Dark Dynamic Therapy: Photosensitization without Light Excitation Using Chemiluminescence Resonance Energy Transfer in a Dioxetane-Erythrosin B Conjugate.

Reactive oxygen species (e.g., singlet oxygen) are the primary cytotoxic agents used in the clinically approved technique photodynamic therapy (PDT). Although singlet oxygen has high potential to effectively kill tumor cells, its production via light excitation of a photosensitizer has been limited by the penetration depth and delivery of light in tissue. To produce singlet oxygen without light excitation, we describe the use of Schaap's chemiluminescent scaffold comprising an adamantylidene-dioxetane motif. Functionalizing this scaffold with a photosensitizer, Erythrosin B, resulted in spontaneous chemiluminescence resonance energy transfer (CRET) leading to the production of singlet oxygen. We show that this compound is cell permeable and that the singlet oxygen produced via CRET is remarkably efficient in killing cancer cells at low micromolar concentrations. Moreover, we demonstrate that protection of the phenol on the chemiluminescent scaffold with a nitroreductase-responsive trigger group allows for cancer-selective dark dynamic cell death. Here, we present the concept of dark dynamic therapy using a small cell-permeable molecule capable of producing the effects of PDT in cells, without light.

Introducing the Tellurophene-Appended BODIPY: PDT Agent with Mass Cytometry Tracking Capabilities.

The synthesis and characterization of the first BODIPY appended to the five-membered heterocylic tellurophene [Te] moiety is reported. By incorporating tellurophene at the meso position, the tellurophene-appended boron-dipyrromethene dye (BODIPY) acts as a multimodal agent, becoming a potent photosensitizer with a mass cytometry tag. To synthesize the compound, we developed a method to enable late-stage Suzuki-Miyaura coupling by preparing and isolating tellurophene-2-BPin in a one-step procedure from the parent tellurophene. Coupling to a meso-substituted BODIPY functionalized with a pendant aryl bromide provides the desired tellurophene-appended BODIPY. This compound demonstrated a singlet oxygen quantum yield of 0.26 ± 0.01 and produced a light dose-dependent cytotoxicity with nanomolar IC50 values against 2D cultured HeLa cells and high efficacy against 3D cultured HeLa tumor spheroids, proving to be a strong photosensitizer. The presence of the tellurophene moiety could be detected using mass cytometry, thus showcasing the ability of a tellurophene-appended BODIPY as a novel photodynamic-therapy-mass-cytometry theranostic agent.