Conversion of albumin into a BODIPY-like photosensitizer by a flick reaction, tumor accumulation and photodynamic therapy.

The accumulation of photosensitizers (PSs) in lesion sites but not in other organs is an important challenge for efficient image guiding in photodynamic therapy. Cancer cells are known to express a significant number of albumin-binding proteins that take up albumin as a nutrient source. Here, we converted albumin to a novel BODIPY-like PS by generating a tetrahedral boron environment via a flick reaction. The formed albumin PS has almost the same 3-dimensional structural feature as free albumin because binding occurs at Sudlow Site 1, which is located in the interior space of albumin. An i.v. injection experiment in tumor-bearing mice demonstrated that the human serum albumin PS effectively accumulated in cancer tissue and, more surprisingly, albumin PS accumulated much more in the cancer tissue than in the liver and kidneys. The albumin PS was effective at killing tumor cells through the generation of reactive oxygen species under light irradiation. The crystal structure of the albumin PS was fully elucidated by X-ray crystallography; thus, further tuning of the structure will lead to novel physicochemical properties of the albumin PS, suggesting its potential in biological and clinical applications.

Synthesis and optical properties of tyramine-functionalized boron dipyrromethene dyes for cell bioimaging.

Tyramine signaling amplification (TSA) technology is generally applied in immunofluorescence, enzyme-linked immunoassays, in situ hybridization techniques, etc. Successful amplification of fluoresence signals cannot be achieved without excellent fluorescent dyes. BODIPY fluorophore is an ideal probe for cell fluorescence imaging, but pristine BODIPY cannot be direct used in the TSA system. In the paper, the new red-shifted tyramide-conjugated BODIPY (BDP-B/C/D) was synthesized via the Knoevenagel condensation reaction, which based on the tyramide-conjugated BODIPY (BDP-A). The synthesized dyes were combined with tyramine to obtain which could be used as a fluorescent substrate for enzymatic reaction of TSA. By using the selected substrate (BDP-C) in TSA, we found it to be more sensitive than the commercial dye 594 styramide for the detection of low-abundance antigen proteins.

Biotin-Pt(IV)-Ru(II)-Boron-Dipyrromethene Prodrug as "Platin Bullet" for Targeted Chemo- and Photodynamic Therapy.

Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)-Ru(II) complex, cis,cis,trans-[Pt(NH3)2Cl2{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl2 (Pt-Ru-B, 2), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (Ru-B, 1) photosensitizer having N,N,N-donor tpy (4'-phenyl-2,2':6',2″-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). Pt-Ru-B exhibited intense absorption near 500 nm and emission near 513 nm (λex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (ΦΔ) of ∼0.64 from 1,3-diphenylisobenzofuran experiments. Pt-Ru-B exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. Pt-Ru-B showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and Pt-Ru-B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.

Active Magnesium Boride/Alginate Hydrogels Rejuvenate Senescent Cells.

The clearance of senescent cells may be detrimental to low cell density diseases, such as intervertebral disc degeneration (IVDD), and rejuvenating these cells presents a formidable obstacle. In this study, we investigate a mild-alkalization strategy employing magnesium boride-alginate (MB-ALG) hydrogels to rejuvenate senescent cells associated with age-related diseases. MB-ALG hydrogels proficiently ensnare senescent cells owing to their surface roughness. The hydrolysis of MB-ALG hydrogels liberates hydroxide ions (OH-), effecting a transition from an acidic microenvironment (pH ∼ 6.2) to a mildly alkaline state (pH ∼ 8.0), thereby fostering senescent cell proliferation via activation of the PI3K/Akt/mTOR pathway. Additionally, H2 aids in ROS clearance, which reduces cellular oxidative stress. And, Mg2+ rejuvenates senescent cells by inhibiting Ca2+ influx and fine-tuning the sirt1-p53 signaling pathways. Both in vitro and in vivo experiments conducted on rat intervertebral discs corroborate the sustained antisenescence and rejuvenation properties of MB-ALG hydrogels, with effects persisting for up to 12 weeks postoperation. These discoveries elucidate the role of mild-alkalization in dictating cellular destiny and provide key insights for addressing age-related diseases.

Bodipy-Based highly sensitive hydrogen sulfide fluorescent probe and its fluorescence imaging in cells and zebrafish.

Hydrogen sulfide (H2S) is a crucial endogenous gasotransmitter that plays a role in various physiological and pathological processes. Therefore, accurate and rapid monitoring of H2S in organisms is highly significant for understanding the underlying pathological mechanisms and facilitating early diagnosis of related diseases. In this study, we developed a novel fluorescent probe, B-CHO-NO2, based on a bodipy fluorophore, which exhibits excellent sensitivity and selectivity towards H2S. The design of the probe exploits the nucleophilicity of H2S by introducing a formyl group as the ortho-participating moiety, significantly enhancing the reaction rate with H2S. In cellular and zebrafish models, the probe B-CHO-NO2 successfully achieved fluorescence imaging of endogenous and exogenous H2S. The development of probe B-CHO-NO2 provides a powerful tool for biological studies of H2S and diagnosis of related diseases.

AIE-active large Stokes-shift BODIPY Functionalized with Carbazolyl for Lysosome-Targeted Imaging in Living Cells.

A large number of studies have shown that lysosomal microcircumstances changes can affect many physiological and pathological processes at the cellular level. However, the visual detection of lysosomal microcircumstances is relatively difficult due to low pH (4.5-6.0) value in lysosomal that require the probe not only stable under acidic condition but also has a good localization effect to lysosomal. Obviously, novel fluorescent which possessed both acidic stability and lysosomal-target property together with lysosomal viscosity active is highly demanded. Herein, a novel BODIPY molecular CarBDP based on carbazole group was rationally designed and synthesized for the lysosomal imaging. CarBDP exhibited AIE feature with a large Stokes shift of up to 157 nm. More importantly, co-localization assay of the CarBDP-treated MCF-7 cells indicated that CarBDP has a good localization effect on lysosomal (Rr = 0.7109) due to the carbazole group while the normal BODIPY that without carbazole group (PhBDP) shows poor localization performance, this was the first time that a small molecule can locate lysosomes only based on carbazole group. CarBDP exhibits strong solid emission with long fluorescence decay lifetime (τ = 44.54 ns) and was stable under acid condition.The probe CarBDP assembled with carbazole group was successfully utilized for lysosomal localization and mapping lysosomal viscosity in live cells, which provides a novel candidate tool for the determination of lysosomal microcircumstances.

Electronic properties of single vacancy defect in boron nitride nanoribbons with edge perturbation.

Two-dimensional material hexagonal boron nitride (h-BN), and its one-dimensional thin strips, boron nitride nanoribbons (BNNRs) are electrically insulating with high thermal stability, making them excellent thermal conductors suitable for high-temperature application. BNNRs are wide bandgap semiconductors with bandgaps ranging from 4 to 6 eV. This study investigates the electronic properties of BNNRs with single vacancy defects in armchair and zigzag configurations. The nearest-neighbour tight-binding model and numerical method were used to simulate the electronic properties of BNNRs with a single vacancy, including band structure and local density of states. The alpha and beta matrices were adjusted to account for missing boron or nitrogen atoms. Furthermore, a small perturbations were introduced to model the effects of impurities and edge imperfections. The simulation result from this work was compared with pristine BNNRs to examine the impact of a single vacancy on their electronic properties. The findings reveal that both armchair and zigzag BNNRs with single vacancy defects exhibit distorted band structures and local density of states due to the delocalization of pz orbitals. The valence bands show a higher concentration of nitrogen, while the conduction bands are richer in boron. These findings provide insights into how vacancy defects and edge perturbations can influence the electronic properties of BNNRs, which can guide the design and optimization of BNNR-based electronic devices in future research.

A New BODIPY-Based Receptor for the Fluorescent Sensing of Catecholamines.

The human body synthesizes catecholamine neurotransmitters, such as dopamine and noradrenaline. Monitoring the levels of these molecules is crucial for the prevention of important diseases, such as Alzheimer's, schizophrenia, Parkinson's, Huntington's, attention-deficit hyperactivity disorder, and paragangliomas. Here, we have synthesized, characterized, and functionalized the BODIPY core with picolylamine (BDPy-pico) in order to create a sensor capable of detecting these biomarkers. The sensing properties of the BDPy-pico probe in solution were studied using fluorescence titrations and supported by DFT studies. Catecholamine sensing was also performed in the solid state by a simple strip test, using an optical fiber as the detector of emissions. In addition, the selectivity and recovery of the sensor were assessed, suggesting the possibility of using this receptor to detect dopamine and norepinephrine in human saliva.

BODIPYs α-appended with distyryl-linked aryl bisboronic acids: single-step cell staining and turn-on fluorescence binding with D-glucose.

Small-molecule sensors that are selective for particular sugars are rare. The synthesis of BODIPYs appended with two boronic acid units is reported, alongside cellular staining/labelling and turn-on fluorescence binding data for carbohydrates. The structural frameworks were designed using computational methods, leaning on the chelation characteristics of bis(boronic acids) and the photophysical properties of BODIPYs. Selective binding to glucose is demonstrated via emission and absorption methods, and the challenges of using NMR data for studying carbohydrate binding are discussed. Furthermore, crystal structures, cell permeability and imaging properties of the BODIPYs appended with two boronic acid units are described. This work presents boronic-acid-appended BODIPYs as a potential framework for tunable carbohydrate sensing and chemical biology staining.

Synthesis of D-A-type groups modified aza-BODIPY fluorescent dye encapsulated by amphiphilic polypeptide nanoparticles for NIR-II phototheranostics.

An innovative organic small molecule with a D-A structure was synthesized by connecting triphenylamine to BODIPY via a thiophene bridge. Triphenylamine and thiophene units ingeniously modulate the balance between steric hindrance and π-π interactions around the flat aza-BODIPY core. The molecule exhibits near-infrared fluorescence absorption and emits at roughly 1100 nm, featuring a significant Stokes shift. Both the molecule and its nanoparticles demonstrate high stability and achieve a remarkable 35 % photothermal conversion efficiency when conjugated with the P(OEGMA)20-P(Asp)14 copolymer. In vitro assessments show low dark toxicity and outstanding biocompatibility. Moreover, in vivo studies and photothermal therapy in mice indicate substantial tumor shrinkage and reduced recurrence, confirming its potential in cancer treatment. These results highlight the promise of this organic molecule and its nanoparticles for NIR-II imaging-guided photothermal therapy, introducing a novel approach to phototheranostic applications for cancer management.

Dual regulation of thermal conductivity and mechanical performance of nano cellulose-based composite via mimicking plant cell wall structure.

Combining thermal conductive fillers and flexible polymers is an agile approach to fabricating composites with heat-conducting performance. However, the thermal conductivity of the composites is hard to reach an equal level to the functional fillers. The mainspring is that the thermally conductive pathways within the composite could not be well-constructed due to the air-induced interface thermal resistance. Herein, inspired by the plant cell wall structure, polyvinyl alcohol (PVA) with abundant hydroxyl groups was adopted as a binder for boosting the thermally conductive pathways construction between cellulose nanofiber (CNF) and alkalized hexagonal boron nitride (BN-OH), also for strengthening the mechanical performance of the composite. The results showed that the tensile strength and through-plane thermal conductivity of the composite were high up to 91.0 MPa and 2.2 W m-1 K-1 at 40 wt% PVA content, exhibiting 121 % and 450 % enhancements compared to pure CNF film (41.2 MPa and 0.4 W m-1 K-1). Moreover, the composite also presented high thermal stability (decomposition temperature of onset was 218 °C) and good hydrophobicity properties. Overall, this study innovatively proposes an idea for enhancing the thermal conductivity and improving the mechanical properties of the composite, which is indispensable for developing thermal management materials for next-generation electronics.

Extracellular Vesicles Comprising Carborane Prepared by a Host Exchanging Reaction as a Boron Carrier for Boron Neutron Capture Therapy.

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

Photodynamic therapy with Photoditazine increases microviscosity of cancer cells membrane in cellulo and in vivo.

Photodynamic therapy (PDT) is a minimally invasive method for cancer treatment, one of the effects of which is the oxidation of membrane lipids. However, changes in biophysical properties of lipid membranes during PDT have been poorly explored. In this work, we investigated the effects of PDT on membrane microviscosity in cancer cells in the culture and tumor xenografts. Membrane microviscosity was visualized using fluorescence lifetime imaging microscopy (FLIM) with a viscosity-sensitive rotor BODIPY2. It was found that PDT using chlorine e6-based photosensitizer Photoditazine caused a quick, steady elevation of membrane microviscosity both in cellulo and in vivo. The proposed mechanisms responsible for the increase in microviscosity was lipid peroxidation by reactive oxygen species that resulted in a decrease of phosphatidylcholine and the fraction of unsaturated fatty acids in the membranes. Our results suggest that the increased microviscosity is an important factor that contributes to tumor cell damage during PDT.

Near-infrared pH-switchable BODIPY photosensitizers for dual biotin/cRGD targeted photodynamic therapy.

Photodynamic therapy (PDT) is a clinically-approved cancer treatment that is based on production of cytotoxic reactive oxygen species to induce cell death. However, its efficiency depends on distribution of photosensitizer (PS) and depth of light penetration through the tissues. Tendency of pathological cancer tissues to exhibit lower pH than healthy tissues inspired us to explore dual-targeted pH-activatable photosensitizers based on tunable near-infrared (NIR) boron-dipyrromethene (BODIPY) dyes. Our BODIPY PSs were designed to carry three main attributes: (i) biotin or cRGD peptide as an effective cancer cell targeting unit, (ii) amino moiety that is protonated in acidic (pH <6.5) conditions for pH-activation of the PS based on photoinduced electron transfer (PET) and (iii) hydrophilic groups enhancing the water solubility of very hydrophobic BODIPY dyes. Illumination of such compounds with suitable light (>640nm) allowed for high phototoxicity against HeLa (αvß3 integrin and biotin receptor positive) and A549 (biotin receptor positive) cells compared to healthy MRC-5 (biotin negative) cells. Moreover, no dark toxicity was observed on selected cell lines (>10 µM) providing promising photosensitizers for tumour-targeted photodynamic therapy.

Molecular engineering of BODIPY-bridged fluorescent probes for lysosome imaging - a computational study.

Lysosome imaging plays an important role in diagnosing many diseases and understanding various intracellular processes. Recently, B0 was reported as a fluorescent probe capable of detecting lysosomal viscosity changes. BODIPY is fused into the molecule as a bridge between the acceptor and donor components of B0, yielding nine new B molecules. Computational design and analysis of their optoelectronic properties were conducted to evaluate their effectiveness as fluorescent probes for lysosome imaging, with a specific target of HSA inside lysosomes. Optimized geometries reveal excellent π electron delocalization, resulting in nearly planar molecular structures. Frontier molecular orbital analysis suggests intramolecular charge transfer, along with π-π* transitions, from donor to bridge. TD-DFT calculations were performed to study absorption properties in the solvent phase, with B3PW91 showing good agreement with experiments. Molecular docking studies indicate that B derivatives can bind with HSA, and molecular dynamics simulations confirm their HSA targeting ability. This investigation highlights the introduction of BODIPY as a bridge for developing new probes capable of producing NIR fluorescence for bio-imaging, aiding in disease diagnosis.

Synthesis and Photodynamic Activities of Pyridine- or Pyridinium-Substituted Aza-BODIPY Photosensitizers.

In this work, various novel pyridinyl- and pyridinium-modified Aza-BODIPY PSs were designed and constructed based on monoiodo Aza-BODIPY PSs (BDP-4 and BDP-15) in an attempt to construct "structure-inherent organelles-targeted" PSs to endow potential organelle-targeting ability. Pyridinyl PSs displayed potent photodynamic efficacy, and monorigidified PSs were very effective. The monorigidified PS 20 with meta-pyridinyl moiety displayed the most potent photoactivity and negligible dark toxicity with a favorable dark/phototoxicity ratio (>4800). To our surprise, monorigidified PS with meta-pyridinyl moiety (e.g., 20) was lipid droplet-targeted. 20 showed good cellular uptake and intracellular ROS generation compared with BDP-15. The preliminary cell death process exploration indicated that 20 resulted in lipid peroxidation and induced cell death through an iron-independent ferroptosis-like cell death pathway. In vivo antitumor efficacy experiments manifested that 20 significantly inhibited tumor growth and outperformed BDP-15 and Ce6 even under a single low-dose light irradiation (30 J/cm2).

Molecular Engineering of a Doubly Quenched Fluorescent Probe Enables Ultrasensitive Detection of Biothiols in Highly Diluted Plasma and High-Fidelity Imaging of Dihydroartemisinin-Induced Ferroptosis.

The occurrence and development of diseases are accompanied by abnormal activity or concentration of biomarkers in cells, tissues, and blood. However, the insufficient sensitivity and accuracy of the available fluorescence probes hinder the precise monitoring of associated indexes in biological systems, which is generally due to the high probe intrinsic fluorescence and false-negative signal caused by the reactive oxygen species (ROS)-induced probe decomposition. To resolve these problems, we have engineered a ROS-stable, meso-carboxylate boron dipyrromethene (BODIPY)-based fluorescent probe, which displays quite a low background fluorescence due to the doubly quenched intrinsic fluorescence by a combined strategy of the photoinduced electron transfer (PET) effect and "ester-to-carboxylate" conversion. The probe achieved a high S/N ratio with ultrasensitivity and good selectivity toward biothiols, endowing its fast detection capability toward the biothiol level in 200×-diluted plasma samples. Using this probe, we achieved remarkable distinguishing of liver injury plasma from normal plasma even at 80× dilution. Moreover, owing to its good stability toward ROS, the probe was successfully employed for high-fidelity imaging of the negative fluctuation of the biothiol level in nonsmall-cell lung cancer (NSCLC) during dihydroartemisinin-induced ferroptosis. This delicate design of suppressing intrinsic fluorescence reveals insights into enhancing the sensitivity and accuracy of fluorescent probes toward the detection and imaging of biomarkers in the occurrence and development of diseases.

In vivo fluorescence imaging of nanocarriers in near-infrared window II based on aggregation-caused quenching.

Accurate fluorescence imaging of nanocarriers in vivo remains a challenge owing to interference derived mainly from biological tissues and free probes. To address both issues, the current study explored fluorophores in the near-infrared (NIR)-II window with aggregation-caused quenching (ACQ) properties to improve imaging accuracy. Candidate fluorophores with NIR-II emission, ACQ984 (λem = 984 nm) and IR-1060 (λem = 1060 nm), from the aza-BODIPY and cyanine families, respectively, were compared with the commercial fluorophore ICG with NIR-II tail emission and the NIR-I fluorophore P2 from the aza-BODIPY family. ACQ984 demonstrates high water sensitivity with complete fluorescence quenching at a water fraction greater than 50%. Physically embedding the fluorophores illuminates various nanocarriers, while free fluorophores cause negligible interference owing to the ACQ effect. Imaging based on ACQ984 revealed fine structures in the vascular system at high resolution. Moreover, good in vivo and ex vivo correlations in the monitoring of blood nanocarriers can be established, enabling real-time noninvasive in situ investigation of blood pharmacokinetics and dynamic distribution in various tissues. IR-1060 also has a good ACQ effect, but the lack of sufficient photostability and steady post-labeling fluorescence undermines its potential for nanocarrier bioimaging. P2 has an excellent ACQ effect, but its NIR-I emission only provides nondiscriminative ambiguous images. The failure of the non-ACQ probe ICG to display the biodistribution details serves as counterevidence for the improved imaging accuracy by NIR-II ACQ probes. Taken together, it is concluded that fluorescence imaging of nanocarriers based on NIR-II ACQ probes enables accurate in vivo bioimaging and real-time in situ pharmacokinetic analysis.

Heavy-atom-free triplet benzothiophene-fused BODIPY derivatives for lipid droplet-specific biomaging and photodynamic therapy.

The twist fusion of a benzothiophene group and the introduction of a 4-methyloxystyryl donor group to the BODIPY core resulted in large spin-orbit coupling values and smaller singlet-triplet energy gaps for the novel infrared absorbed photosensitizers named BSBDP. They show a high reactive oxygen species efficiency exceeding 69% and a fluorescence quantum yield of 23% and are successfully applied in imaging-guided photodynamic therapy in vitro and in vivo.

Molecular insights reveal how the glycolipids in cell membrane mitigates nanomaterial's invasion.

Nanomaterial-cellular membrane interaction is crucial for the cytotoxicity of such materials in theoretical investigations. However, previous research often used cellular membrane models with one or few lipid types, which deviates significantly from realistic membrane compositions. Here, employing molecular dynamics (MD) simulations, we investigate the impact of a typical nanomaterial, boron nitride (BN), on a cellular membrane model based on the realistic small intestinal epithelial cell (SIEC) membrane. This membrane contains a complex composition, including abundant glycolipids. Our MD simulations reveal that BN nanosheet can partially insert into the SIEC membrane, maintaining a stable binding conformation without causing obvious structural changes. Dynamic analyses suggest that van der Waals (vdW) interactions drive the binding process between BN and the SIEC membrane. Further simulation of the interaction between BN nanosheet and deglycosylated SIEC membrane confirms that BN nanosheet cause significant structural damage to deglycosylated SIEC membranes, completely inserting into the membrane, extracting lipids, and burying some lipid hydrophilic heads within the membrane interior. Quantitative analyses of mean squared displacements (MSD) of membranes, membrane thicknesses, area per lipid, and order parameters indicate that BN nanosheet causes more substantial damage to deglycosylated SIEC membrane than to intact SIEC membrane. This comparison suggests the molecular mechanism involved in mitigating BN invasion by SIEC membrane that the polysaccharide heads of glycolipids in the SIEC membrane form a significant steric hindrance on membrane surface, not only hindering the insertion of BN, but also resisting the lipid extraction by BN. Free energy calculations further support this conclusion. Overall, our MD simulations not only shed new light into the reduced impact of BN nanosheet on the realistic SIEC membrane but also highlight the importance of glycolipids in protecting cell membranes from nanomaterial invasion, contributing to a deeper understanding of nanomaterial-realistic cell membrane interactions.