Design, Synthesis and Characterization of Multi-Functionalized Two-Photon Caging Platforms and their Application to Neurotransmitter Photorelease

Description

This is a chemistry proposal focusing on design, synthesis characterization of multifunctionalized two-photon caging platforms and their applications to neurotransmitter photorelease. Recently, the development of two-photon photocleavable molecules is emerging because using two-photon excitation light source is beneficial to biological systems and provide a fine intrinsic 3D localization. Unfortunately, the majority of photolabile protecting groups synthesized nowadays are designed for one-photon applications. Although some of the PPGs were designed to absorb near-infrared light, they still exhibit low two-photon sensitivity. To address these problems, we propose to 1) to design and synthesize a series of multi-functionalized two-photon caging molecules using a modular approach via typical chemical reactions such as Heck and Sonogashira coupling reactions; 2) to conjugate a large variety of bioactive molecules functionalized with carboxyl-, amine-, azide-, and/or bromide groups to mask their bioactivity; 3) to employ these 2P caging platforms as useful tools for photorelease of neurotransmitters in intact brain tissue. As expected, these newly synthesized organic molecules will exhibit large two-photon photolysis cross-section values and high photocleavage efficiency. They become caging tools for protecting bioactive molecules by covalent bond formation and then restoring their biological functions by reversible bond breaking upon near infrared irradiation. As compared to other stimuli-responsive tools, the proposed photon uncaging system is highly biocompatible and non-toxicity. The regulation of bioactive molecule release by two-photon light is in a clean, remote-control, non-toxic and noninvasive manner. This would result in a new paradigm of inputs which allows for spatial and temporal control with high specificity and vanquishing the drawback of chemical inputs such as delivery kinetics and waste accumulation. This newly developed tandem system for two-photon uncaging provides an instantaneous and remote control of quantitative photorelease of bioactive molecules in which it will be beneficial to the community of human healthcare in strengthening therapeutic activity, reducing the side effects, diminishing the needed drug dosage during treatment in addition to the neurophysiologists for the study of receptor functions and synaptic integration with subcellular precision. Additionally, facile design of synthetic pathways and synthesis of a new series of effective two-photon photocleavage molecules are beneficial to synthetic chemists and photochemists for the development of new caged compounds that will enable to integrate to other materials as light-triggered carriers for targeted drug delivery. We envision that these two-photon photoactive molecules can be adopted to revolutionize cell physiology and neurosciences, and hold promise toward use in clinical settings in near future.