Self‐propagating amplification reactions for molecular detection and signal amplification: Advantages, pitfalls, and challenges

Abstract

Self-propagating cascade reactions are a recent development for chemo-sensing protocols. These cascade reactions, in principle, offer low limits of detection by virtue of exponential signal amplification, and are initiated by a specific, pre-planned molecular detection event. This combination of selectivity for a detection event followed by in situ signal amplification is achieved by exploitation of mechanistic organic chemistry, and thus has resulted in various chemo-sensing protocols that employ one or more reagents to achieve the desired selectivity and sensitivity for an assay. Species such as hydrogen peroxide, thiols, and fluoride, have been used as active reagents to initiate the first examples of self-propagating signal amplification reactions, although many other active reagents should be compatible with the approaches. A common feature of the reagents that support the self-propagating signal amplification reactions is the involvement of quinonemethide intermediates resulting from elimination of optical reporters and/or active reagents, where the latter propagates the signal amplification reaction. The early examples of these amplification sequences, however, are slow to reach full signal, thus leaving time for background reactions to generate non-specific signals. This issue of background has limited practical applications of these self-propagating signal amplification reactions, as has challenging synthetic routes to the reagents, as well as the potential for other chemical species to interfere with the detection and signal amplification processes. Thus, the goal of this review is to summarize the progress of self-propagating signal amplification technology, identify the pitfalls of current designs, and by doing so, to stimulate future studies in this growing and promising research area.

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s

“…More generally, these studies provide a structural and mechanistic basis for the design of selfimmolative polymers or linkers for applications where appropriate environmental triggers can lead to selective degradation, degradation product amplication, or payload release. [1][2][3]5,8,16 Abbreviations…”

“…[1][2][3] These stimuli-responsive degradations are now being leveraged in biomedical materials as a means to initiate complexation and then release therapeutic cargos under specic biological conditions/environments. [1][2][3][4][5][6][7][8][9] These features provide an attractive platform for the delivery of compounds, such as drugs, proteins or polynucleotides, which must be protected until they reach their therapeutic destination. Several classes of stimuli-responsive degrading materials have been reported in the literature: end-capped systems that upon cleavage of a terminal group undergo an end-to-end (or self-immolative) degradation, and systems in which the polymer backbone is cleaved by appropriately positioned nucleophiles.…”

“…Self-immolative polymers that undergo quinone (or azaquinone) methide elimination upon removal of an endcap have been investigated in detail by Shabat, 10 Gillies, 7, 11 Phillips, 12-14 and others. 1,3 Various types of stimuli have been explored to trigger the removal of the terminal end-group, including pH changes, enzymatic activities, or oxidative cleavage with H 2 O 2 .…”

Dynamic contrast with reversibly photoswitchable fluorescent labels for imaging living cells

“…Such a detection level is at the limits required for real time imaging of key cell factors such as transcription factors or RNA molecules. Strategies of signal amplications relying on reaction cascades 4 or labeling with enzymes 5 are currently under development.…”

Base-triggered self-amplifying degradable polyurethanes with the ability to translate local stimulation to continuous long-range degradation

“…An alternative approach uses autocatalytic degradation chemistry wherein a specic catalytic trigger causes chain cleavage and generation of additional triggers for acceleration of the degradation. [17][18][19][20][21] Phillips and coworkers reported that ROMP polymers with appropriate pendant chains could exhibit dramatic changes in macroscopic properties through amplied, self-propagating side-chain reactions. 22,23 In particular, a global switch in hydrophobicity and a change in the optical properties of a lm occurred with local stimulation.…”