Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release

Abstract

Singlet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride‐triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds.

A Review on Gold Nanoclusters for Cancer Phototherapy

“…In PDT, 1 O 2 produced by PSs has a very short lifetime (<40 ns) and a very short diffusion distance of 20 nm, which is significantly smaller than the cell diameter. This will result in incomplete tumor ablation, which would eventually cause tumor recurrence. , In PTT, especially high-temperature PTT, due to heat conduction, heat will inevitably affect normal tissues adjacent to tumors, causing additional injury or trauma . Therefore, accurate phototherapy is urgently required.…”

“…This will result in incomplete tumor ablation, which would eventually cause tumor recurrence. 99,100 In PTT, especially high-temperature PTT, due to heat conduction, heat will inevitably affect normal tissues adjacent to tumors, causing additional injury or trauma. 101 Therefore, accurate phototherapy is urgently required.…”

Iridium(III)-Based Infrared Two-Photon Photosensitizers: Systematic Regulation of Their Photodynamic Therapy Efficacy

“…1,2 The functionality of PDT is, to a specific extent, dependent on the presence of oxygen. 3,4 The efficacy of PDT is significantly diminished in tumors, especially in large solid tumors, due to the presence of a hypoxic environment. 5,6 The integration of PDT with various other innovative therapeutic approaches, including photothermal therapy (PTT), photoacoustic therapy (PAT), photochemotherapy (PCT), and immunogenic cell death (ICD), has the potential to synergistically enhance treatment effectiveness and minimize the required dosage of therapeutic agents.…”

“…Photodynamic therapy (PDT) is a promising approach for cancer treatment, wherein the activation of photosensitizers (PSs) by light irradiation leads to the generation of reactive oxygen species (ROS). This process ultimately induces the noninvasive eradication of tumor cells. , The functionality of PDT is, to a specific extent, dependent on the presence of oxygen. , The efficacy of PDT is significantly diminished in tumors, especially in large solid tumors, due to the presence of a hypoxic environment. , The integration of PDT with various other innovative therapeutic approaches, including photothermal therapy (PTT), photoacoustic therapy (PAT), photochemotherapy (PCT), and immunogenic cell death (ICD), has the potential to synergistically enhance treatment effectiveness and minimize the required dosage of therapeutic agents. − Taking a step back to assert, for PDT alone, the mechanisms underlying the construction of highly active molecules or materials through structural regulation are considered to be largely unidentified. , …”

Enzyme activatable photodynamic therapy agents targeting melanoma

“…11 PSs activatable by reductive enzymes of hypoxic cancer cells have also been widely studied. [12][13][14][15] The reductive power of cancer with an increased level of glutathione tripeptides is also used to control photodynamic action. [16][17][18][19] Various enzymes with characteristic tissue specific expression in the malignant site are used to differentiate cancer cells including matrix metalloproteinases, β-galactosidase and γ-glutamyltranspeptidase.…”