Department of Chemistry, The University of Texas at Austin , Austin, Texas 78712-1224, United States.
Department of Biological Sciences, Laboratory of Stem Cell Research and Biotechnology, Hyupsung University , Hwasung-si 18330, Korea.
J Am Chem Soc. 2017 Jun 7;139(22):7595-7602. doi: 10.1021/jacs.7b02396. Epub 2017 May 10.
A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.
在光动力癌症治疗 (PDT) 中，一个主要的挑战是避免 PDT 诱导的缺氧，这可能通过激活各种血管生成因子导致癌症复发和进展，并显著降低治疗效果。本文报道了一种乙酰唑胺 (AZ) 偶联的 BODIPY 光敏剂 (AZ-BPS)，旨在通过将抗血管生成治疗与 PDT 的优势相结合，减轻基于 PDT 的缺氧的影响。AZ-BPS 对表达碳酸酐酶 IX (CAIX) 的侵袭性癌细胞 (MDA-MB-231 细胞) 具有特异性亲和力。与缺乏乙酰唑胺单元的类似 PDT 试剂 BPS 相比，它显示出增强的光细胞毒性。与 BPS 相比，AZ-BPS 还在异种移植小鼠肿瘤再生长模型中显示出增强的体内疗效，这归因于 PDT 诱导的 ROS 生成和 CAIX 敲低对肿瘤血管生成的抑制作用。AZ-BPS 在从乳腺癌患者收集的临床样本中成功进行了评估。因此，我们认为，这里描述的联合方法代表了一种有吸引力的治疗方法，可用于靶向表达 CAIX 的肿瘤。
