aza-BODIPY Dyes Research Articles

Harnessing Dual Phototherapy and Immune Activation for Cancer Treatment: The Development and Application of BODIPY@F127 Nanoparticles.

Conventional phototherapeutic agents are typically used in either photodynamic therapy (PDT) or photothermal therapy (PTT). However, efficacy is often hindered by hypoxia and elevated levels of heat shock proteins in the tumor microenvironment (TME). To address these limitations, a formylated, near-infrared (NIR)-absorbing and heavy-atom-free Aza-BODIPY dye is presented that exhibits both type-I and type-II PDT actions with a high yield of reactive oxygen species (ROS) and manifests efficient photothermal conversion by precise adjustments to the conjugate structure and electron distribution, leading to a large amount of ROS production even under severe hypoxia. To improve biosafety and water solubility, the dye with an amphiphilic triblock copolymer (Pluronic F-127), yielding BDP-6@F127 nanoparticles (NPs) is coated. Furthermore, inspired by the fact that phototherapy triggers the release of tumor-associated antigens, a strategy that leverages potential immune activation by combining PDT/PTT with immune checkpoint blockade (ICB) therapy to amplify the systemic immune response and achieve the much-desired abscopal effect is developed. In conclusion, this study presents a promising molecular design strategy that integrates multimodal therapeutics for a precise and effective approach to cancer therapy.

GSH-responsive bithiophene Aza-BODIPY@HMON nanoplatform for achieving triple-synergistic photoimmunotherapy

Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON’s large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON’s rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11 %. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.

Aza-BODIPY-based logic gate chemosensors and their applications

Dimethylaniline-substituted aza-BODIPY dyes (DA, DM, DP) were designed and synthesized aiming for ion detection. The Zn2+ recognition ability was found in all compounds and the binding mechanism was possibly via dimethylaniline sites linked to the aza-BODIPY core. Upon Zn2+ addition, the new absorption band and the color change occurred due to the altered charge transfer of the adducts. The custom-made colorimeter was successfully integrated into the dye’s application, demonstrating a good linear relationship between resistance values and Zn2+ concentration. The chromophore test strips were fabricated and exhibited distinct color changes upon aqueous Zn2+ exposure. The compound DA also exhibits logical behavior with DA-Zn2+-Cu2+ system. In terms of environmental hazards, the compounds exhibited no adverse effect on Pseudomonas putida at the concentration level of 0.2 mg/mL. These findings indicated that all synthesized aza-BODIPYs might be suitable for chemosensor probes for Zn2+ detection with possibly low environmental risk.

Near-Infrared Absorbing Aza-BODIPY Dyes for Optoelectronic Applications.

Organic dyes that absorb light in the visible to near-infrared region have garnered significant interest, owing to their extensive utility in organic photovoltaics and various biomedical applications. Aza-boron-dipyrromethene (Aza-BODIPY) dyes are a class of chromophores with impressive photophysical properties such as tunable absorption from the visible region towards near infrared (NIR) region, high molar absorptivity, and fluorescence quantum yield. In this review, we discuss the developments in the aza-BODIPYs, related to their synthetic routes, photophysical properties and their applications. Their design strategies, modifications in chemical structures, mode/position of attachment, and their impact on photo-physical properties are reviewed. The potential applications of aza-BODIPY derivatives such as organic solar cells, photodynamic therapy, boron-neutron capture therapy, fluorescence sensors, photo-redox catalysis, photoacoustic probes and optoelectronic devices are explained.

Control of Kinetic Pathways toward Supramolecular Chiral Polymorphs for Tunable Circularly Polarized Luminescence.

An amphiphilic aza-BODIPY dye (S)-1 bearing two chiral hydrophilic side chains with S-stereogenic centers was synthesized. This dye exhibited kinetic-controlled self-assembly pathways and supramolecular chiral polymorphism properties in MeOH/H2O (9/1, v/v) mixed solvent. The (S)-1 monomers first aggregated into a kinetic controlled, off-pathway species Agg. A, which was spontaneously transformed into an on-pathway metastable aggregate (Agg. B) and subsequently into the thermodynamic Agg. C. The three aggregate polymorphs of dye (S)-1 displayed distinct optical properties and nanomorphologies. In particular, chiral J-aggregation characteristics were observed for both Agg. B and Agg. C, such as Davydov-split absorption bands (Agg. B), extremely sharp and intense J-band with large bathochromic shift (Agg. C), non-diminished fluorescence upon aggregation, as well as strong bisignated Cotton effects. Moreover, the AFM and TEM studies revealed that Agg. A had the morphology of nanoparticle while fibril or rod-like helical nanostructures with left-handedness were observed respectively for Agg. B and Agg. C. By controlling the kinetic transformation process from Agg. B to Agg. C, thin films consisting of Agg. B and Agg. C with different ratios were prepared, which displayed tunable CPL with emission maxima at 788-805 nm and g-factors between -4.2×10-2 and -5.1×10-2.

Engineering aggregates of julolidine-substituted aza-BODIPY nanoparticles for NIR-II photothermal therapy

Near infrared-II (NIR-II) dyes have unique advantages in biomedical applications owing to the powerful ability in penetrating biological tissues. Herein, NIR-II aza-BODIPY dye, QLD-BDP, was developed with julolidine at 1,7-sites and p-dimethylaminophenyl group at 3,5-sites. According to X-ray analysis, QLD-BDP exhibits significant distortion, and this molecule appears a bowl shaped structure. The photothermal conversion efficiency of the self-assembled QLD-BDP nanoparticles (QLD-BDP-NPs) can reach 50.5%, with maximum emission at 998 nm by the aggregate. QLD-BDP-NPs can cause the complete destruction of 4T1 multicellular spheroids (MCSs), indicating a photothermal therapy (PTT) effect.

Tuning Shortwave-Infrared J-aggregates of Aromatic Ring-Fused Aza-BODIPYs by Peripheral Substituents for Combined Photothermal and Photodynamic Therapies at Ultralow Laser Power.

Achieving photothermal therapy (PTT) at ultralow laser power density is crucial for minimizing photo-damage and allowing for higher maximum permissible skin exposure. However, this requires photothermal agents to possess not just superior photothermal conversion efficiency (PCE), but also exceptional near-infrared (NIR) absorptivity. J-aggregates, exhibit a significant redshift and narrower absorption peak with a higher extinction coefficient. Nevertheless, achieving predictable J-aggregates through molecular design remains a challenge. In this study, we successfully induced desirable J-aggregation (λabs max : 968 nm, ϵ: 2.96×105 M-1 cm-1 , λem max : 972 nm, ΦFL : 6.2 %) by tuning electrostatic interactions between π-conjugated molecular planes through manipulating molecular surface electrostatic potential of aromatic ring-fused aza-BODIPY dyes. Notably, by controlling the preparation method for encapsulating dyes into F-127 polymer, we were able to selectively generate H-/J-aggregates, respectively. Furthermore, the J-aggregates exhibited two controllable morphologies: nanospheres and nanowires. Importantly, the shortwave-infrared J-aggregated nanoparticles with impressive PCE of 72.9 % effectively destroyed cancer cells and mice-tumors at an ultralow power density of 0.27 W cm-2 (915 nm). This phototherapeutic nano-platform, which generates predictable J-aggregation behavior, and can controllably form J-/H-aggregates and selectable J-aggregate morphology, is a valuable paradigm for developing photothermal agents for tumor-treatment at ultralow laser power density.

Triphenylamine-functionalized aza-BODIPY dyes: synthesis, characterization, and their application as hole transport materials in perovskite solar cells

Triphenylamine-functionalized NIR-absorbing aza-BODIPY dyes 1–3 were synthesized and their properties were investigated in detail. A PCE of 18.12% was achieved for the PSCs employing dye 1 as the dopant-free hole transporting material.

N-type conjugated polymer semiconductor materials based on Aza-BODIPY dye with Naphthodipyrrolopyrrole (NDP-AB)

So far, the charge carrier mobility as well as the stability of n-type semiconductors fall behind when compared to the p-type ones. Therefore, exploring high-performance n-type semiconductor materials plays a crucial role in the further development of organic field-effect transistors (OFETs) for industrial applications. Naphthodipyrrolopyrrole-based dimeric aza-boron dipyrromethene dyes (NDP-AB) present strong electron-deficient units, which are rarely investigated. In this work, the NDP-AB chromophore is, for the first time, introduced as the acceptor in donor-acceptor type polymers. The results show that the NDP-AB based polymers exhibit extra-low LUMO energy levels, which endow the semiconductor layer with the ability to form Ohmic contacts with electrodes. This is advantageous for electron injection. In addition, the polymers present not only a strong aggregation as well as short π-π stacking d-spacing, but also a good planar polymer backbone and strong ICT effect. That phenomenon is advantage for the electron carrier transport across the adjacent molecules and the individual molecule. As a consequence, the NDP-AB-based polymers exhibit n-type behavior with electron transport mobility up to 0.89 cm2 V−1 s−1. This work demonstrate that NDP-AB is a promising electron-deficient building block for high-performance n-type semiconductors.

Aza-BODIPY dye with unexpected bromination and high singlet oxygen quantum yield for photoacoustic imaging-guided synergetic photodynamic/photothermal therapy

Introducing heavy halogen atoms into organic small molecules is a practical strategy for efficient singlet oxygen (1O2) generation. Generally, bromine or iodine atoms are introduced on the aza-boron-dipyrromethene (aza-BODIPY) core, rather than on the periphery aryl rings for efficient 1O2 generation. Herein, an aza-BODIPY dye NBDPBr with unexpected bromination on the periphery aryl rings was synthesized for photoacoustic (PA) imaging-guided synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) in tumor cells. Owing to unexcepted bromination at the periphery aryl rings, NBDPBr demonstrated an outstanding singlet oxygen quantum yield (ΦΔ) of 66% which was superior to similar brominated photosensitizers previously reported. After encapsulation with amphiphilic polymer F-127, hydrophilic NBDPBr nanoparticles (NPs) were fabricated and exhibited an excellent photothermal conversion efficiency (η) of 43.0% under 660 nm photoirradiation. In vivo PA imaging results demonstrated that NBDPBr NPs could specifically accumulate at tumor sites and realized the maximum tumor retention at 7 h post-injection. All the in vitro and in vivo results indicated the significant potence of NBDPBr with unexpected bis-bromination for PA imaging-guided synergetic PDT/PTT.

Near-infrared fluorescent Aza-BODIPY dyes: Rational structural design and biomedical imaging

Near-infrared dyes have attracted widespread attention due to their intense absorption and emission in the near-infrared region. As an important class of heteroatom-containing BODIPY derivatives, Aza-BODIPY dyes display excellent performances, such as red-shifted spectra, high molar extinction coefficients, and good photostability. In this review, we summarize the latest advances in Aza-BODIPY dyes. The regulation strategies for photophysical properties and their applications in biomedical imaging are highlighted. Furthermore, we discuss the versatile imaging applications of Aza-BODIPY dyes in cancer diagnoses, organ injuries, and surgical navigation. The future challenges and development prospects of Aza-BODIPY dyes in biomedical field are also presented. We aim at providing meaningful inspiration for further development of functional organic dyes with excellent properties. It is believed that this review will illuminate the way for the development of new Aza-BODIPY contrast agents as well as other organic photosensitizer-based contrast agents in future clinical practices.

An amphiphilic near-infrared Mn,O-chelated metallo-azadipyrromethene dye: Synthesis, acid-responsive properties, and aggregation pathway control

A new amphiphilic Mn,O-chelated azadipyrromethene dye 1 bearing dodecyl chains at the 1,7-phenyls and oligo(ethylene glycol) chains at the 3,5-phenyls was synthesized and characterized. The dye 1 exhibited an absorption maximum in NIR at 823 nm, which is largely bathochromically shifted as compared with the known aza-BODIPY as well as the B,O-chelated aza-BODIPY dyes. Meanwhile, the electrochemical studies of this dye indicated a lower HOMO-LUMO gap in comparison with the boron-chelated analogues. This dye also displayed the acid-responsive properties, as indicated by the hypsochromical shift of ca. 94 nm of the absorption band as well as the occurrence of fluorescence emission at 751 nm upon adding trifluoroacetic acid (TFA) into the dye 1 solution. Moreover, in highly polar solvent MeOH the amphiphilic dye 1 self-assembled into H-type aggregates, which exhibited a fibrous morphology in AFM studies. Further temperature-dependent UV/Vis absorption spectroscopic studies revealed a cooperative aggregation mechanism of dye 1 in MeOH. Based on the acid-responsive properties of 1, a method of control of the aggregation pathway of dye 1 by using acid and base was proposed and demonstrated by UV/Vis spectroscopic studies.

Tuning the Photophysical Properties of Aza-BODIPYs in the Near-Infrared Region by Introducing Electron-Donating Thiophene Substituents.

This study presents the synthesis, the spectroscopic and electrochemical properties of new bis- and tetra-substituted azaboron-dipyrromethene (aza-BODIPY) dyes substituted by different electron donating groups connected to the aza-BODIPY core through a thiophene unit. In line with theoretical calculations, experimental measurements point out the positive impact of the thiophene group that behave as a secondary donor group leading to an enhancement of the intramolecular charge transfer process in comparison to previously reported aza-BODIPY dyes. This heterocycle has also been found to tune the oxidative potential and to stabilize the electro-generated species.

Syntheses, optical properties, and bioimaging application of near-infrared aza-BODIPY dyes with electronic push–pull system

It is still a challenging work of developing near-infrared (NIR) fluorescence dyes with excellent optical properties. Herein, we synthesized a series of NIR aza-BODIPY fluorescence dyes with electronic push–pull system and further investigated their photophysical properties, photostability, and application in cellular imaging. It was found that introducing electron-withdrawing groups (EWGs) on the para-position of aza-BODIPY 1,7-phenyls not only leads to the significant redshift of absorption and fluorescence emission bands of aza-BODIPY dyes but also increases their fluorescence quantum yield and photostablility. The DFT calculations and cyclic voltammetry measurements proved that introducing EWGs on para-position of 1,7-phenyls can decrease the energy level difference between HOMO and LUMO, resulting in the redshift of maximum absorption and emission wavelengths. On the basis of the feasible experiment results of cellular imaging and cytotoxicity assay, it is expected that the optimized aza-BODIPY dyes have a bright application prospect for in vivo cellular or tissue imaging.

NIR-II Aza-BODIPY Dyes Bioconjugated to Monoclonal Antibody Trastuzumab for Selective Imaging of HER2-Positive Ovarian Cancer.

Using fluorescence-guided surgery (FGS) to cytoreductive surgery helps achieving complete resection of microscopic ovarian tumors. The use of visible and NIR-I fluorophores has led to beneficial results in clinical trials; however, involving NIR-II dyes seems to outperform those benefits due to the deeper tissue imaging and higher signal/noise ratio attained within the NIR-II optical window. In this context, we developed NIR-II emitting dyes targeting human epidermal growth factor receptor 2 (HER2)-positive ovarian tumors by coupling water-soluble NIR-II aza-BODIPY dyes to the FDA-approved anti-HER2 antibody, namely, trastuzumab. These bioconjugated NIR-II-emitting dyes displayed a prolonged stability in serum and a maintained affinity toward HER2 in vitro. We obtained selective targeting of HER2 positive tumors (SKOV-3) in vivo, with a favorable tumor accumulation. We demonstrated the fluorescence properties and the specific HER2 binding of the bioconjugated dyes in vivo and thus their potential for NIR-II FGS in the cancer setting.

Synthesis and in vitro photodynamic activity of aza-BODIPY-based photosensitizers.

Aza-BODIPY dyes have recently come to attention owing to their excellent chemical and photophysical properties. In particular, their absorption and emission maxima can efficiently be shifted to the red or even to the NIR spectral region. On this basis, aza-BODIPY derivatives are widely investigated as fluorescent probes or phototherapeutic agents. Here we report the synthesis of a set of novel aza-BODIPY derivatives as potential photosensitizers for use in photodynamic therapy. Triazolyl derivatives were obtained via Cu(I)-catalyzed azide-alkyne cycloaddition as the key step. In vitro photodynamic activities of the newly synthesized compounds were evaluated on the A431 human epidermoid carcinoma cell line. Structural differences influenced the light-induced toxicity of the test compounds markedly. Compared to the initial tetraphenyl aza-BODIPY derivative, the compound bearing two hydrophilic triethylene glycol side chains showed substantial, more than 250-fold, photodynamic activity with no dark toxicity. Our newly synthesized aza-BODIPY derivative, acting in the nanomolar range, might serve as a promising candidate for the design of more active and selective photosensitizers.

Functional supramolecular aggregates based on BODIPY and aza-BODIPY dyes: control over the pathway complexity

The recent advances in the supramolecular assembly of BODIPY and aza-BODIPY dyes are reviewed, emphasizing the control over the kinetic pathway complexity of this class of dyes, and the prospects for future research are summarized.

A near-infrared organic photodetector based on an aza-BODIPY dye for a laser microphone system

A near-infrared aza-BODIPY dye is developed for organic photodetectors. The device achieves a high D* value and a fast-response speed of 0.5 μs. Importantly, our work innovatively utilizes the high-performance NIR OPD in the laser microphone system.

Multiplexed Detection of Human Papillomavirus Based on AzaBODIPY-Doped Silica-Coated Polystyrene Microparticles

Human papillomavirus (HPV) DNA detection can enable the early diagnosis of high-risk HPV types responsible for cervical cancer. HPV detection is also essential for investigating the clinical behavior and epidemiology of particular HPV types, characterization of study populations in HPV vaccination trials and monitoring the efficacy of HPV vaccines. In this study, two azaBODIPY dyes (1 and 2) were used as references and were doped into polystyrene particles (PS40), while a short HPV DNA single strand was used as a target molecule and was covalently bound to the silica shell. These particles were employed as optical probes in 1:1 hybridization assays, and their potential applicability as a tool for multiplex assays for the detection of different strands of HPV was evaluated using flow cytometry. A good separation in the fluorescence of the four different concentrations prepared for each dye was observed. To perform the hybridization assays, HPV18, HPV16, HPV11 and HPV6 single strands were attached to the particles through EDC-mediated coupling. The c-DNA-1-PS40 and c-DNA-2-PS40 particles exhibited low limit of detection (LOD) and quantification (LOQ) values for HPV11, and a narrow detection range was obtained. Multiplexed assay experiments were successfully performed for both particles, and the results proved that c-DNA-1-PS40 could potentially be used as a tool for multiplexing assays and merits further in-depth study in this context.

Hypoxia-Activatable Nanovesicles as In Situ Bombers for Combined Hydrogen-Sulfide-Mediated Respiration Inhibition and Photothermal Therapy.

Photothermal therapy (PTT) has emerged as a promising alternative or supplement to cancer treatments. While PTT induces the ablation of solid tumors, its efficiency is hampered by self-recovery within impaired cancer cells through glycolysis and respiration metabolism. Based on this, the introduction of hydrogen sulfide (H2S)-mediated respiration inhibition is a good choice to make up for the PTT limitation. Herein, nanovesicles (NP1) are integrated by a hypoxia-responsive conjugated polymer (P1), polymetric H2S donor (P2), and near-infrared (NIR) light-harvesting aza-BODIPY dye (B1) for the delivery of H2S and synergistic H2S gas therapy/PTT. The scaffold of NP1 undergoes disassembly in the hypoxic environments, thus triggering the hydrolysis of P2 to continuously long-term release H2S. Dependent on the superior photothermal ability of B1, NP1 elicits high photothermal conversion efficiency (η = 19.9%) under NIR light irradiation for PTT. Moreover, NP1 serves as in situ H2S bombers in the hypoxic tumor environment and suppresses the mitochondrial respiration through inhibiting expression of cytochrome c oxidase (COX IV) and cutting off the adenosine triphosphate (ATP) generation. Both in vitro and in vivo results demonstrate good antitumor efficacy of H2S gas therapy/PTT, which will be recommended as an advanced strategy for cancer therapeutics.