Planar-structured thiadiazoloquinoxaline-based NIR-II dye for tumor phototheranostics.

Second near-infrared (NIR-II) fluorescence imaging shows huge application prospects in clinical disease diagnosis and surgical navigation, while it is still a big challenge to exploit high performance NIR-II dyes with long-wavelength absorption and high fluorescence quantum yield. Herein, based on planar π-conjugated donor-acceptor-donor systems, three NIR-II dyes (TP-DBBT, TP-TQ1, and TP-TQ2) were synthesized with bulk steric hindrance, and the influence of acceptor engineering on absorption/emission wavelengths, fluorescence efficiency and photothermal properties was systematically investigated. Compared with TP-DBBT and TP-TQ2, the TP-TQ1 based on 6,7-diphenyl-[1,2,5]thiadiazoloquinoxaline can well balance absorption/emission wavelengths, NIR-II fluorescence brightness and photothermal effects. And the TP-TQ1 nanoparticles (NPs) possess high absorption ability at a peak absorption of 877 nm, with a high relative quantum yield of 0.69% for large steric hindrance hampering the close π-π stacking interactions. Furthermore, the TP-TQ1 NPs show a desirable photothermal conversion efficiency of 48% and good compatibility. In vivo experiments demonstrate that the TP-TQ1 NPs can serve as a versatile theranostic agent for NIR-II fluorescence/photoacoustic imaging-guided tumor phototherapy. The molecular planarization strategy provides an approach for designing efficient NIR-II fluorophores with extending absorption/emission wavelength, high fluorescence brightness, and outstanding phototheranostic performance.

J-Aggregate Promoting NIR-II Emission for Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

J-aggregate is a promising strategy to enhance second near-infrared window (NIR-II) emission, while the controlled synthesis of J-aggregated NIR-II dyes is a huge challenge because of the lack of molecular design principle. Herein, bulk spiro[fluorene-9,9'-xanthene] functionalized benzobisthiadiazole-based NIR-II dyes (named BSFX-BBT and OSFX-BBT) are synthesized with different alkyl chains. The weak repulsion interaction between the donor and acceptor units and the S…N secondary interactions make the dyes to adopt a co-planar molecular conformation and display a peak absorption >880 nm in solution. Importantly, BSFX-BBT can form a desiring J-aggregate in the condensed state, and femtosecond transient absorption spectra reveal that the excited states of J-aggregate are the radiative states, and J-aggregate can facilitate stimulated emission. Consequently, the J-aggregated nanoparticles (NPs) display a peak emission at 1124 nm with a high relative quantum yield of 0.81%. The efficient NIR-II emission, good photothermal effect, and biocompatibility make the J-aggregated NPs demonstrate efficient antitumor efficacy via fluorescence/photoacoustic imaging-guided phototherapy. The paradigm illustrates that tuning the aggregate states of NIR-II dye via spiro-functionalized strategy is an effective approach to enhance photo-theranostic performance.

Structural effect of NIR-II absorbing charge transfer complexes and its application on cysteine-depletion mediated ferroptosis and phototherapy.

Second near-infrared (NIR-II) absorbing organic photothermal agents (PTAs) usually suffer from laborious and time-consuming synthesis; therefore, it is of importance to develop a simple and easy-to-handle method for the preparation of NIR-II PTAs. Charge-transfer complexes (CTCs) can be easily used to construct NIR-II absorbing PTAs, although the relationship between their molecular structure and photophysical properties is yet to be uncovered. Herein, three kinds of electron donors with different substitutions (chloroethyl, ethyl, and methyl) were synthesized and assembled with electron-deficient F4TCNQ to afford corresponding CTC nanoparticles (Cl-F4, Et-F4, and Me-F4 NPs). The large energy gap (>0.61 eV) between HOMO of the donor and LUMO of the acceptor made the CTCs exhibit high charge transfer (>0.93) and dramatic differences in photophysical properties. Additionally, Et-F4 NPs possess the highest NIR-II absorption ability and best photothermal effect because of different packing modes (mass extinction coefficient of 11.0 L g-1 cm-1 and photothermal conversion efficiency of 40.2% at 1060 nm). The mixed stacking mode formed strong charge-transfer absorption bands, indicating that the photophysical properties of CTCs can be tailored by changing the molecular structure and aggregate behaviors. Furthermore, Et-F4 NPs with cyano groups could specifically react with cysteine to block the intracellular biosynthesis of GSH and result in ROS accumulation and ferroptosis. Et-F4 NPs possess outstanding antitumor efficacy for the combined actions of NIR-II triggered photothermal killing effect and ferroptosis in vivo.

Functional black phosphorus nanosheets for mitochondria-targeting photothermal/photodynamic synergistic cancer therapy.

Organelle-targeting nanosystems are envisioned as promising tools for phototherapy, which can generate heat or reactive oxygen species (ROS) induced cytotoxicity in the targeted location but leave the surrounding biological tissues undamaged. In this work, an imaging-guided mitochondria-targeting photothermal/photodynamic nanosystem has been developed on the basis of functionalized black phosphorus (BP) nanosheets (NSs). In the nanosystem, BP NSs are coated with polydopamine (PDA) and then covalently linked with both chlorin e6 (Ce6) and triphenyl phosphonium (TPP) through carbodiimide reaction between the amino group and the carboxyl group, forming BP@PDA-Ce6&TPP NSs. Due to the strong absorbance of BP@PDA in the near-infrared region and the highly efficient ROS generation of Ce6, the as-prepared nanosystem with mitochondria-targeting capacity (TPP moiety) shows remarkably enhanced efficiency in cancer cell killing. Combined photothermal and photodynamic therapy is implemented and monitored by in vivo fluorescence imaging, achieving excellent performance in inhibiting tumor growth. This study presents a novel nanotheranostic agent for mitochondria-targeting phototherapy, which may open new horizons for biomedicine.

Tumor-Microenvironment-Responsive Nanoconjugate for Synergistic Antivascular Activity and Phototherapy.

Insufficient oxygen supply (hypoxia), short half-life (<40 ns) of singlet oxygen, and up-regulation of the heat shock protein expression in solid tumors impede the photodynamic and photothermal therapeutic efficacy. Herein, a near-infrared carrier-free nanoconjugate direct-acting antiviral (DAA) with synergistic antivascular activity and pH-responsive photodynamic/photothermal behavior was designed and synthesized to improve cancer treatment efficacy. Obtained by the self-assembly approach, the biocompatible DAA nanoparticles (NPs) displayed amplifying pH-responsive photodynamic/photothermal performance in an acidic tumor microenvironment due to the protonation of diethylaminophenyl units. Most important, the antivascular agent 5,6-dimethylxanthenone-4-acetic acid, targeting the vascular endothelial growth factor, can be smartly released from the pro-drug DAA via ester bond hydrolysis at the subacid endocytosis organelles in the endothelial cells, which can effectively destroy the vascular region to prevent tumor proliferation and metastasis. Hence, DAA NPs can specifically target vascular endothelial cells and tumorous lysosomes with desired cellular damage properties in vitro. Therefore, the tumors can be ablated completely with no recurrence and side effects in vivo, which implies that DAA NPs provide a promising approach for cancer treatment via synergistic antivascular activity and photodynamic/photothermal therapy.

2-Pyridone-functionalized Aza-BODIPY photosensitizer for imaging-guided sustainable phototherapy.

To overcome irradiation-dependence of cancer phototherapy, a near infrared aza-BODIPY-based photothermogenic photosensitizer BDY with 2-Pyridone group has been synthesized for imaging-guided photothermal synergistic sustainable photodynamic therapy. Multifunctional water-soluble BDY nanoparticles (NPs), with high photothermal conversion efficiency of 35.7% and excellent singlet oxygen (1O2) generation ability, are prepared by self-assembling. The reversible transformation between 2-pyridone moiety and its endoperoxide form endows BDY with continuous 1O2 generation ability under illumination and non-illumination conditions. Simultaneously, BDY NPs exhibit excellent tumor targeting properties by enhanced permeability and retention (EPR) effect and photoacoustic imaging (PAI) ability. Furthermore, the photothermal assisted sustainable photodynamic therapy can significantly inhibit tumor growth (93.4% inhibition) with almost no side effects by intermittent laser illumination. The finding highlights that this photothermal synergistic sustainable phototherapy presents great potential for clinical applications.