A selenium-based NIR-II photosensitizer for a highly effective and safe phototherapy plan.

High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy. However, current Food and Drug Administration (FDA)-approved organic fluorophores exhibit poor chemical stability and photostability as well as short emission wavelength, limiting their clinical usage. To address this, we developed Se-IR1100, a novel organic photosensitizer with a photostable and thermostable benzobisthiadiazole (BBTD) backbone. By incorporating selenium as a heavy atom and constructing a D-A-D structure, Se-IR1100 exhibits a maximum fluorescence emission wavelength of 1100 nm. Compared with FDA-approved indocyanine green (ICG), DSPE-PEGylated Se-IR1100 nanoparticles exhibit prominent photostability and long-lasting photothermal effects. Upon 808 nm laser irradiation, Se-IR1100 NPs efficiently convert light energy into heat and reactive oxygen species (ROS), inducing cancer cell death in cellular studies and living organisms while maintaining biocompatibility. With salient photostability and a photothermal conversion rate of 55.37%, Se-IR1100 NPs hold promise as a superior photosensitizer for diagnostic and therapeutic agents in oncology. Overall, we have designed and optimized a multifunctional photosensitizer Se-IR1100 with good biocompatibility that performs NIR-II fluorescence imaging and phototherapy. This dual-strategy method may offer novel approaches for the development of multifunctional probes using dual-strategy or even multi-strategy methods in bioimaging, disease diagnosis, and therapy.

Acceptor engineering of metallacycles with high phototoxicity indices for safe and effective photodynamic therapy.

Although metallacycle-based photosensitizers have attracted increasing attention in biomedicine, their clinical application has been hindered by their inherent dark toxicity and unsatisfactory phototherapeutic efficiency. Herein, we employ a π-expansion strategy for ruthenium acceptors to develop a series of Ru(ii) metallacycles (Ru1-Ru4), while simultaneously reducing dark toxicity and enhancing phototoxicity, thus obtaining a high phototoxicity index (PI). These metallacycles enable deep-tissue (∼7 mm) fluorescence imaging and reactive oxygen species (ROS) production and exhibit remarkable anti-tumor activity even under hypoxic conditions. Notably, Ru4 has the lowest dark toxicity, highest ROS generation ability and an optimal PI (∼146). Theoretical calculations verify that Ru4 exhibits the largest steric bulk and the lowest singlet-triplet energy gap (ΔE ST, 0.62 eV). In vivo studies confirm that Ru4 allows for effective and safe phototherapy against A549 tumors. This work thus is expected to open a new avenue for the design of high-performance metal-based photosensitizers for potential clinical applications.

Engineered Metallacycle-Based Supramolecular Photosensitizers for Effective Photodynamic Therapy.

Although metallacycle-based supramolecular photosensitizers (PSs) have attracted increasing attention in biomedicine, their clinical translation is still hindered by their inherent dark toxicity. Herein, we report what to our knowledge is the first example of a molecular engineering approach to building blocks of metallacycles for constructing a series of supramolecular PSs (RuA-RuD), with the aim of simultaneously reducing dark toxicity and enhancing phototoxicity, and consequently obtaining high phototoxicity indexes (PI). Detailed in vitro investigations demonstrate that RuA-RuD display high cancer cellular uptake and remarkable antitumor activity even under hypoxic conditions. Notably, RuD exhibited no dark toxicity and displayed the highest PI value (≈406). Theoretical calculations verified that RuD has the largest steric hindrance and the lowest singlet-triplet energy gap (ΔEST , 0.61 eV). Further in vivo studies confirmed that RuD allows safe and effective phototherapy against A549 tumors.

Rationally designed Ru(II) metallacycles with tunable imidazole ligands for synergistical chemo-phototherapy of cancer.

Herein, we construct a series of Ru(II) metallacycles with multimodal chemo-phototherapeutic properties, which exhibited much higher anticancer activity and better cancer-cell selectivity than cisplatin. The antitumor mechanism could be ascribed to the activation of caspase 3/7 and the resulting apoptosis. These results open new possibilities for Ru(II) metallacycles in biomedicine.

Rationally designed Ru(ii)-metallacycle chemo-phototheranostic that emits beyond 1000 nm.

Ruthenium complexes are emerging as potential complements to platinum drugs. They also show promise as photo-diagnostic and therapeutic agents. However, most ruthenium species studied to date as potential drugs are characterized by short excitation/emission wavelengths. This limits their applicability for deep-tissue fluorescence imaging and light-based therapeutic treatments. Here, we report a Ru(ii) metallacycle (Ru1100) that emits at ≥1000 nm. This system possesses excellent deep-tissue penetration capability (∼7 mm) and displays good chemo-phototherapeutic performance. In vitro studies revealed that Ru1100 benefits from good cellular uptake and produces a strong anticancer response against several cancer cell lines, including a cisplatin-resistant A549 cell line (IC50 = 1.6 µM vs. 51.4 µM for cisplatin). On the basis of in vitro studies, it is concluded that Ru1100 exerts its anticancer action by regulating cell cycle progression and triggering cancer cell apoptosis. In vivo studies involving the use of a nanoparticle formulation served to confirm that Ru1100 allows for high-performance NIR-II fluorescence imaging-guided precise chemo-phototherapy in the case of A549 tumour mouse xenografts with no obvious side effects. This work thus provides a paradigm for the development of long-wavelength emissive supramolecular theranostic agents based on ruthenium.

NIR-II Emissive Ru(II) Metallacycle Assisting Fluorescence Imaging and Cancer Therapy.

Despite the success of emissive Ruthenium (Ru) agents in biomedicine, problems such as the visible-light excitation/emission and single chemo- or phototherapy modality still hamper their applications in deep-tissue imaging and efficient cancer therapy. Herein, an second nearinfrared window (NIR-II) emissive Ru(II) metallacycle (Ru1000, λem  = 1000 nm) via coordination-driven self-assembly is reported, which holds remarkable deep-tissue imaging capability (≈6 mm) and satisfactory chemo-phototherapeutic performance. In vitro results indicate Ru1000 displays promising cellular uptake, good cancer-cell selectivity, attractive anti-metastasis properties, and remarkable anticancer activity against various cancer cells, including cisplatin-resistant A549 cells (IC50  = 3.4 × 10-6  m vs 92.8 × 10-6  m for cisplatin). The antitumor mechanism could be attributed to Ru1000-induced lysosomal membrane damage and mitochondrial-mediated apoptotic cell death. Furthermore, Ru1000 also allows the high-performance in vivo NIR-II fluorescence imaging-guided chemo-phototherapy against A549 tumors. This work may provide a paradigm for the development of long-wavelength emissive metallacycle-based agents for future biomedicine.

Construction of emissive ruthenium(II) metallacycle over 1000 nm wavelength for in vivo biomedical applications.

Although Ru(II)-based agents are expected to be promising candidates for substituting Pt-drug, their in vivo biomedical applications are still limited by the short excitation/emission wavelengths and unsatisfactory therapeutic efficiency. Herein, we rationally design a Ru(II) metallacycle with excitation at 808 nm and emission over 1000 nm, namely Ru1085, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity. In vitro studies indicate that Ru1085 exhibits prominent cell uptake and desirable anticancer capability against various cancer cell lines, especially for cisplatin-resistant A549 cells. Further studies reveal Ru1085 induces mitochondria-mediated apoptosis along with S and G2/M phase cell cycle arrest. Finally, Ru1085 shows precise NIR-II fluorescence imaging guided and long-term monitored chemo-phototherapy against A549 tumor with minimal side effects. We envision that the design of long-wavelength emissive metallacycle will offer emerging opportunities of metal-based agents for in vivo biomedical applications.

NIR-II emissive multifunctional AIEgen with single laser-activated synergistic photodynamic/photothermal therapy of cancers and pathogens.

Despite the wide application of the traditional NIR-I phototheranostic platforms in basic research and clinical studies, problems such as tissue scattering, auto-fluorescence combined with aggregation caused quenching hamper precise image-guided phototherapy. Herein, we developed a multifunctional NIR-II phototheranostic platform using a novel AIE-based dye (ZSY-TPE) for single laser-activated imaging-guided combined photothermal and photodynamic therapies of tumors and pathogens. As confirmed through in vivo studies, the ZSY-TPE dots displayed precise and efficient high-performance NIR-II imaging-guided combination phototherapy against 4T1 tumor as well as S. aureus-infected mice models without any noticeable side effects. The current study demonstrates ZSY-TPE as a powerful phototheranostic platform for precise NIR-II fluorescence/PA imaging and synergistic photodynamic/photothermal therapy of tumors and bacterial infections.

Melanin-dot-mediated delivery of metallacycle for NIR-II/photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy.

Discrete Pt(II) metallacycles have potential applications in biomedicine. Herein, we engineered a dual-modal imaging and chemo-photothermal therapeutic nano-agent 1 that incorporates discrete Pt(II) metallacycle 2 and fluorescent dye 3 (emission wavelength in the second near-infrared channel [NIR-II]) into multifunctional melanin dots with photoacoustic signal and photothermal features. Nano-agent 1 has a good solubility, biocompatibility, and stability in vivo. Both photoacoustic imaging and NIR-II imaging in vivo confirmed that 1 can effectively accumulate at tumor sites with good signal-to-background ratio and favorable distribution. Guided by precise dual-modal imaging, nano-agent 1 exhibits a superior antitumor performance and less severe side effects compared with a single treatment because of the high efficiency of the chemo-photothermal synergistic therapy. This study shows that nano-agent 1 provides a promising multifunctional theranostic platform for potential applications in biomedicine.