BODIPY Research Articles

Identification of a luminescent platinum(II) complex with BODIPY derivative as novel photodynamic therapy agent for triple negative breast cancer cells

Triple-negative breast cancer (TNBC) is one of the most malignant breast tumors for its poor prognosis and high tumor recurrence. It is urgent to develop new strategy or effective agents to overcome resistance and improve therapeutic effectiveness. Boron-dipyrromethene (BODIPY) based photosensitizers possess exciting photophysical features suitable for theranostic applications, namely, photodynamic therapy (PDT). We have designed a luminescent monofunctional platinum(II) complex with BODIPY derivative, namely I2BC-Pt, as novel high PDT agent against triple negative breast cancer (TNBC). The di-iodinated BODIPY complex I2BC-Pt showed excellent PDT effect against TNBC cells in green light (520 nm) giving IC50 values of 0.11–0.13 μM in MDA-MB-231 and MDA-MB-468 cells. I2BC-Pt predominately aggregated in the mitochondria of MDA-MB-231 cells and emitted green fluorescence. Besides, the anticancer mechanism studies demonstrated that I2BC-Pt could help DNA repair through attenuating RAD51, FoxM1 and BRCA1/2, and induce p53-mediated apoptosis of TNBC cells. Taken together, I2BC-Pt could be potentially developed as a BODIPY-based photosensitizers for TNBC therapy.

Stimuli-Responsive Boron-Based Materials in Drug Delivery.

Drug delivery systems, which use components at the nanoscale level as diagnostic tools or to release therapeutic drugs to particular target areas in a regulated manner, are a fast-evolving field of science. The active pharmaceutical substance can be released via the drug delivery system to produce the desired therapeutic effect. The poor bioavailability and irregular plasma drug levels of conventional drug delivery systems (tablets, capsules, syrups, etc.) prevent them from achieving sustained delivery. The entire therapy process may be ineffective without a reliable delivery system. To achieve optimal safety and effectiveness, the drug must also be administered at a precision-controlled rate and the targeted spot. The issues with traditional drug delivery are overcome by the development of stimuli-responsive controlled drug release. Over the past decades, regulated drug delivery has evolved considerably, progressing from large- and nanoscale to smart-controlled drug delivery for several diseases. The current review provides an updated overview of recent developments in the field of stimuli-responsive boron-based materials in drug delivery for various diseases. Boron-containing compounds such as boron nitride, boronic acid, and boron dipyrromethene have been developed as a moving field of research in drug delivery. Due to their ability to achieve precise control over drug release through the response to particular stimuli (pH, light, glutathione, glucose or temperature), stimuli-responsive nanoscale drug delivery systems are attracting a lot of attention. The potential of developing their capabilities to a wide range of nanoscale systems, such as nanoparticles, nanosheets/nanospheres, nanotubes, nanocarriers, microneedles, nanocapsules, hydrogel, nanoassembly, etc., is also addressed and examined. This review also provides overall design principles to include stimuli-responsive boron nanomaterial-based drug delivery systems, which might inspire new concepts and applications.

Metal‐Free Far‐Red Light‐Driven Photolysis via Triplet Fusion to Enhance Checkpoint Blockade Immunotherapy

AbstractMetal‐free long‐wavelength light‐driven prodrug photoactivation is highly desirable for applications such as neuromodulation, drug delivery, and cancer therapy. Herein, via triplet fusion, we report on the far‐red light‐driven photo‐release of an anti‐cancer drug by coupling the boron‐dipyrromethene (BODIPY)‐based photosensitizer with a photocleavable perylene‐based anti‐cancer drug. Notably, this metal‐free triplet fusion photolysis (TFP) strategy can be further advanced by incorporating an additional functional dopant, i.e. an immunotherapy medicine inhibiting the indoleamine 2,3‐dioxygenase (IDO), with the far‐red responsive triplet fusion pair in an air‐stable nanoparticle. With this IDO inhibitor‐assisted TFP system we observed efficient inhibition of primary and distant tumors in a mouse model at record‐low excitation power, compared to other photo‐assisted immunotherapy approaches. This metal‐free TFP strategy will spur advancement in photonics and biophotonics fields.

Metal-Free Far-Red Light-Driven Photolysis via Triplet Fusion to Enhance Checkpoint Blockade Immunotherapy.

Metal-free long-wavelength light-driven prodrug photoactivation is highly desirable for applications such as neuromodulation, drug delivery, and cancer therapy. Herein, via triplet fusion, we report on the far-red light-driven photo-release of an anti-cancer drug by coupling the boron-dipyrromethene (BODIPY)-based photosensitizer with a photocleavable perylene-based anti-cancer drug. Notably, this metal-free triplet fusion photolysis (TFP) strategy can be further advanced by incorporating an additional functional dopant, i.e. an immunotherapy medicine inhibiting the indoleamine 2,3-dioxygenase (IDO), with the far-red responsive triplet fusion pair in an air-stable nanoparticle. With this IDO inhibitor-assisted TFP system we observed efficient inhibition of primary and distant tumors in a mouse model at record-low excitation power, compared to other photo-assisted immunotherapy approaches. This metal-free TFP strategy will spur advancement in photonics and biophotonics fields.

Isomer engineering to adjusting full width at half maximum and emission wavelength for efficient solution-processed red OLEDs

Given the great effect of red dyes with high color purity on ultrahigh-definition displays, exploring new red fluorophores remains urgent. In this work, two novel boron dipyrromethene derivatives (BODIPYs), named o-OMB and p-OMB, were designed and synthesized by adjusting the substitution position of methoxy group. The introduction of tert-butylbenzene units increases steric hindrance and adjacent distance between the host and guest to inhibit adverse Dexter energy transfer. Regioisomerization of methoxy group has a certain impact on photophysical properties, including the distribution of frontier molecular orbitals and recombination energy. The recombination energy of p-OMB is much smaller than that of o-OMB, and the Eg of the former is 1.94 eV less than that of the latter 2.02 eV. Compared with o-OMB, p-OMB with para-substituent has narrower emission spectrum with a FWHM of 37 nm and red-shifted emission wavelength of 634 nm. The solution-processed based-p-OMB OLEDs show a maximum EQE of 1.3% and standard red emission with CIE coordinates of (0.67, 0.33) when using PhCz-4CzTPN as a sensitizer.

Ultrafast Charge Separation Driven by Torsional Motion in Orthogonal Boron Dipyrromethene Dimer

In this work, the photoinduced charge separation (CS) via symmetry breaking in an orthogonal meso-β-linked boron dipyrromethene (BODIPY) dimer was investigated by polarized transient absorption spectroscopy. The time constant about 0.76 ps of the CS reaction determined in dimethyl sulfoxide is much faster than the solvation dynamics. The observed transient anisotropy of the BODIPY anion band implies that both hole and electron transfers occur with similar probabilities. The bidirectional charge transfer processes suggest that the locally excited state is weakly coupled to the polar solvent, and the solvation coupled excited-state structural relaxation within the BODIPY monomeric unit is rather limited. In combination with the electronic excitation analysis based on time-dependent density-functional theory calculations, we deduced that the CS in the orthogonal BODIPY dimer is enabled via the torsional motion associated with covalently connected BODIPY units, promoting the electronic coupling, and irrelevant to the dynamic solvent relaxation.

Fluorescent probes based on a tetrad BODIPY structure for detection of a wide range of water contents in organic solvents

A series of tetrad Boron dipyrromethene (BODIPY) derivatives containing a variety of nitrogen-heterocyclic meso-substituents were synthesized. All exhibited fluorescence enhancement in the presence of water in organic solvents. Water-soluble tetrad BODIPY derivatives were obtained by displacement of fluoride at the boron atom by a bicyclic structure, and their fluorescence response was observed over a wide range of water contents in various organic solvents. The presence of acids or metal ions induced only a fluorescence shift and retained the fluorescence efficiency.

Highly Efficient Singlet Oxygen Generation by BODIPY-Ruthenium(II) Complexes for Promoting Neurite Outgrowth and Suppressing Tau Protein Aggregation.

Singlet oxygen (1O2) has been recently identified as a key molecule against toxic Aβ aggregation, which is associated with the currently incurable Alzheimer's disease (AD). However, limited research has studied its efficiency against tau protein aggregation, the other major hallmark of AD. Herein, we designed and synthesized boron-dipyrromethene (BODIPY)-ruthenium conjugates and isolated three isomers. Under visible-light irradiation, the ε isomer can be photoactivated and efficiently generate singlet oxygen. Particularly, the complex demonstrated successful results in attenuating tauopathy─an appreciable decrease to 43 ± 2% at 100 nM. The photosensitizer was further found to remarkably promote neurite outgrowth and significantly increased the length and number of neurites in nerve cells. As a result of effective photoinduced singlet oxygen generation and proactive neurite outgrowth, the hybrid design has great potential for therapeutics for Alzheimer's disease.

Synthesis, crystal structure, and photophysical properties of mononuclear and dinuclear palladium BODIPY chromophores

AbstractMononuclear and dinuclear palladium‐centered boron dipyrromethene (BODIPY) complexes, HBDPPdI and BDPPd2I2, respectively, were synthesized by the direct insertion of a palladium source into iodine‐substituted BODIPY chromophores. The molecular structures of both metal complexes were characterized using several analytical techniques, including single crystal x‐ray diffraction, to find that Pd(0) is coordinated directly to the ligand through a PdC bond facilitated by the insertion reaction. The photophysical properties of these complexes were also detailed.

A tricarbonyl rhenium(I) complex decorated with boron dipyrromethene for endoplasmic reticulum-targeted photodynamic therapy

Organelle-targeted photodynamic therapy (PDT) has recently emerged as a promising strategy for developing effective and precise cancer therapy. Selective generation of highly cytotoxic reactive oxygen species (ROS) in the endoplasmic reticulum (ER) region by PDT can effectively kill cancer cells. In this work, an ER-targeted tricarbonyl Re(I) complex (Re-BDP) was designed and synthesized by combining a tricarbonyl Re(I) unit and a photoactive boron dipyrromethene (BODIPY) chromophore moiety. Complex Re-BDP was characterized by ESI-MS, 1H NMR spectroscopy, FT-IR spectroscopy, and high-performance liquid chromatography (HPLC). The complex displayed strong absorbance (ε = 6.56 × 104/M−1 cm−1 in CH2Cl2) in the visible light region (∼512 nm) and a high singlet oxygen quantum yield (ΦΔ = 0.89 in methanol). Co-localization assays revealed that it accumulated preferentially in the ER. Complex Re-BDP exhibited high phototoxicity upon visible light (525 nm) irradiation toward human cervical cancer HeLa, human lung cancer A549 and human breast cancer MDA-MB-231 cells. Mechanism experiments showed that complex Re-BDP caused reactive oxygen species (ROS) generation and induced ER stress in HeLa cells upon light irradiation, leading to caspase-dependent apoptosis, accompanied by mitochondrial dysfunction. Overall, the results demonstrate that complex Re-BDP is a promising phototherapeutic agent for ER-targeted cancer phototherapy. This work highlights the effectiveness of developing efficient organelle-targeted metal-based phototherapeutic agents by appropriate conjugation of metal complexes and organic chromophores.

Chemical biology fluorescent tools for in vitro investigation of the multidrug resistant P-glycoprotein (P-gp) expression in tumor cells.

Selective P-glycoprotein (P-gp)-targeted fluorescent conjugates are desirable tools to investigate the role of P-gp, a protein strongly implicated in mediating multidrug resistance and a major cause of chemotherapy failure. Herein, we report the development of 25 novel fluorescent small-molecule conjugates with varying physicochemical and optical properties, and their biological evaluation in a cell model as P-gp targeted constructs. This investigation revealed relationships between molecular structure and cell behavior and uncovered the capacity of conjugates with varying fluorophores to selectively target P-gp. Sulfocyanine 3 labeled conjugates (5, 10, 24, 29, 34) showed a particular intracellular staining pattern. Other conjugates bearing a boron dipyrromethene (BODIPY) core (3, 8, 13, 22, 27 (BODIPY FL), 12 (BODIPY 564/570) and 4, 9 (BODIPY 650/665)) or a 7-nitrobenz-2-oxa-1,3-diazole (NBD) core (11, 30) showed potential for global P-gp direct detection and quantification. These fluorescent conjugates holds key advantages over existing methods for drug resistance evaluation with regards to P-gp expression and could be used as innovative tools in preclinical assays and clinical diagnosis.

Spin-orbit charge-transfer intersystem crossing in heavy-atom-free orthogonal covalent boron-dipyrromethene heterodimers.

Boron-dipyrromethene (BODIPY) derivatives are prospective organic-based triplet photosensitizers. Since the triplet generation yield of the parent BODIPY is low, heavy atoms are widely used to improve the triplet yield. However, the dimerization of BODIPYs can also significantly improve their ability to produce triplets. Through a comparative study of the triplet formation dynamics of two heavy-atom-free orthogonal covalent BODIPY heterodimers that differ in their dihedral angles, we have demonstrated that the mechanism of spin-orbit charge-transfer intersystem crossing (SOCT-ISC) promotes the triplet generation of BODIPY heterodimers in solution. Different from the general understanding of SOCT-ISC, the heterodimer with a smaller dihedral angle and low structural rigidity showed better triplet generation due to (a) the stronger inter-chromophoric interaction in the heterodimer, which promoted the formation of a solvent-stabilized charge-transfer (CT) state, (b) the more favorable energy level alignment with sizeable spin-orbit coupling strength, and (c) the balance between the stabilized singlet CT state and limited direct charge recombination to the ground state in a weakly polar solvent. The complete spectral characterization of the triplet formation dynamics clarified the SOCT-ISC mechanism and important factors affecting the triplet generation in BODIPY heterodimers.

Ultra-small NIR J-aggregates of BODIPY for potent phototheranostics.

Cancer phototheranostics that combines diagnosis with phototherapy has emerged as a new mode of precise treatment. Nevertheless, taking highly effective phototheranostics into consideration, it is still a tremendous challenge to design multifunctional photothermal agents (PTAs) that combine the features of intensive near-infrared (NIR) absorption/emission, high photothermal conversion efficiency (PCE) and preferable tumor accumulation. Herein, seeking a convenient method to facilitate absorption red-shift, promote the accumulation of drugs in tumors and heighten the PCE appears to be particularly important for cancer theranostics. In this work, heavy-atom-free boron dipyrromethene (BODIPY) was assembled with F127 to fabricate ultra-small J-aggregated nanoparticles (named as BNPs). Compared to free BODIPY, BNPs exhibited 63 nm redshifted absorption, deep-tissue fluorescence imaging, enhanced cellular uptake, preferable tumor accumulation, elevated PCE, excellent photothermal stability and water dispersibility. In vivo experiments demonstrated that BNPs could behave as high-performance tumor fluorescent imaging probes and antitumor PTAs to conduct NIR imaging-guided PTT. This work offers a novel J-aggregated framework on developing robust diagnostic and therapeutic agents.

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.

Record release of tetramethylguanidine using a green light activated photocage for rapid synthesis of soft materials.

Photocages have enabled spatiotemporally governed organic materials synthesis with applications ranging from tissue engineering to soft robotics. However, the reliance on high energy UV light to drive an often inefficient uncaging process limits their utility. These hurdles are particularly evident for more reactive cargo, such as strong organobases, despite their attractive potential to catalyze a range of chemical transformations. Herein, two metal-free boron dipyrromethene (BODIPY) photocages bearing tetramethylguanidine (TMG) cargo are shown to induce rapid and efficient polymerizations upon exposure to a low intensity green LED. A suite of spectroscopic characterization tools were employed to identify the underlying uncaging and polymerization mechanisms, while also determining reaction quantum efficiencies. The results are directly compared to state-of-the-art TMG-bearing ortho-nitrobenzyl and coumainylmethyl photocages, finding that the present BODIPY derivatives enable step-growth polymerizations that are >10× faster than the next best performing photocage. As a final demonstration, the inherent multifunctionality of the present BODIPY platform in releasing radicals from one half of the molecule and TMG from the other is leveraged to prepare polymers with starkly disparate physical properties. The present findings are anticipated to enable new applications of photocages in both small-molecule photochemistry for medicine and advanced manufacturing of next generation soft materials.

Thiophene-fused boron dipyrromethenes as energy efficient near-infrared photocatalysts for radical polymerizations

A series of thiophene-fused boron dipyrromethene (BODIPY) photoredox catalysts are systematically examined to identify structure–reactivity relationships that enable efficient near-infrared light-induced polymerizations.

Fully-unfused electron acceptors based on a steric boron dipyrromethene (BODIPY) core for organic solar cells

Multi-functional steric BODIPY core was employed to improve light harvesting and modify intermolecular stacking for fully-unfused electron acceptors.

Synthesis, structure and spectroscopic properties of BODIPY dyes incorporating the pentafluorosulfanylphenyl group

Six compounds (BD1–BD6) are discussed based on the borondipyrromethene (BODIPY) core and functionalised in the meso position or the 3,5-positions with pentafluorosulfanylaryl subunits.

Crystalline radicals derived from boron-dipyrromethene and its heavier analogues

The first series of radicals derived from boron-dipyrromethene (BODIPY) and its heavier analogues have been isolated and fully characterized.

Biotin and boron-dipyrromethene-tagged platinum(IV) prodrug for cellular imaging and mito-targeted photocytotoxicity in red light.

A platinum(IV) prodrug, cis,cis,trans-[Pt(NH3)2Cl2(biotin)(L)] (1), derived from cisplatin, where HL is the PEGylated red-light active boron-dipyrromethene (BODIPY) ligand, was synthesized, characterized and its photocytotoxicity evaluated. The complex showed a near-IR absorption band at 653 nm (ε ∼9.19 × 104 M-1 cm-1) in dimethyl sulfoxide and Dulbecco's phosphate-buffered saline (1 : 1 v/v) at pH 7.2. When excited at 630 nm, it showed an emission band at 677 nm in DMSO with a fluorescence quantum yield of 0.13. The 1,3-diphenylisobenzofuran titration experiment gave a singlet oxygen quantum yield (ΦΔ) of ∼0.32. A mechanistic DNA photocleavage study revealed singlet oxygen as the reactive oxygen species (ROS). The complex with biotin and PEGylated-distyryl-BODIPY showed significantly higher cellular uptake in A549 cancer cells as compared to non-cancerous Beas-2B cells from flow cytometry, indicating selectivity towards cancer cells. A dichlorodihydrofluorescein diacetate assay showed cellular ROS generation. Confocal images revealed predominant internalization in the mitochondria. The prodrug showed remarkable photodynamic therapy (PDT) activity in cancerous A549 and multidrug-resistant MDA-MB-231 cells with a high photocytotoxicity index value (half-maximal inhibitory concentration (IC50): 0.61-1.54 μM in red light), while being non-toxic in the dark. The chemo-PDT activity was significantly less in non-tumorigenic lung epithelial cells (Beas-2B). The prodrug effectively triggered cellular apoptosis, which was confirmed by the Annexin V-FITC/propidium iodide assay, and the alteration of the mitochondrial membrane potential was substantiated by the JC-1 dye assay. The β-tubulin immunofluorescence assay confirmed that incubating the cells with a light-treated complex resulted in the rapture of the cytoskeletal structure and the formation of apoptotic bodies. The results demonstrate that the prodrug triggered apoptosis via DNA damage, a reduction in mitochondrial function and disruption of the cytoskeletal framework.