
文献类型：
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作者：
Cirillo, Silvia;Tomeh, Mhd Anas;Zhao, Xiubo
抗菌/抗癌肽（Antimicrobial/anti - cancer peptides, AMPs/ACPs）作为一种新的治疗药物在癌症治疗中显示出很好的效果。其中，设计的两亲性α -螺旋肽G(IIKK)(3)I-NH2 （G3）在靶向癌细胞方面表现出很强的亲和力和特异性。在这里，我们报告了G3如何穿透癌细胞的新见解。G3对HCT-116结肠癌细胞表现出高特异性，与HDFs（人新生儿原发性真皮成纤维细胞）对照相比。在高浓度多肽作用下，扫描电镜观察到明显的癌细胞细胞膜断裂。内吞途径的基因敲低表明，能量依赖的内吞途径是肽摄取所必需的。此外，G3可以保护和选择性地将sirna传递到癌细胞中，并成功调节其基因表达。基因传递也在三维癌球体中进行了测试，并显示了对癌球体的深度渗透传递。最后，对G3对斑马鱼胚胎的体内毒性进行了评价，结果表明，G3的毒性随浓度的增加而增加。然而，当与siRNA络合时，肽的毒性减弱。此外，在有效基因传递的浓度范围内，毒性可以忽略不计。目前的结果表明，G3是一种很有希望的癌症治疗药物。
Antimicrobial/anticancer peptides (AMPs/ACPs) have shown promising results as new therapeutic agents in cancer thearpy. Among them, the designed amphiphilic alpha-helical peptide G(IIKK)(3)I-NH2 (G3) displayed great affinity and specificity in targeting cancer cells. Here, we report new insights on how G3 penetrates cancer cells. G3 showed high specificity to HCT-116 colon cancer cells compared to the HDFs (human neonatal primary dermal fibroblasts) control. With high concentrations of peptide, a clear cancer cell membrane disruption was observed through SEM. Gene knockdown of the endocytic pathways demonstrated that an energy-dependent endocytic pathway is required for the uptake of the peptide. In addition, G3 can protect and selectively deliver siRNAs into cancer cells and successfully modulated their gene expression. Gene delivery was also tested in 3D cancer spheroids and showed deep penetration delivery into the cancer spheroids. Finally, the in vivo toxicity of G3 was evaluated on zebrafish embryos, showing an increasing toxicity effect with concentration. However, the toxicity of the peptide was attenuated when complexed with siRNA. In addition, negligible toxicity was observed at the concentration range for efficient gene delivery. The current results demonstrate that G3 is promising as an excellent agent for cancer therapy.