Towards therapeutic automata and hypoxia activated singlet oxygen generators

Abstract

Photodynamic therapy (PDT) is a treatment modality depends on the efficient generation of singlet oxygen (1O2) through excitation of a particular chromophore (sensitizer) followed by an energy transfer to the dissolved oxygen in tumor tissues. Cytotoxic singlet oxygen and other secondary products (reactive oxygen species, ROS) are responsible for the apoptotic and necrotic deaths of the tumor cells. We present a molecular 1:2 demultiplexer (DEMUX) which acts as a "terminator" automaton: once powered up by photoexcitation, the agent releases singlet oxygen to kill cancer cells. Once the cancer cells start apoptosis, the agent interacts with the exposed phosphatidylserines on the external leaflet, and autonomously switches to the signaling mode, turning on a bright emission signal, and turning off singlet oxygen generation. So, the output can switch between singlet oxygen and a confirmatory fluorescence emission for apoptosis, which are mutually exclusive in this design. The automaton that we present here, is based on logic gate considerations and a sound photophysical understanding of the system, and should be a very convincing case of molecular logic with a clear path of progress towards practicality. In another project, we are very much interested in transforming PDT into a more manageable and broadly applicable therapeutic protocol. Our approach to achieve that is to separate photosensitization event from the delivery of singlet oxygen, which is the primary cytotoxic agent of PDT. Thus, a storage compound (endoperoxide) for singlet oxygen has to be designed, which can react with molecular oxygen under typical photosensitization conditions, and then the metastable compound has to be transferred to the tumor site which would release its cargo in response to a chemical or enzymatic cue. This approach assumes that singlet oxygen produced stoichiometrically (as opposed to catalytically through photosensitization) by the chemical transformation of the carrier molecule, would be enough to trigger apoptotic response in cancer cells.