COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models. (December 2018)

• Record Type: Journal Article
• Authors: Kim, Hyeong Seok; Sharma, Amit; Ren, Wen Xiu; Han, Jiyou; Kim, Jong Seung
• Is Part Of: Biomaterials. Volume 185(2018)
• Page Start: 63
• Page End: 72
• Publication Date: 2018-12
• Subjects: Anti-angiogenesis -- COX-2 -- Hypoxia -- Indomethacin -- Cancer therapy; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2018.09.006
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: 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 thatDA andTA 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.