Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.

抗血管生成，即阻断血管生成途径，已经被认为是当前癌症治疗方式中的重要组成部分。然而，随着肿瘤血管生成和再生的持续存在，相关的益处已被证明是适度的，这可能是由于其他不确定的复杂血管生成机制所致。本文中，我们开发了消炎痛（IMC）整合系统，可在癌症治疗学应用中介导缺氧反应性前药（TA）和诊断剂（DA）。环氧合酶2（COX-2）在几种癌症类型中的表达升高与严重的支持肿瘤的血管生成因子密切相关。我们利用COX-2抑制的策略很好地增强了抗血管生成诱导的缺氧反应性前药激活。无论在体外和体内结果证明DA和TA对COX-2阳性（+ ve）HeLa和A549癌细胞系具有特异性，并在缺氧条件下具有活化作用。与对照（R1和抗癌药物SN-38）相比，TA在异种移植小鼠模型中以较低的剂量显示出延长的肿瘤保留和增强的治疗效果。我们的结果显着强调了COX-2阻断介导的抗血管生成在补充缺氧反应性药物递送系统（DDS）中的重要性，并且可能有利于更有效的抗肿瘤疗法的快速发展。