Abstract 4302: The development study of hypoxia responsive chemiluminescent probe for tumor hypoxia imaging

Abstract

Abstract Introduction: The tumor microenvironment is recognized as a major factor that influences not only the response to conventional anticancer therapies but also the potential for malignant progression and metastasis. Therefore, it is considered that tumor hypoxia imaging is critical for cancer diagnosis and therapy. As optical modalities offer the advantages of non-invasive, easy-to-handle, and cost-effective imaging, much effort has been done to develop synthetic fluorescent imaging probes for tumor hypoxia. In particular, we focus our attention on chemiluminescence imaging which can avoid interference from tissue autofluorescence and scattering light. We therefore show the development of hypoxia responsive chemiluminescent probe, which has the advantage of lower detection limits and improved signal-to-noise ratio compared to existing fluorescent probes. Results and discussion: In our molecular design, luminescence is derived from 1,2-dioxetane cleavage triggered by hypoxia-selective enzymatic reduction of electron-deficient aromatics. At the start, nitrobenzyl moiety was chosen as a bioreductively cleavable protective group linked to 1,2-dioxetane moiety through phenyl ether linker to construct synthetic probe NB-Adm. The compound was synthesized from 2-adamantanone in 19% (overall yield, 6 steps). Then NB-Adm was attempted to be reduced by nitroreductase, however, no luminescence was observed. HPLC analysis of the reaction mixture indicated that our expected reduction did not occur, probably because bulky adamantane moiety prevented the enzymatic reaction owing to steric hindrance. Therefore, a self-immolative linker was employed to keep away 1,2-dioxetane moiety from enzyme recognition moiety. In this time, quinone moiety was chosen as a protective group which was expected to be better substrate than nitrophenyl one in terms of their redox potential. This newly designed compound, TMQ-Adm was synthesized from 2-adamantanone in 16% (overall yield, 6 steps). By the use of TMQ-Adm, we successfully observed luminescent emission from the reaction with nitroreductase. This implied that our bioredctively activatable probe can be applicable for chemiluminescence imaging for tumor hypoxia. Now we are investigating to develop chemiluminescent probe to realize in vivo imaging of tumor hypoxia by improving luminescent quantum yield under physiological condition. Citation Format: Kensuke Okuda, Toru Ban, Tasuku Hirayama, Hideko Nagasawa. The development study of hypoxia responsive chemiluminescent probe for tumor hypoxia imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4302. doi:10.1158/1538-7445.AM2014-4302