ABSTRACT
Novel BODIPY photosensitizers were developed for imaging-guided photodynamic therapy. The introduction of a strong electron donor to the BODIPY core through a phenyl linker combined with the twisted arrangement between the donor and the BODIPY acceptor is essential for reducing the energy gap between the lowest singlet excited state and the lowest triplet state (ΔEST ), leading to a significant enhancement in the intersystem crossing (ISC) of the BODIPYs. Remarkably, the BDP-5 with the smallest ΔEST (ca. 0.44â eV) exhibited excellent singlet oxygen generation capabilities in both organic and aqueous solutions. BDP-5 also displayed bright emission in the far-red/near-infrared region in the condensed states. More importantly, both inâ vitro and inâ vivo studies demonstrated that BDP-5 NPs displayed a high potential for photodynamic cancer therapy and bioimaging.
Subject(s)
Boron Compounds/chemistry , Boron Compounds/pharmacology , Drug Design , Molecular Imaging/methods , Photochemotherapy/methods , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Boron Compounds/therapeutic use , Cell Line, Tumor , Humans , Photosensitizing Agents/therapeutic useABSTRACT
A novel strategy for designing highly efficient and activatable photosensitizers that can effectively generate reactive oxygen species (ROS) under both normoxia and hypoxia is proposed. Replacing both oxygen atoms in conventional naphthalimides (RNI-O) with sulfur atoms led to dramatic changes in the photophysical properties. The remarkable fluorescence quenching (ΦPL ≈ 0) of the resulting thionaphthalimides (RNI-S) suggested that the intersystem crossing from the singlet excited state to the reactive triplet state was enhanced by the sulfur substitution. Surprisingly, the singlet oxygen quantum yield of RNI-S gradually increased with increasing electron-donating ability of the 4-R substituents (MANI-S, ΦΔ ≈ 1.00, in air-saturated acetonitrile). Theoretical studies revealed that small singlet-triplet energy gaps and large spin-orbit coupling could be responsible for the efficient population of the triplet state of RNI-S. In particular, the ROS generation ability of MANI-S was suppressed under physiological conditions due to their self-assembly and was significantly recovered in cancer cells. More importantly, cellular experiments showed that MANI-S still produced a considerable amount of ROS even under severely hypoxic conditions (1% O2) through a type-I mechanism.
Subject(s)
Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Drug Design , HeLa Cells , Humans , Molecular Structure , Oxygen , PhotochemotherapyABSTRACT
The naphthoimidazolium borane 4 is shown to be a selective probe for HOCl over other reactive oxygen species. Unlike other boronate-reactive oxygen species (ROS) fluorogenic probes that are oxidized by HOCl through a nucleophilic borono-Dakin oxidation mechanism, probe 4 is distinguished by its electrophilic oxidation mechanism involving B-H bond cleavage. Two-photon microscopy experiments in living cells and tissues with the probe 4 demonstrate the monitoring of endogenous HOCl generation and changes in HOCl concentrations generated in the endoplasmic reticulum during oxidative stress situations.
Subject(s)
Boranes/chemistry , Endoplasmic Reticulum/metabolism , Fluorescent Dyes/chemistry , Hypochlorous Acid/analysis , Imidazoles/chemistry , Animals , Boranes/chemical synthesis , Boranes/radiation effects , Cell Line, Tumor , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Humans , Hydrolysis , Hypochlorous Acid/metabolism , Imidazoles/chemical synthesis , Imidazoles/radiation effects , Male , Mice , Microscopy/methods , Oxidation-Reduction , RAW 264.7 Cells , Rats, Sprague-Dawley , Ultraviolet RaysABSTRACT
Theranostics that combines both diagnosis and therapy into a single platform has recently emerged as a promising biomedical approach for cancer treatment; however, the development of efficient theranostic agents with excellent optical properties remains a challenge. Here, we report novel mitochondria-targeting BODIPY photosensitizers (R-BODs) that possess considerable singlet oxygen generation capabilities and good fluorescence properties for imaging-guided photodynamic therapy (PDT). The incorporation of sulfur atoms into the π-conjugated skeleton of BODIPY along with the introduction of different functional groups at the meso-position of the BODIPY core is essential for tuning the photophysical and photosensitizing properties. Notably, the MeOPh-substituted thiophene-fused BODIPY (MeO-BOD, R = p-methoxyphenyl) displayed the highest singlet oxygen generation capability (Φ Δ ≈ 0.85 in air-saturated acetonitrile) and a moderate fluorescence quantum yield (Φ f = 17.11). Furthermore, MeO-BOD showed good biocompatibility, low dark toxicity and superior fluorescence imaging properties in living cells. More importantly, the PDT efficacy of mitochondria-specific anchoring of MeO-BOD was remarkably amplified with an extremely low half-maximal inhibitory concentration (IC50) value of 95 nM. We believe that the incorporation of an electron-donating group at the meso-position of the thiophene-fused BODIPY platform may be an effective approach for developing theranostic agents for precision cancer therapy.
ABSTRACT
Novel thiocarbonyl derivatives (NIS and CRNS) with excellent ROS generation abilities are synthesized and studied as potential photosensitizers for one- and two-photon excited photodynamic therapy. In particular, NIS-Me and CRNS display outstanding phototoxicity toward HeLa cells under two-photon excitation (800 nm) with negligible dark toxicity.