Hydrogen Sulfide Responsive Phototherapy Agents: Design Strategies and Biological Applications

Abstract

Hydrogen sulfide (H2S) is one of the critical gasotransmitters, which play important roles in regular physiological processes, especially in vital signaling pathways. However, fluctuations in endogenous H2S concentration can be linked to serious health problems, such as neurodegenerative diseases, cancer, diabetes, inflammation, cardiovascular diseases, and hypertension. Thus, it has attracted a great deal of attention in therapeutic applications, specifically in the field of phototherapy. Photodynamic therapy (PDT) and photothermal therapy (PTT) are two subclasses of phototherapy, which utilize either reactive oxygen species (ROS) or local temperature increase upon irradiation of a photosensitizer (PS) to realize the therapeutic action. Phototherapies offer unique advantages compared to conventional methods; thus, they are highly promising and popular. One of the design principles followed in new generation PSs is to build activity-based PSs, which stay inactive before getting activated by disease-associated stimuli. These activatable PSs dramatically improve the selectivity and efficacy of the therapy. In this review, we summarize small molecule and nanomaterial-based PDT and PTT agents that are activated selectively by H2S to initiate their cytotoxic effect. We incorporate single mode PDT and PTT agents along with synergistic and/or multimodal photosensitizers that can combine more than one therapeutic approach. Additionally, H2S-responsive theranostic agents, which offer therapy and imaging at the same time, are highlighted. Design approaches, working principles, and biological applications for each example are discussed in detail.

A hydrogen sulfide and tyrosinase responsive dual-locked fluorophore for selective imaging of melanoma cells

“…These cells are both Tyr and H 2 S positive, but Tyr activity is lower compared to B16-F10 cells. 34,42 As shown in Fig. S9 (ESI †), fluorescence intensities were found to be weaker in HeLa and A549 cells as expected, which is in good agreement with the previous literature.…”

“…[25][26][27][28][29] To this end, several fluorescent probes have been developed to detect Tyr and H 2 S individually in melanoma cancer cell lines. 18,[30][31][32][33][34] Recently, a Tyr activatable chemiluminescent probe whose response can be promoted upon addition of a glutathione (GSH) was reported. 35 However, a H 2 S and Tyr dual responsive imaging agent has not been reported yet.…”

A mitochondria-targeted chemiluminescent probe for detection of hydrogen sulfide in cancer cells, human serum and in vivo

“…To address the drawbacks of conventional techniques, fluorescent probes that can offer real-time imaging opportunities, high spatial and temporal resolution, and selectivity without destruction of cells or tissues are highly promising. To this end, numerous activitybased fluorophores have been introduced to image endogenous H 2 S activity [58][59][60][61] including several probes targeting mitochondria. [62][63][64][65] H 2 S has also been used for prodrug activation in numerous literature examples owing to its correlation with tumorogenesis.…”

“…5,45,48 Common H 2 S-triggered reactions that have been used in the activation of these agents and probes are based on nucleophilic addition, thiolysis, reduction of the azide and copper precipitation. 61,[66][67][68] Although highly valuable results have been obtained with conventional fluorophores, their intrinsic problems such as the need for external light irradiation, limited penetration of the excitation light, and the autofluorescence-induced low signal-to-noise ratio limit their broader acceptance and application areas, especially in in vivo models.…”