ReviewChemiluminescence as diagnostic tool. A review
Introduction
In clinical chemistry, most of the compounds of interest are present in the body fluids at concentrations so low that common analytical methods are not efficient for their determination. In 1959, Yalow and Berson proposed to determine these products using antibody antigen reactions after radiolabeling of one of the partners, the antigen (insulin) in order to discriminate bound and free components [1]. This method is now widely used but known drawbacks of radioisotopes e.g. health hazard, waste disposal problems, short half-life, conjugate radiolysis and legislative bias have induced intensive search for alternative labels [2], [3], [4]. Moreover, the widespread opinion that radioactive labels are unsuitable for non-separation protocols increases the need for compounds allowing non-isotopic detection although homogeneous immunoassays have been described, using low-energy as well as high-energy radioisotopes, since the past decade [5], [6]. Luminescence and especially chemiluminescence is one of these alternatives.
Luminescence is a term used to describe the emission light, which occurs when a molecule in an excited state relaxes to its ground state. The various types of luminescence differ from the source of energy to obtain the excited state. This energy can be supplied by electromagnetic radiation (photoluminescence also termed as fluorescence or phosphorescence), by heat (pyroluminescence), by frictional forces (triboluminescence), by electron impact (cathodoluminescence) or by crystallization (crystalloluminescence). In chemiluminescence, the energy is produced by a chemical reaction [7]. Since excitation is not required for sample radiation, problems frequently encountered in photoluminescence as light scattering or source instability are absent in chemiluminescence. High backgrounds due to unselective photoexcitation are absent too: there is no need for time resolved detection. Consequently, luminometers based on a rough light detection by photomultiplier tubes are among the cheapest devices in the field [8], [9], [10].
In an excellent paper, Rongen et al. have reviewed the main advantages of chemiluminescence labeling and detection in immunoassays [11]. They have pointed out the large linear response reaching up to six orders of magnitude, the fast emission of light especially when it is generated in a single flash, the high stability of several reagents and most of the conjugates (increased stability is often observed after conjugation), the low consumption of expensive reagents. They have also noted the short incubation times owing to the high sensitivity generally achieved, the full compatibility with homogeneous or heterogeneous, competitive or not competitive, direct or indirect immunoassays or immunometric assays developed in one step as well as two steps formats and finally the absence of toxicity. These statements valid until 1994, especially the last one, remain true at the present time.
Kricka and his co-workers have also published several review articles dealing with chemiluminescence. Some of these cover the early developments of chemiluminescence [12] or applications to all fields which can benefit from chemiluminescence [13] while others published regularly up to 1997 are devoted to recent advances of this method in clinical chemistry [14], [15], [16], [17], [18], [19], [20], [21].
Although chemiluminescence has been widely used as detection method in many fields as flow injection analysis [22], high performance liquid chromatography [23], capillary electrophoresis [24] and thin layer chromatography [25], this paper will focus on applications in the field of diagnostic.
Section snippets
Generalities
Chemiluminescence, which is the phenomenon observed when the vibronically excited product of an exoergic reaction relaxes to its ground state with emission of photons, can be defined in simplistic terms: chemical reactions that emit light [26]. The chemical reaction produces energy in sufficient amount (approximately 300 kJ mol−1 for blue light emission and 150 kJ mol−1 for red light emission) to induce the transition of an electron from its ground state to an excited electronic state. This
History
Luminous animals are known since the ancient Greek civilization but ‘artificial’ chemiluminescence was first described in 1877 by Radziszewski who observed the yellow light emission when oxygen was bubbled into an alkaline ethanolic solution of 2,4,5-triphenylimidazole (lophine) [33]. Fifty years later, Albrecht reported the luminescent properties of 5-amino-2,3-dihydrophtalazine-1,4-dione (luminol) [34]. Acridinium derivatives were known as chemiluminogenic molecules since Gleu and Petsch, in
Reaction mechanism
Luminol derivatives react following a simplified reaction scheme given at the Fig. 2. The key intermediate is an α-hydroxyperoxide obtained by oxidation of the heterocyclic ring. The decomposition pattern of this intermediate leading to the excited state and the light emission is unique and depends only on the pH of the system. In contrast, the first step is strongly dependent of the composition of the medium [39].
In aprotic media (dimethylsulphoxide or dimethylformamide), only oxygen and a
Reaction mechanism
The mechanism has been studied in detail by McCapra [36], [148], [149]. The most probable mechanism is presented at Fig. 6. All intermediates, except the dioxetanone, have been isolated and characterized [150]. From spectrophotometrical (bright blue chemiluminescence from acridone and bright yellow–green chemiluminescence from its anion) and chemical (effects of base concentration and solvent composition) arguments, White hesitates to recognize the dioxetanone ring as an intermediate in the
Coelenterazine and synthetic derivatives
The structure of coelenterazine is given at Table 2. Coelenterazine, which is the prosthetic group of a coelenterate protein [197], has been synthesized by different methods [198], [199], [200], [201].
The chemiluminescence of coelenterazine is triggered by the superoxide anion. In contrast with luminol, the reaction is very specific and there is no need for catalytic removal of hydrogen peroxide before its determination. Consequently, coelenterazine has been proposed as a sensitive and
Dioxetanes
From the chemiluminescence mechanism of previously developed chemiluminogenic tracers, it can be predicted that substituted 1,2-dioxetanes be luminogenic emitters [8]. 3-3,4-trimethyl-1,2-dioxetane has been synthesized since 1969. More than 200 different molecules have been prepared up to now [214].
Reaction mechanism
Several oxalate derivatives are oxidized by hydrogen peroxide giving high-energy intermediates. A gaseous intermediate has been isolated from the reaction mixture of oxalate and hydrogen peroxide and used subsequently to produce emission in the presence of a fluorescent acceptor molecule. The proposed intermediate is dioxetanedione. In contrast with the chemiluminogenic compounds cited above, the high-energy intermediate produced in this reaction is not fluorescent and, therefore, cannot emit
Conclusions
This review deals with the application of various chemiluminescent detection methods in the fields of diagnostic and biomedical research. Compounds belonging to five chemical classes: acylhydrazides, acridinium derivatives, dioxetanes, coelenterazines and peroxyoxalic derivatives are currently used. Each of them has advantages well balanced by some drawbacks with the result that none can be definitively preferred to the others.
Acylhydrazides like (iso)luminol are still the most frequently used
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