Near-infrared Heptamethine Cyanine Research Articles

Near-Infrared Heptamethine Cyanine Photosensitizers with Efficient Singlet Oxygen Generation for Anticancer Photodynamic Therapy.

Near-infrared photosensitizers are valuable tools to improve treatment depth in photodynamic therapy (PDT). However, their low singlet oxygen (1O2) generation ability, indicated by low 1O2 quantum yield, presents a formidable challenge for PDT. To overcome this challenge, the heptamethine cyanine was decorated with biocompatible S (Scy7) and Se (Secy7) atom. We observe that Secy7 exhibits a redshift in the main absorption to ~840 nm and an ultra-efficient 1O2 generation capacity. The emergence of a strong intramolecular charge transfer effect between the Se atom and polymethine chain considerably narrows the energy gap (0.51 eV), and the heavy atom effect of Se strengthens spin-orbit coupling (1.44 cm-1), both of which greatly improved the high triplet state yield (61%), a state that determines the energy transfer to O2. Therefore, Secy7 demonstrated excellent 1O2 generation capacity, which is ~24.5-fold that of indocyanine green, ~8.2-fold that of IR780, and ~1.3-fold that of methylene blue under low-power-density 850 nm irradiation (5 mW cm-2). Secy7 exhibits considerable phototoxicity toward cancer cells buried under 12 mm of tissue. Nanoparticles formed by encapsulating Secy7 within amphiphilic polymers and lecithin, demonstrated promising antitumor and anti-pulmonary metastatic effects, exhibiting remarkable potential for advancing PDT in deep tissues.

An Intramolecular Rotor-Bridged Dimeric Cyanine Photothermal Transducer for Efficient Near-Infrared II Fluorescence Imaging-Guided Mitochondria-Targeted Phototherapy.

Near-infrared (NIR) heptamethine cyanine (HCy) dyes are promising photothermal transducers for image-guided cancer treatment owing to their prominent photophysical properties and high photothermal conversion ability. However, HCy photothermal transducers usually have poor photostability due to degradation induced by the self-generated reactive oxygen species. Herein, a novel mitochondria-targeting dimeric HCy dye, named dimeric oBHCy, is rationally designed, exhibiting strong near-infrared II (NIR-II) fluorescence emission, high photothermal conversion efficiency (PCE), and excellent photostability. The large π-conjugation and drastic intramolecular motion of the diphenol rotor in the dimeric oBHCy enhance the nonradiative energy dissipation and suppress the intersystem crossing process, thereby achieving a high PCE (49.2%) and improved photostability. Impressively, dimeric oBHCy can precisely target mitochondria and induce mitochondrial damage upon NIR light irradiation. Under the guidance of in vivo NIR-II fluorescence imaging, efficient NIR light-activated photothermal therapy of 4T1 breast tumors is accomplished with a tumor inhibitory rate of 96% following a single injection of the dimeric oBHCy. This work offers an innovative strategy for designing cyanine photothermal transducers with integrated NIR-II fluorescence and photothermal properties for efficient cancer theranostics.

Structure-Inherent Tumor-Targeted IR-783 for Near-Infrared Fluorescence-Guided Photothermal Therapy.

IR-783, a commercially available near-infrared (NIR) heptamethine cyanine dye, has been used for selective tumor imaging in breast, prostate, cervical, and brain cancers in vitro and in vivo. Although the molecular mechanism behind the structure-inherent tumor targeting of IR-783 has not been well-demonstrated, IR-783 has unique properties such as a good water solubility and low cytotoxicity compared with other commercial heptamethine cyanine dyes. The goal of this study is to evaluate the phototherapeutic efficacy of IR-783 as a tumor-targeted photothermal agent in human colorectal cancer xenografts. The results demonstrate that IR-783 shows both the subcellular localization in HT-29 cancer cells and preferential accumulation in HT-29 xenografted tumors 24 h after its intravenous administration. Furthermore, the IR-783 dye reveals the superior capability to convert NIR light into heat energy under 808 nm NIR laser irradiation in vitro and in vivo, thereby inducing cancer cell death. Taken together, these findings suggest that water-soluble anionic IR-783 can be used as a bifunctional phototherapeutic agent for the targeted imaging and photothermal therapy (PTT) of colorectal cancer. Therefore, this work provides a simple and effective approach to develop biocompatible, hydrophilic, and tumor-targetable PTT agents for targeted cancer phototherapy.

Discovery of a mitochondrial G-quadruplex targeted fluorescent ligand via a slight variation on the near-infrared heptamethine cyanine scaffold

The heptamethine cyanine dyes are one kind of promising near-infrared (NIR) compounds, holding great potential in both diagnostic and therapeutic regions. Remolding such structures to realize detection of unclarified biotargets or interfering with them seems to be important in the field of chemical biology. In this study, we developed a fluorescent ligand (IR1) targeting mitochondrial G-quadruplexes (mitoG4s) by a slight variation on the typical NIR scaffold (IR780). This ligand could be applied for sensing mitoG4s by fluorescence, making it different from the unmodified dye whose fluorescence was quenched by mitoG4s. Then, IR1 was demonstrated to accumulate in the mitochondria through a mitochondrial membrane potential (MMP) dependent manner. Some of IR1 then bound to mitoG4s, causing mtDNA loss and mitochondrial dysfunction, which thereby triggered PANoptosis, including apoptosis, autophagy and pyroptosis. To the best of our knowledge, IR1 was the first NIR fluorescent ligand with emission centered at above 800 nm for mitoG4s, and the first example causing PANoptosis among the reported mitoG4-targeted ligands.

Fluorescence Imaging Using Deep-Red Indocyanine Blue, a Complementary Partner for Near-Infrared Indocyanine Green.

Indocyanine Blue (ICB) is the deep-red pentamethine analogue of the widely used clinical near-infrared heptamethine cyanine dye Indocyanine Green (ICG). The two fluorophores have the same number of functional groups and molecular charge and vary only by a single vinylene unit in the polymethine chain, which produces a predictable difference in spectral and physicochemical properties. We find that the two dyes can be employed as a complementary pair in diverse types of fundamental and applied fluorescence imaging experiments. A fundamental fluorescence spectroscopy study used ICB and ICG to test a recently proposed Förster Resonance Energy Transfer (FRET) mechanism for enhanced fluorescence brightness in heavy water (D2O). The results support two important corollaries of the proposal: (a) the strategy of using heavy water to increase the brightness of fluorescent dyes for microscopy or imaging is most effective when the dye emission band is above 650 nm, and (b) the magnitude of the heavy water florescence enhancement effect for near-infrared ICG is substantially diminished when the ICG surface is dehydrated due to binding by albumin protein. Two applied fluorescence imaging studies demonstrated how deep-red ICB can be combined with a near-infrared fluorophore for paired agent imaging in the same living subject. One study used dual-channel mouse imaging to visualize increased blood flow in a model of inflamed tissue, and a second mouse tumor imaging study simultaneously visualized the vasculature and cancerous tissue in separate fluorescence channels. The results suggest that ICB and ICG can be incorporated within multicolor fluorescence imaging methods for perfusion imaging and hemodynamic characterization of a wide range of diseases.

Discovery of Near-Infrared Heptamethine Cyanine Probes for Imaging-Guided Surgery in Solid Tumors.

Near-infrared (NIR) fluorescence imaging has attracted much attention in image-guided interventions with unique advantages. However, the clinical translation rate of fluorescence probes is extremely low, primarily due to weak lesion signal contrast and poor specificity. To address this dilemma, a series of small-molecule near-infrared fluorescence probes have been designed for tumor imaging. Among them, YQ-04-03 showed notable optical stability and remarkable sensitivity toward tumor targeting. Moreover, within a specific concentration and time range against oxidizing reducing agents and laser, it demonstrated better stability than ICG. The retention time of YQ-04-03 in tumors was significantly longer compared to other nonspecific uptake sites in the subjects, and its tumor-to-normal tissue ratio (TNR) outperformed ICG. Successful resection of in situ hepatocarcinoma and peritoneal carcinoma was achieved using probe imaging guidance, with the smallest visual lesion resected measuring approximately 1 mm3. Ultimately, this probe holds great potential for advancing tumor tracer.

Near-Infrared Molecular Logic Gate for In Situ Construction and Quantification of Cell-Macromolecule Conjugates.

Engineering cell surfaces with macromolecules offers the potential to manipulate and control their phenotype and function for cell-based therapies. In situ construction and real-time evaluation of cell-macromolecule conjugates are vital for characterizing their dynamics, mobility, and function but remain a great challenge. Herein, we design a near-infrared (NIR) heptamethine cyanine (LS)-bearing dibenzocyclooctyne (DBCO) and norbornene (NB) in its structure for rapid and selective bioorthogonal "click" coupling to azide-labeled cells and tetrazine-functionalized macromolecular precursors. Specifically, only orthogonal dual "click" cell-macromolecule conjugates turn on NIR fluorescence, in which LS behaves as an AND logic gate, with azide- and tetrazine-derivatives being "input" and the emission intensity as the output. LS enables in situ construction and real-time evaluation of the process and functional effects that macromolecules "graft to" cells with high cytocompatibility. This probe is tailor-made for live-cell microscopy technologies, which may open new opportunities for promoting further developments in cell-tracking and cell-based therapies.

Heavy-atom engineered hypoxia-responsive probes for precisive photoacoustic imaging and cancer therapy

Photoacoustic agents combining photodynamic therapy (PDT) and photothermal therapy (PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared (NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging (PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol, -thio, and -seleno moieties into NIR heptamethine cyanine (Cy7) skeleton (Cy7-X-NH2, X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT. Additionally, we designed a series of nitroreductase (NTR)-activated photoacoustic probes (Cy7-X-NO2, X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe, Cy7-Se-NO2-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.

A Novel Near-Infrared Trifluoromethyl Heptamethine Cyanine Dye with Mitochondria-Targeting for Integration of Collaborative Treatment of Photothermal and Sonodynamic Therapy

A Novel Near-Infrared Trifluoromethyl Heptamethine Cyanine Dye with Mitochondria-Targeting for Integration of Collaborative Treatment of Photothermal and Sonodynamic Therapy

A Tumor-Targeting Near-Infrared Heptamethine Cyanine Photosensitizer with Twisted Molecular Structure for Enhanced Imaging-Guided Cancer Phototherapy.

In recent years, cancer phototherapy has been extensively studied as noninvasive cancer treatment. To present efficient recognition toward cancer cells, most photosensitizers (PSs) are required to couple with tumor-targeted ligands. Interestingly, the heptamethine cyanine IR780 displays an intrinsic tumor-targeted feature even without modification. However, the photothermal efficacy and photostability of IR780 are not sufficient enough for clinical use. Herein, we involve a twisted structure of tetraphenylethene (TPE) between two molecules of IR780 to improve the photothermal conversion efficiency (PCE). The obtained molecule T780T shows strong near-infrared (NIR) fluorescence and improved PCE (38.5%) in the dispersed state. Also, the photothermal stability and ROS generation capability of T780T at the NIR range (808 nm) are both promoted. In the aqueous phase, the T780T was formulated into uniform nanoaggregates (∼200 nm) with extremely low fluorescence and PTT response, which would reduce in vivo imaging background and side effect of PTT response in normal tissues. After intravenous injection into tumor-bearing mice, the T780T nanoaggregates display high tumor accumulation and thus remarkably inhibit the tumor growth. Moreover, the enhanced photostability of the T780T allows for twice irradiation after one injection and leads to more significant tumor inhibition. In summary, our study presents a tumor-targeted small-molecule PS for efficient cancer therapy and brings a new design of heptamethine cyanine PS for potential clinical applications.

Near-Infrared Heptamethine Cyanine Dyes for Nanoparticle-Based Photoacoustic Imaging and Photothermal Therapy.

We have synthesized and characterized a library of near-infrared (NIR) heptamethine cyanine dyes for biomedical application as photoacoustic imaging and photothermal agents. These hydrophobic dyes were incorporated into a polymer-based nanoparticle system to provide aqueous solubility and protection of the photophysical properties of each dye scaffold. Among those heptamethine cyanine dyes analyzed, 13 compounds within the nontoxic polymeric nanoparticles have been selected to exemplify structural relationships in terms of photostability, photoacoustic imaging, and photothermal behavior within the NIR (∼650-850 nm) spectral region. The most contributing structural features observed in our dye design include hydrophobicity, rotatable bonds, heavy atom effects, and stability of the central cyclohexene ring within the dye core. The NIR agents developed within this project serve to elicit a structure-function relationship with emphasis on their photoacoustic and photothermal characteristics aiming at producing customizable NIR photoacoustic and photothermal tools for clinical use.

Near-infrared heptamethine cyanine dye-based nanoscale coordination polymers with intrinsic nucleus-targeting for low temperature photothermal therapy

Intrinsic nucleus-targeting organic-inorganic hybridization nanomaterials: nano coordination polymers self-assembly from newly designed HI-4COOH and Hf 4+ with high photothermal conversion efficiency and nucleus-targeting for low power density and temperature photothermal therapy. • First nanoscale coordination polymer (NCP) that shows both intrinsic nucleus-targeting and strong near-infrared absorption. • Significant improvement of antitumor efficacy under low power density and temperature in vitro and in vivo . • The biocompatible NCP could be completely cleaned up within 14 days in vivo . Effective photothermal therapy (PTT) under low temperature (< 50 °C) and power density (< 0.4 W/cm 2 ) avoiding the damage of skin and normal organs. Here, we report a novel heptamethine cyanine dye-based nanoscale coordination polymer (NCP), Hf-HI-4COOH, as an exceptionally effective photosensitizer for nucleus-targeting low temperature PTT. Hf-HI-4COOH shows strong near-infrared absorption and high photothermal conversion efficiency (39.51 %). Further, it exhibits intrinsic nucleus-targeting property and cell inhibition under low power density in vitro . Moreover, the long blood circulation, high tumor accumulation, and nucleus-targeting contribute to significant inhibition of breast tumors in tumor-bearing mice under low temperature (48 °C) and power density (0.3 W/cm 2 ) without obvious toxicity. In general, we establish a nucleus-targeting Hf-HI-4COOH for enhanced PTT with low temperature and power density.

Near-infrared heptamethine cyanines (Cy7): from structure, property to application.

Heptamethine cyanine dyes (Cy7) have attracted much attention in the field of biological application due to their unique structure and attractive near infrared (NIR) photophysical properties. In this review, the influences of different modification sites on the absorption characteristics, photostability, Stokes shift, fluorescence characteristics, water solubility, and singlet oxygen generation efficiency of this class of dyes are summarized, and the application development of the corresponding dyes in the field of biological application is introduced, which will provide a reference for the optimization and improvement of heptamethine cyanine dyes in the future.

Detection of Selenocysteine with a Ratiometric near-Infrared Fluorescent Probe in Cells and in Mice Thyroid Diseases Model.

The pathological progression of thyroid diseases poses a serious threat to human health. Because thyroid diseases are closely related to selenocysteine (Sec), it is necessary to investigate the relationship between Sec and thyroid diseases. Herein, we design and synthesize a ratiometric near-infrared fluorescent probe (Mito-Cy-Sec) to analyze the fluctuations and roles of Sec in cells and in mice thyroid diseases model. The probe is composed of a near-infrared heptamethine cyanine fluorophore, an acrylamide as the response moiety, and a lipophilic triphenylphosphonium cation as the mitochondrial localization group. After reacting with Sec for 5 min, the probe Mito-Cy-Sec exhibits a distinct ratiometric fluorescence signal accompanied by a color change from green to blue. The applicability of Mito-Cy-Sec in mitochondrial localization is assessed via the super-resolution imaging. Mito-Cy-Sec has been successfully applied to detect the fluctuations of Sec concentration in human thyroid epithelial/cancer cell lines (Nthy-ori-3 cells/BHT101 cells) and mice thyroid disease (thyroiditis and thyroid cancer) models. Besides, both of our probes Mito-Cy-Sec and commercial ROSGreen H2O2 are employed to examine the interrelationship between H2O2 and Sec in cells and in mice models. The results demonstrate that the relevant-levels between H2O2 and Sec are exactly negative correlation. The related-levels of Sec and H2O2 may be identified as diagnostic indicators for the auxiliary diagnosis of thyroid diseases. We suppose that our probe Mito-Cy-Sec can be employed as a promising chemical tool for the diagnosis of thyroid diseases.

Near-Infrared Fluorescent Sorbitol Probe for Targeted Photothermal Cancer Therapy.

Photothermal therapy (PTT) using a near-infrared (NIR) heptamethine cyanine fluorophore has emerged as an alternative strategy for targeted cancer therapy. NIR fluorophores showing a high molar extinction coefficient and low fluorescence quantum yield have considerable potential applications in photothermal cancer therapy. In this study, a bifunctional sorbitol–ZW800 conjugate was used as an advanced concept of photothermal therapeutic agents for in vivo cancer imaging and therapy owing to the high tumor targetability of the sorbitol moiety and excellent photothermal property of NIR heptamethine cyanine fluorophore. The sorbitol–ZW800 showed an excellent photothermal effect increased by 58.7 °C after NIR laser irradiation (1.1 W/cm2) for 5 min. The HT-29 tumors targeted by sorbitol–ZW800 showed a significant decrease in tumor volumes for 7 days after photothermal treatment. Therefore, combining the bifunctional sorbitol–ZW800 conjugate and NIR laser irradiation is an alternative way for targeted cancer therapy, and this approach holds great promise as a safe and highly efficient NIR photothermal agent for future clinical applications.

IR-783 inhibits breast cancer cell proliferation and migration by inducing mitochondrial fission.

IR-783, a near-infrared heptamethine cyanine dye, has been reported to possess cancer targeting and anticancer effects; However, the molecular mechanism by which IR-783 exhibits anti-breast cancer activity is unclear. In the present study, the inhibitory effects of IR-783 on the proliferation and migration of breast cancer cells were investigated. Our results revealed that IR-783 inhibited MDA-MB-231 and MCF-7 cell proliferation in a dose- and time-dependent manner by inducing cell cycle arrest at the G0/G1 phase. In addition, a Transwell assay demonstrated that IR-783 treatment suppressed the migratory ability of MDA-MB-231 and MCF-7 cells. Furthermore, IR-783 treatment decreased the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 in MDA-MB-231 cells. Furthermore, IR-783 induced MDA-MB-231 and MCF-7 cell mitochondrial fission, and also decreased the levels of ATP. This was accompanied with a decrease in polymerized filamentous actin, which is the fundamental component of filopodia at the cell surface. Collectively, the results of the present study demonstrated that IR-783 inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells by inducing mitochondrial fission and subsequently decreasing ATP levels, resulting in cell cycle arrest and filopodia formation suppression. These findings suggest that IR-783 may be developed into an effective novel drug for treating breast cancer.

Design, Synthesis, and Evaluation of Monoamine Oxidase A Inhibitors⁻Indocyanine Dyes Conjugates as Targeted Antitumor Agents.

Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1–G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 μM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer.

Determination of phosphate anions with a near-infrared heptamethine cyanine dye in a neutral aqueous solution

A novel strategy was developed for the detection of phosphate anions with anionic heptamethine cyanine and Tb3+ in the NIR region.

Evaluation Selenocysteine Protective Effect in Carbon Disulfide Induced Hepatitis with a Mitochondrial Targeting Ratiometric Near-Infrared Fluorescent Probe.

As important active sites of oxidoreductase in mitochondria, selenocysteine (Sec) takes the responsibility for cytoprotective effect and intracellular redox homeostasis. Carbon disulfide (CS2) is a common solvent in industry, which can inhibit the activities of oxidoreductase and induce oxidative stress. It is necessary to investigate the cytoprotective effect of Sec against CS2 exposure. After integrated, the response moiety 2,4-dinitrobenzenesulfonamide and mitochondrial targeting moiety into the near-infrared heptamethine cyanine fluorophore, we develop a mitochondrial targeting near-infrared ratiometric fluorescent probe Mito- diNO2 for the selective and sensitive analysis of Sec concentration fluctuations in living cells and in mice models under the stimulation of CS2. The probe can effectively accumulate in mitochondria and selectively detect the endogenous Sec concentrations in BRL 3A, RH-35, HL-7702, HepG2, and SMMC-7721 cell lines. The results indicate that CS2 exposure can lead to a decrease of Sec level and result in mitochondrial related acute inflammation. The exogenous supplement of Sec can protect cells from oxidative damage and reduce the symptoms of inflammation. We also establish CS2 induced acute and chronic hepatitis mice models to examine the tissue toxicity of CS2 and cytoprotection of Sec in liver. The organism can increase the concentration of Sec to deal with the damage caused by CS2 in acute hepatitis mice model. Also the exogenous supplement of Sec for the two mice models can effectively defend the CS2 induced liver damage. The real-time imaging of Sec concentrations in liver can be used to assess the degrees of liver injury during CS2 poisoning. The above applications make our probe a potential candidate for the clinical accurate diagnosis and treatment of CS2 poisoning.

Cyanine-Containing Polymeric Nanoparticles with Imaging/Therapy-Switchable Capability for Mitochondria-Targeted Cancer Theranostics

Theranostic nanoparticles (NPs) capable of mitochondrial targeting/imaging, cancer/normal cell differentiation, early stage cancer diagnosis, and mitochondria-based photothermal therapy (PTT) were developed. The NPs were fabricated by physical encapsulation of near-infrared (NIR) heptamethine cyanine dye me-IR825 into the inner core of the micelle-forming copolymer Pluronic F127 (PF127). The PF127/me-IR825 NPs exhibited two fluorescence emissions at ∼610 nm (excited by 550 nm) and 845 nm (excited by 780 nm). The former was used for in vitro mitochondrial fluorescence imaging, cancer/normal cell differentiation, and early stage cancer detection with high fluorescence contrast. The latter was used for in vivo NIR fluorescence imaging. Besides, the NPs could also be used for in vivo photoacoustic imaging under 808 nm excitation. After irradiation by an 808 nm laser at an elevated power density, the NPs achieved excellent photothermal tumor ablation both in vitro and in vivo. Furthermore, me-IR825 inside the ...