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Abstract Phototherapy approaches include photodynamic therapy (PDT), which utilizes chemically stable photocatalysts to sensitize the conversion of endogenous molecules such as oxygen (O₂) to form transient reactive species such as¹O₂, and photopharmacology, a complementary approach that relies on molecules that undergo self‐modifying photochemistry, such as bond cleavage reactions or isomerization, for the creation of biologically active products. While Ru(II) polypyridyl systems have demonstrated utility for both approaches, related organometallic systems are relatively less explored. Here, the photochemistry and photobiological responses were compared for five Ru(II) arene compounds containing photolabile monodentate azine ligands and the π‐expansive bidentate ligands dipyrido[3,2‐a:2′,3′‐c]phenazine (dppz), 4,5,9,16‐tetraaza‐dibenzo[a,c]naphthacene (dppn), and α‐terthienyl‐appended imidazo[4,5‐f][1,10]phenanthroline (IP‐3T). The compounds demonstrated significant light‐mediated photocytotoxicity in lung cancer and melanoma cell lines, with up to 6000‐fold increases in cytotoxicity upon irradiation. The arene systems were capable of partitioning between different excited state relaxation pathways, both releasing the monodentate ligand and generating¹O₂, but with notably low yields that did not correlate with the photocytotoxicity of the systems. The organometallic compounds exhibit less mixing of the metal‐associated and ligand‐centered excited states than analogous polypyridyl coordination compounds, providing a structurally, photochemically, and photobiologically distinct class of compounds that can support both metal‐ and ligand‐centered reactivity. 

Abstract Incomplete surgical resection in head and neck cancer can lead to locoregional recurrence in >35% of patients. Approaches such as image‐guided surgery (IGS) and post‐operative photodynamic therapy (PDT) have been proposed to reduce recurrence rates. However, the PDT doses needed to eliminate all unresected diseases are not established. This in vitro proof‐of‐concept study aims to predict head and neck tumor nodule viability in vitro following PDT with TLD1433 using the IGS probe ABY‐029. ABY‐029 is an EGFR‐specific affibody‐IRDye800CW conjugate that has undergone Phase 0 evaluation studies in head and neck cancer, among others. TLD1433 is a ruthenium‐based photosensitizer in a Phase II trial for non‐muscle invasive bladder cancer. Here, we demonstrate that decreases in fluorescence emission of ABY‐029 bound to MOC1 mouse head and neck cancer nodules in vitro can be predictive of TLD1433 PDT responses. Results show that photoactivation of TLD1433 produces reactive oxygen species (ROS) that reduce MOC1 nodule fractional viability in a manner that is inversely correlated with ABY‐029 fluorescence intensity (Pearson'sr = −0.9148,R² = 0.8369,p < 0.0001). We hypothesize that this is due to ROS‐mediated degradation of IRDye800CW. The findings warrant further studies using head and neck cancer nodules with heterogenous PDT responses and EGFR expression levels. If successful, the future goal would be to use ABY‐029 to guide the dosimetry of intraoperative PDT of the surgical bed after IGS to eliminate all microscopic diseases, reduce recurrence rates, and prolong survival. 

Abstract This study employs TLD1433, a Ru^II‐based photodynamic therapy (PDT) agent in human clinical trials, as a benchmark to establish protocols for studying the excited‐state dynamics of photosensitizers (PSs)in cellulo, in the local environment provided by human cancer cells. Very little is known about the excited‐state properties of any PS in live cells, and for TLD1433, it isterra incognita. This contribution targets a general problem in phototherapy, which is how to interrogate the light‐triggered, function‐determining processes of the PSs in the relevant biological environment, and establishes methodological advances to study the ultrafast photoinduced processes for TLD1433 when taken up by MCF7 cells. We generalize the methodological developments and results in terms of molecular physics by applying them to TLD1433’s analogue TLD1633, making this study a benchmark to investigate the excited‐state dynamics of phototoxic compounds in the complex biological environment. 

Ligand photoejection from a strained Ru(ii) polypyridyl complex (RuP) results in dramatic modulation of amyloid-β (Aβ) peptide aggregation with the ejected ligand displaying additional benefits by limiting ROS generationviaCu sequestration. 

Traditional external light-based Photodynamic Therapy (PDT)’s application is limited to the surface and minimal thickness tumors because of the inefficiency of light in penetrating deep-seated tumors. To address this, the emerging field of radiation-activated PDT (radioPDT) uses X-rays to trigger photosensitizer-containing nanoparticles (NPs). A key consideration in radioPDT is the energy transfer efficiency from X-rays to the photosensitizer for ultimately generating the phototoxic reactive oxygen species (ROS). In this study, we developed a new variant of pegylated poly-lactic-co-glycolic (PEG-PLGA) encapsulated nanoscintillators (NSCs) along with a new, highly efficient ruthenium-based photosensitizer (Ru/radioPDT). Characterization of this NP via transmission electron microscopy, dynamic light scattering, UV-Vis spectroscopy, and inductively coupled plasma mass-spectroscopy showed an NP size of 120 nm, polydispersity index (PDI) of less than 0.25, high NSCs loading efficiency over 90% and in vitro accumulation within the cytosolic structure of endoplasmic reticulum and lysosome. The therapeutic efficacy of Ru/radioPDT was determined using PC3 cell viability and clonogenic assays. Ru/radioPDT exhibited minimal cell toxicity until activated by radiation to induce significant cancer cell kill over radiation alone. Compared to protoporphyrin IX-mediated radioPDT (PPIX/radioPDT), Ru/radioPDT showed higher capacity for singlet oxygen generation, maintaining a comparable cytotoxic effect on PC3 cells.