A Nitronaphthalimide Probe for Fluorescence Imaging of Hypoxia in Cancer Cells

Rashmi Kumari,Ganesh Venkatachalam,Suresh D. Kulkarni,Badri Narain Pandey,Thivaharan Varadavenkatesan,Anil Kumar N. V,Raghumani Singh Ningthoujam,Vasumathy R,Dhanya Sunil

doi:10.1007/s10895-021-02800-6

Abstract

The bioreductive enzymes typically upregulated in hypoxic tumor cells can be targeted for developing diagnostic and drug delivery applications. In this study, a new fluorescent probe 4−(6−nitro−1,3−dioxo−1H−benzo[de]isoquinolin−2(3H)−yl)benzaldehyde (NIB) based on a nitronaphthalimide skeleton that could respond to nitroreductase (NTR) overexpressed in hypoxic tumors is designed and its application in imaging tumor hypoxia is demonstrated. The docking studies revealed favourable interactions of NIB with the binding pocket of NTR-Escherichia coli. NIB, which is synthesized through a simple and single step imidation of 4−nitro−1,8−naphthalic anhydride displayed excellent reducible capacity under hypoxic conditions as evidenced from cyclic voltammetry investigations. The fluorescence measurements confirmed the formation of identical products (NIB-red) during chemical as well as NTR−aided enzymatic reduction in the presence of NADH. The potential fluorescence imaging of hypoxia based on NTR-mediated reduction of NIB is confirmed using in-vitro cell culture experiments using human breast cancer (MCF−7) cells, which displayed a significant change in the fluorescence colour and intensity at low NIB concentration within a short incubation period in hypoxic conditions.Graphical abstract

Highlights

Cancer is a pathological condition wherein cells undergo abnormal and uncontrolled division in an alarming rate to form a malignant tumor which can subsequently invade the surrounding tissues and later metastasize to secondary locations [1]
As normal cellular environment does not comprise of these unique and hostile settings perceived in hypoxic tumours, the oxygen gradient in solid tumors can be exploited for developing hypoxia based cancer imaging to aid diagnostic purposes, and in fabricating hypoxia specific drug delivery systems for cancer therapy
The present study demonstrated the design of a nitronaphthalimide derivative NIB which displayed excellent molecular interactions in docking studies with E. coli−NTR

Summary

Introduction

Cancer is a pathological condition wherein cells undergo abnormal and uncontrolled division in an alarming rate to form a malignant tumor which can subsequently invade the surrounding tissues and later metastasize to secondary locations [1]. Remarkable increase in fluorescence intensity and colour change from blue to green upon chemical and NTR-mediated reductions of NIB.

Results

Conclusion