Activity-Based Optical Sensing Enabled by Self-Immolative Scaffolds: Monitoring of Release Events by Fluorescence or Chemiluminescence Output

ConspectusFunctional molecular scaffolds comprised of self-immolative adaptors are being used in widespread applications in the fields of enzyme activity analyses, signal amplification, and bioimaging. Optically detected chemical probes are very promising compounds for sensing and diagnosis, since they present several attractive features such as high specificity, low detection limits, fast response times, and technical simplicity. During the last two decades, we have developed several distinct molecular scaffolds that harness the self-immolative disassembly feature of these adaptors to amplify chromogenic output for diagnosis and drug delivery applications. In order to study the molecular behavior of the various amplification systems, an optical output, used to monitor the progress of the disassembly pattern, was required. Therefore, over the course of our research, diverse molecular scaffolds that produce an optical signal in response to a disassembly step, were evaluated. These optically active scaffolds have been incorporated into self-immolative dendrimers and self-immolative polymers to implement unique disassembly properties that result with linear and exponential signal amplification capabilities. In addition, some scaffolds, aimed for linker technology, were used in delivery systems to monitor release of drug molecules. The optical signal used to monitor the release event could be produced by analysis of reporter molecules with chromogenic or fluorogenic properties. Recently, we have also developed molecular scaffolds modified to produce a chemiluminescent signal to monitor the self-immolative disassembly step. The main advantage of these scaffolds over others is the use of chemiluminescence as an output signal. It is well-known that chemiluminescence is considered as one the most sensitive diagnostic methods due to its high signal-to-noise ratio. The unique structures of the self-immolative chemiluminescence scaffolds have been used in the design of three different distinctive concepts: self-immolative chemiluminescence polymers, auto-inductive amplification systems with chemiluminescence signal and monitoring of drug release by a chemiluminescence output. Furthermore, we reported the design and synthesis of the first theranostic prodrug for the monitoring of drug release achieved by a chemiluminescence mode of action. Quinone-methide elimination has proven to serve as a valuable functional tool for composing molecular scaffolds with self-immolative capabilities. Such scaffolds function as molecular adaptors that can almost simultaneously release a target molecule with an accompanied emission of a light signal that is used to monitor the release event. We anticipate that these self-immolative scaffolds will continue to find utility as functional linkers in various chemical and biological research areas such as drug delivery, theranostic applications, and as molecular sensors with signal amplification.