Cyclometalated iridium(III) complexes containing an anthracene unit for sensing and imaging singlet oxygen in cellular mitochondria.

Singlet oxygen (1O2), as a highly reactive oxygen species, plays an important role in the physical, chemical and biomedical fields, especially during photodynamic therapy (PDT) process. In this work, two iridium(III) complexes containing an anthracene unit in their diimine ligand were designed and synthesized to monitor 1O2 in living cells. The complexes were weakly emissive owing to the photoinduced electron transfer process, but exhibited intense luminescence upon capturing 1O2, resulting from the formation of the corresponding endoperoxide analogues. The remarkable turn-on luminescence response was specific toward 1O2 and in preference to other reactive oxygen species. The utilization of one of the complexes for imaging 1O2 in living cells has also been demonstrated using three different cells lines. Cells incubated with the complexes were hardly emissive. Further light irradiation at 475 nm triggered intracellular emission turn on, indicative of the production of 1O2 photochemically. The emissive pattern was well colocalized with commercially available MitoTracker, suggesting the potential applications of the complexes for imaging mitochondria 1O2. The 1O2 capturing properties rendered the complexes low photocytotoxicity since 1O2-caused oxidative damage toward cellular molecules and structures was inhibited.

Phosphorescent iridium(iii) complexes capable of imaging and distinguishing between exogenous and endogenous analytes in living cells.

Many luminescent probes have been developed for intracellular imaging and sensing. During cellular luminescence sensing, it is difficult to distinguish species generated inside cells from those internalized from extracellular environments since they are chemically the same and lead to the same luminescence response of the probes. Considering that endogenous species usually give more information about the physiological and pathological parameters of the cells while internalized species often reflect the extracellular environmental conditions, we herein reported a series of cyclometalated iridium(iii) complexes as phosphorescent probes that are partially retained in the cell membrane during their cellular uptake. The utilization of the probes for sensing and distinguishing between exogenous and endogenous analytes has been demonstrated using hypoxia and hypochlorite as two examples of target analytes. The endogenous analytes lead to the luminescence response of the intracellular probes while the exogenous analytes are reported by the probes retained in the cell membrane during their internalization.

Phosphorescent Starburst Pt(II) Porphyrins as Bifunctional Therapeutic Agents for Tumor Hypoxia Imaging and Photodynamic Therapy.

It is very meaningful to develop bifunctional therapeutic agents which can monitor the tumor hypoxia in real time as well as maintain good photodynamic therapy (PDT) effect under hypoxia. To achieve it, herein, a series of hydrophilic phosphorescent starburst Pt(II) porphyrins as bifunctional therapeutic agents for simultaneous tumor hypoxia imaging and highly efficient PDT have been rationally designed and synthesized. They have been obtained by using Pt(II) porphyrins as the functional core and cationic oligofluorenes as the arms. Such a three-dimensional structural feature ensures their hydrophilicity, ultrasensitive oxygen-sensing performance, and high 1O2 quantum yields. Furthermore, the O2-sensitive phosphorescence lifetimes of starburst Pt(II) porphyrins are beneficial to eliminate the interference from background fluorescence remarkably and enhance the signal-to-noise ratio of hypoxia imaging by using phosphorescence lifetime imaging microscopy. Their PDT effects were also evaluated both in vitro (under both hypoxia and normoxia) and in vivo. As a result, tumor hypoxia can be significantly differentiated and tumor growth can be inhibited effectively, while the systemic toxicity is not observed. All of these results demonstrate that starburst Pt(II) porphyrins could be used as the promising bifunctional therapeutic agents for early diagnosis and treatment of cancer.

Utilizing Intramolecular Photoinduced Electron Transfer to Enhance Photothermal Tumor Treatment of Aza-BODIPY-Based Near-Infrared Nanoparticles.

Photothermal therapy (PTT) as a kind of noninvasive tumor treatment has attracted increasing research interest. However, the efficiency of existing PTT agents in the near-infrared (NIR) region is the major problem that has hindered further development of PTT. Herein, we present an effective strategy to construct the efficient photothermal agent by utilizing an intramolecular photoinduced electron transfer (PeT) mechanism, which is able to dramatically improve photothermal conversion efficiency in the NIR region. Specifically, an NIR dye (A1) constructed with dimethylamine moiety as the electron donor and the aza-BODIPY core as the electron acceptor is designed and synthesized, which can be used as a class of imaging-guided PTT agents via intramolecular PeT. After encapsulation with biodegradable polymer DSPE-mPEG5000, nanophotothermal agents with a small size exhibit excellent water solubility, photostability, and long-time retention in tumor. Importantly, such nanoparticles exhibit excellent photothermal conversion efficiency of ∼35.0%, and the PTT effect in vivo still remains very well even with a low dosage of 0.05 mg kg-1 upon 808 nm NIR laser irradiation (0.5 W cm-2). Therefore, this reasonable design via intramolecular PeT offers guidance to construct excellent photothermal agents and subsequently may provide a novel opportunity for future clinical cancer treatment.

Enhanced singlet oxygen generation of a soft salt through efficient energy transfer between two ionic metal complexes.

In this study, a soft salt complex based photosensitizer has been developed for photodynamic therapy (PDT) of cancer cells. The iridium(iii) complex [Ir(L)(L')]3+(PF6-)3 (C1) with L and L' being terpyridine ligands (L = 4'-phenyl-2,2':6',2''-terpyridine, L' = 3-([2,2':6',2''-terpyridin]-4'-yl)-9-hexyl-9H-carbazole) was chosen as the cationic component, and the iridium(iii) complex [Ir(dfppy)2CN2]-Bu4N+ (A1) was selected as the anionic component. Complexes C1 and A1 are directly connected through electrostatic interaction to form a soft salt based photosensitizer (S1), which exhibited an enhanced singlet oxygen generation rate because of efficient energy transfer between two ionic metal complexes. Furthermore, this novel photosensitizer was successfully applied in photodynamic therapy (PDT) of cancer cells for the first time.

Achieving efficient photodynamic therapy under both normoxia and hypoxia using cyclometalated Ru(ii) photosensitizer through type I photochemical process.

Photodynamic therapy (PDT) through the generation of singlet oxygen utilizing photosensitizers (PSs) is significantly limited under hypoxic conditions in solid tumors. So it is meaningful to develop effective PSs which can maintain excellent therapeutic effects under hypoxia. Here we reported a coumarin-modified cyclometalated Ru(ii) photosensitizer (Ru2), which exhibits lower oxidation potential and stronger absorption in the visible region than the coumarin-free counterpart. The evaluation of the PDT effect was performed under both normoxia and hypoxia. The results showed that Ru2 has a better therapeutic effect than the coumarin-free counterpart in in vitro experiments. Especially under hypoxia, Ru2 still retained an excellent PDT effect, which can be attributed to the direct charge transfer between the excited PS and an adjacent substrate through a type I photochemical process, forming highly-oxidative hydroxyl radicals to damage tumor cells. The anti-tumor activity of Ru2 was further proven to be effective in tumor-bearing mice, and tumor growth was inhibited remarkably under PDT treatment.

Long-Lived Emissive Probes for Time-Resolved Photoluminescence Bioimaging and Biosensing.

In this Review article, we systematically summarize the design and applications of various kinds of long-lived emissive probes for bioimaging and biosensing via time-resolved photoluminescence techniques. The probes reviewed, including lanthanides, transition-metal complexes, organic dyes, carbon and silicon nanoparticles, metal clusters, and persistent phosphores, exhibit longer luminescence lifetimes than that of autofluorescence from biological tissue and organs. When these probes are internalized into living cells or animals, time-gated photoluminescence imaging selectively collects long-lived signals for intensity analysis, while photoluminescence lifetime imaging reports the decay details of each pixel. Since the long-lived signals are differentiated from autofluorescence in the time domain, the imaging contrast and sensing sensitivity are remarkably improved. The future prospects and challenges in this rapidly growing field are addressed.

Rational design of a luminescent nanoprobe for hypoxia imaging in vivo via ratiometric and photoluminescence lifetime imaging microscopy.

A luminescent nanoprobe has been designed for detection of oxygen. The nanoprobe exhibits high sensitivity, selectivity and excellent reversibility, and has been employed for hypoxia imaging in vitro and in vivo by ratiometric and photoluminescence lifetime imaging techniques.

Using a redox-sensitive phosphorescent probe for optical evaluation of an intracellular redox environment.

A reducing intracellular environment is necessary for living cells. Here a redox-sensitive phosphorescent probe Ir-NO has been developed for evaluating the redox environment in living cells. Upon addition of reducing molecules, such as glutathione and ascorbic acid, the phosphorescent intensity of the probe is turned on, and the emission lifetime is elongated evidently. Furthermore, this probe has been used for optical imaging of the intracellular reducing environment by utilizing confocal laser scanning microscopy and phosphorescence lifetime imaging microscopy.