College of Chemical Science and Technology, Yunnan University, Kunming 650091, China.
Amrita Centre for Industrial Research & Innovation, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Coimbatore 64112, India.
J Control Release. 2018 Oct 28;288:14-22. doi: 10.1016/j.jconrel.2018.08.036. Epub 2018 Aug 28.
We report herein, an azo-derivative (AzP1) of FDA approved antineoplastic drug SN-38 (irinotecan analogue) as a theranostic agent with a potential for both tumor hypoxia-specific activation and therapy. The theranostic AzP1 was found to be stable within a biologically relevant pH scale and was chemically inert towards other competitive biological analytes. However, upon treatment with rat-liver microsomes, AzP1 showed a self-calibrated fluorescence enhancement at λ = 560 nm. The cytotoxicity profile of AzP1 was tested in various cancer lines. Under hypoxic conditions, prodrug AzP1 exhibited activation to release the parent drug (SN-38) and enhanced cytotoxicity in cancer cells with concomitant fluorescence enhancement at 560 nm, which served to monitor both the drug activation and tracing purposes. The therapeutic potential of AzP1 for both tumor-specific activation and suppression of tumor weights was validated in xenograft mouse model. Collectively, the synthetic ease and hypoxia-sensitive activation along with promising therapeutic properties highlight the potential of theranostic AzPI in future cancer treatment programs.
我们在此报告，FDA 批准的抗癌药物 SN-38（伊立替康类似物）的偶氮衍生物（AzP1）作为一种治疗诊断试剂，具有肿瘤缺氧特异性激活和治疗的潜力。研究发现，治疗诊断用 AzP1 在生物学相关的 pH 范围内稳定，并且对其他竞争性生物分析物表现出化学惰性。然而，在用大鼠肝微粒体处理时，AzP1 在 λ = 560nm 处显示出自我校准的荧光增强。在各种癌细胞系中测试了 AzP1 的细胞毒性。在缺氧条件下，前药 AzP1 表现出激活作用，释放出母体药物（SN-38），并在癌细胞中增强细胞毒性，同时在 560nm 处荧光增强，用于监测药物激活和追踪目的。在异种移植小鼠模型中验证了 AzP1 对肿瘤特异性激活和抑制肿瘤重量的治疗潜力。总之，合成的简便性、缺氧敏感性激活以及有希望的治疗特性突出了治疗诊断用 AzPI 在未来癌症治疗方案中的潜力。
