School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences , Tel-Aviv University , Tel Aviv 69978 Israel.
Acc Chem Res. 2019 Oct 15;52(10):2806-2817. doi: 10.1021/acs.accounts.9b00338. Epub 2019 Sep 4.
Functional 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.
由自耗性衔接子组成的功能分子支架在酶活性分析、信号放大和生物成像等领域得到了广泛的应用。光检测化学探针是一种很有前途的用于传感和诊断的化合物，因为它们具有高特异性、低检测限、快速响应时间和技术简单等特点。在过去的二十年中，我们开发了几种不同的分子支架，利用这些衔接子的自耗性分解特征来放大显色输出，用于诊断和药物输送应用。为了研究各种放大系统的分子行为，需要有一种光学输出，用于监测分解模式的进展。因此，在我们的研究过程中，评估了各种产生光学信号以响应分解步骤的分子支架。这些具有光学活性的支架已被纳入自耗性树状聚合物和自耗性聚合物中，以实现具有线性和指数信号放大能力的独特分解特性。此外，一些旨在用于连接技术的支架被用于输送系统中，以监测药物分子的释放。用于监测释放事件的光学信号可以通过分析具有显色或荧光性质的报告分子来产生。最近，我们还开发了经过修饰以产生化学发光信号的分子支架，以监测自耗性分解步骤。与其他支架相比，这些支架的主要优势是将化学发光用作输出信号。众所周知，由于其高信噪比，化学发光被认为是最敏感的诊断方法之一。自耗性化学发光支架的独特结构已被用于设计三种不同的独特概念：自耗性化学发光聚合物、具有化学发光信号的自动感应放大系统和通过化学发光输出监测药物释放。此外，我们报告了首例用于监测药物释放的治疗诊断前药的设计和合成，该药物通过化学发光作用模式实现。醌-亚甲醚消除已被证明是一种有价值的功能工具，可用于构建具有自耗性能力的分子支架。这种支架作为分子衔接子，可以几乎同时释放目标分子，并伴随着光信号的发射，用于监测释放事件。我们预计，这些自耗性支架将继续作为功能性连接子在各种化学和生物研究领域得到应用，如药物输送、治疗诊断应用以及作为具有信号放大功能的分子传感器。
