COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models

Hyeong Seok Kim, Amit Sharma, Wen Xiu Ren, Jiyou Han, Jong Seung Kim

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalBiomaterials
Volume185
DOIs
Publication statusPublished - 2018 Dec 1

Keywords

  • Anti-angiogenesis
  • Cancer therapy
  • COX-2
  • Hypoxia
  • Indomethacin

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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