Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, No.100 Science Ave, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, No.100 Science Ave, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China.
Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, No.100 Science Ave, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, No.100 Science Ave, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China.
Int J Pharm. 2023 Feb 5;632:122543. doi: 10.1016/j.ijpharm.2022.122543. Epub 2022 Dec 23.
Tumor necrosis factor receptor-1 (TNFR1) and DEK are closely associated with the development of rheumatoid arthritis (RA). Taking advantage of the high adenosine triphosphate (ATP) in RA microenvironment and the interactions of DNA aptamers with their targets, an ATP-responsive DNA nanodrug was constructed that simultaneously targets TNFR1 and DEK for RA therapy. To this end, DEK target aptamer DTA and TNFR1 target aptamer Apt1-67 were equipped with sticky ends to hybridize with ATP aptamer (Apt) and fabricated DNA nanodrug DAT. Our results showed that DAT was successfully prepared with good stability. In the presence of ATP, DAT was disassembled, resulting in the release of DTA and Apt1-67. In vitro studies demonstrated that DAT was superior to the non-responsive DNA nanodrug TD-3A3T in terms of anti-inflammation activity and ATP was inevitable to maximize the anti-inflammation ability of DAT. The superior efficacy of DAT is attributed to the more potent inhibition of caspase-3 and NETs formation. In vivo results further confirmed the anti-RA efficacy of DAT, whereas the administration routes (intravenous injection and transdermal administration via microneedles) did not cause significant differences. Overall, the present study supplies an intelligent strategy for RA therapy and explores a promising administration route for future clinical medication of RA patients.
肿瘤坏死因子受体-1（TNFR1）和 DEK 与类风湿关节炎（RA）的发生密切相关。利用 RA 微环境中高浓度的三磷酸腺苷（ATP）以及 DNA 适体与靶标之间的相互作用，构建了一种 ATP 响应性 DNA 纳米药物，该药物同时针对 TNFR1 和 DEK 用于 RA 治疗。为此，将 DEK 靶标适体 DTA 和 TNFR1 靶标适体 Apt1-67 配备粘性末端，与 ATP 适体（Apt）杂交，并制备 DNA 纳米药物 DAT。结果表明，DAT 成功制备且稳定性良好。在存在 ATP 的情况下，DAT 发生解组装，导致 DTA 和 Apt1-67 的释放。体外研究表明，DAT 在抗炎活性方面优于非响应性 DNA 纳米药物 TD-3A3T，而 ATP 是最大限度发挥 DAT 抗炎能力所必需的。DAT 的优越疗效归因于更有效的抑制半胱天冬酶-3 和 NETs 的形成。体内结果进一步证实了 DAT 的抗 RA 疗效，而给药途径（静脉注射和通过微针进行经皮给药）并未造成显著差异。总体而言，本研究为 RA 治疗提供了一种智能策略，并探索了未来 RA 患者临床用药的一种有前途的给药途径。
