Zeng Zihua, Tung Ching-Hsuan, Zu Youli
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Cancer Pathology Research Laboratory, Houston Methodist Research Institute, Houston TX 77030, USA.
Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medical College, New York, NY 10021, USA.
Cancers (Basel). 2020 Mar 25;12(4):780. doi: 10.3390/cancers12040780.
Anaplastic large cell lymphoma (ALCL) is the most common T-cell lymphoma in children. ALCL cells characteristically express surface CD30 molecules and carry the pathogenic ALK oncogene, both of which are diagnostic biomarkers and are also potential therapeutic targets. For precision therapy, we report herein a protamine nanomedicine incorporated with oligonucleotide aptamers to selectively target lymphoma cells, a dsDNA/drug payload to efficiently kill targeted cells, and an siRNA to specifically silence ALK oncogenes. The aptamer-equipped protamine nanomedicine was simply fabricated through a non-covalent charge-force reaction. The products had uniform structure morphology under an electron microscope and a peak diameter of 103 nm by dynamic light scattering measurement. Additionally, flow cytometry analysis demonstrated that under CD30 aptamer guidance, the protamine nanomedicine specifically bound to lymphoma cells, but did not react to off-target cells in control experiments. Moreover, specific cell targeting and intracellular delivery of the nanomedicine were also validated by electron and confocal microscopy. Finally, functional studies demonstrated that, through combined cell-selective chemotherapy using a drug payload and oncogene-specific gene therapy using an siRNA, the protamine nanomedicine effectively killed lymphoma cells with little toxicity to off-target cells, indicating its potential for precision therapy.
间变性大细胞淋巴瘤（ALCL）是儿童中最常见的T细胞淋巴瘤。ALCL细胞的特征是表达表面CD30分子并携带致病性ALK癌基因，这两者都是诊断生物标志物，也是潜在的治疗靶点。为了实现精准治疗，我们在此报告一种鱼精蛋白纳米药物，它结合了寡核苷酸适配体以选择性靶向淋巴瘤细胞，双链DNA/药物负载以有效杀死靶向细胞，以及小干扰RNA（siRNA）以特异性沉默ALK癌基因。配备适配体的鱼精蛋白纳米药物通过非共价电荷力反应简单制备而成。产物在电子显微镜下具有均匀的结构形态，通过动态光散射测量其峰值直径为103纳米。此外，流式细胞术分析表明，在CD30适配体的引导下，鱼精蛋白纳米药物特异性结合淋巴瘤细胞，但在对照实验中对非靶向细胞无反应。此外，电子显微镜和共聚焦显微镜也验证了纳米药物的特异性细胞靶向和细胞内递送。最后，功能研究表明，通过使用药物负载进行联合细胞选择性化疗以及使用siRNA进行癌基因特异性基因治疗，鱼精蛋白纳米药物有效地杀死了淋巴瘤细胞，对非靶向细胞几乎没有毒性，表明其具有精准治疗的潜力。
