Search

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.

Osmium (Os)-based photosensitizers (PSs) exhibit unique broad, red-shifted absorption, favoring PDT activity at greater tissue depths. We recently reported on a potent Os(II) PS, rac-[Os(phen)2(IP-4T)](Cl)2 (ML18J03) with submicromolar hypoxia activity. ML18J03 exhibits a low luminescence quantum yield of 9.8 × 10−5 in PBS, which limits its capacity for in vivo luminescence imaging. We recently showed that formulating ML18J03 into 10.2 nm DSPE-mPEG2000 micelles (Mic-ML18J03) increases its luminescence quantum yield by two orders of magnitude. Here, we demonstrate that Mic-ML18J03 exhibits 47-fold improved accumulative luminescence signals in orthotopic AT-84 head and neck tumors. We show, for the first time, that micellar formulation provides up to 11.7-fold tumor selectivity for ML18J03. Furthermore, Mic-ML18J03 does not experience the concentration-dependent quenching observed with unformulated ML18J03 in PBS, and formulation reduces spectral shifting of the emission maxima during PDT (variance = 6.5 and 27.3, respectively). The Mic-ML18J03 formulation also increases the production of reactive molecular species 2–3-fold. These findings demonstrate that micellar formulation is a versatile and effective approach to enable in vivo luminescence imaging options for an otherwise quenched, yet promising, PS.

We report a new class of ruthenium (Ru)-based photosensitizers that induce potent cytotoxicity in melanoma cells following activation with NIR light. In addition to the direct cytotoxic effect, this Ru-based photodynamic therapy induces immunogenic cell death in melanoma cells that can be therapeutically exploited to establish protective antitumor immunity.

Intra-operative photodynamic therapy (IO-PDT) in combination with surgery for the treatment of non-small cell lung cancer and malignant pleural mesothelioma has shown promise in improving overall survival in patients. Here, we developed a PDT platform consisting of a ruthenium-based photosensitizer (TLD1433) activated by an optical surface applicator (OSA) for the management of residual disease. Human lung adenocarcinoma (A549) cell viability was assessed after treatment with TLD1433-mediated PDT illuminated with either 532- or 630-nm light with a micro-lens laser fiber. This TLD1433-mediated PDT induced an EC50 of 1.98 μM (J/cm2) and 4807 μM (J/cm2) for green and red light, respectively. Cells were then treated with 10 µM TLD1433 in a 96-well plate with the OSA using two 2-cm radial diffusers, each transmitted 532 nm light at 50 mW/cm for 278 s. Monte Carlo simulations of the surface light propagation from the OSA computed light fluence (J/cm2) and irradiance (mW/cm2) distribution. In regions where 100% loss in cell viability was measured, the simulations suggest that >20 J/cm2 of 532 nm was delivered. Our studies indicate that TLD1433-mediated PDT with the OSA and light simulations have the potential to become a platform for treatment planning for IO-PDT.