Cannabidiol and Aza-BODIPY Coencapsulation for Photodynamic Therapy Enhancement in Liver Cancer Cells.

Photodynamic therapy (PDT) and cannabidiol (CBD) have been explored for their potential in synergistic cancer treatment. In this study, we employed CBD oil as a lipid phase, encapsulated within AZB-I@Lec-T to create lipid-based nanoparticles. Here, CBD oil does two tasks: it acts as a pyroptosis agent to destroy liver cancer cells and as a lipid phase to dissolve the photosensitizer. It was expected that this system would offer synergistic therapy between CBD and PDT better than a single use of each treatment. With a series of in vitro experiments, the nanoparticles exhibited induced apoptosis in 68% of HepG2 cells treated with AZB-I@Lec-T@CBD and near-infrared (NIR)-light irradiation, reducing expression levels of antioxidant defense system genes. Furthermore, both components worked well in a submicromolar range when combined in our formulation. These results highlight the potential for amplifying primary cellular damage with the combination of PDT and CBD encapsulation, providing a promising therapeutic approach for liver cancer treatment guidelines.

Development of a new series of thioacetal based fluorescence chemosensors for highly sensitive determination of Hg2+ in environmental samples and cell imaging.

Mercury ion is one of the most harmful metal ions with significant hazards to the environment and human health. Thus, the development of innovative, sensitive, and selective sensors to help address the detrimental impacts of heavy metal contamination is necessary. In this work, we present three new chemosensors based on the deprotection reaction of the thioacetal group for distinguishing Hg2+ in environmental samples. These chemosensors show good photophysical properties with high quantum yield in aqueous medium. These prepared chemosensors were employed as fluorometric sensors for the determination of Hg2+ through the quenching of fluorescence emission due to the Hg2+-induced hydrolysis of the thioacetal to the aldehyde group. In the presence of Hg2+, chemosensors showed an emissive color transformation from blue fluorescence to non-fluorescence under UV light, which was readily seen by the visual eye. These chemosensors also exhibited highly distinctive selectivity toward Hg2+ over other interfering metal ions, with detection limits of 1.1 ppb, 13.4 ppb, and 12.7 ppb. Moreover, the practical applicability of chemosensor was successfully demonstrated in real water samples and herb extract samples.

Enhancing Glucose Biosensing with Graphene Oxide and Ferrocene-Modified Linear Poly(ethylenimine).

We designed and optimized a glucose biosensor system based on a screen-printed electrode modified with the NAD-GDH enzyme. To enhance the electroactive surface area and improve the electron transfer efficiency, we introduced graphene oxide (GO) and ferrocene-modified linear poly(ethylenimine) (LPEI-Fc) onto the biosensor surface. This strategic modification exploits the electrostatic interaction between graphene oxide, which possesses a negative charge, and LPEI-Fc, which is positively charged. This interaction results in increased catalytic current during glucose oxidation and helps improve the overall glucose detection sensitivity by amperometry. We integrated the developed glucose sensor into a flow injection (FI) system. This integration facilitates a swift and reproducible detection of glucose, and it also mitigates the risk of contamination during the analyses. The incorporation of an FI system improves the efficiency of the biosensor, ensuring precise and reliable results in a short time. The proposed sensor was operated at a constant applied potential of 0.35 V. After optimizing the system, a linear calibration curve was obtained for the concentration range of 1.0-40 mM (R2 = 0.986). The FI system was successfully applied to determine the glucose content of a commercial sports drink.

Aza-BODIPY-based polymeric nanoparticles for photothermal cancer therapy in a chicken egg tumor model.

A new push-pull aza-BODIPY (AZB-CF3) derivative comprised of dimethylamino groups and trifluoromethyl moieties was successfully synthesized. This derivative exhibited broad absorption in the near-infrared region in the range from 798 to 832 nm. It also exhibited significant near-infrared (NIR) signals in low-polar solvents with emission peaks around 835-940 nm, while non-fluorescence in high-polar environments due to the twisted intramolecular charge transfer (TICT) phenomenon. The nanoprecipitation of this compound with phospholipid-based polyethylene glycol (DSPE-PEG) yielded AZB-CF3@DSPE-PEG nanoparticles (NPs) with a hydrodynamic size of 70 nm. The NPs exhibited good photostability, colloidal stability, biocompatibility, and excellent photothermal (PTT) competence with a conversion efficiency (η) of 44.9%. These NPs were evaluated in vitro and in ovo in a 4T1 breast cancer cell line for NIR light-trigger photothermal therapy. Proven in the chicken egg tumor model, AZB-CF3@DSPE-PEG NPs induced severe vascular damage (∼40% vascular destruction), showed great anticancer efficacy (∼75% tumor growth inhibition), and effectively inhibited distant metastasis via photothermal treatment. As such, this PTT-based nanocarrier system could be a potential candidate for a clinical cancer therapy approach.

Revolutionary Pyrazole-based Aza-BODIPY: Harnessing Photothermal Power Against Cancer Cells and Bacteria.

In the realm of cancer therapy and treatment of bacterial infection, photothermal therapy (PTT) stands out as a potential strategy. The challenge, however, is to create photothermal agents that can perform both imaging and PTT, a so-called theranostic agent. Photothermal agents that absorb and emit in the near-infrared region (750-900 nm) have recently received a lot of attention due to the extensive penetration of NIR light in biological tissues. In this study, we combined pyrazole with aza-BODIPY (PY-AZB) to develop a novel photothermal agent. PY-AZB demonstrated great photostability with a photothermal conversion efficiency (PCE) of up to 33 %. Additionally, PY-AZB can permeate cancer cells at a fast accumulation rate in less than 6 hours, according to the confocal images. Furthermore, in vitro photothermal therapy results showed that PY-AZB effectively eliminated cancer cells by up to 70 %. Interestingly, PY-AZB exhibited antibacterial activities against both gram-negative bacteria, Escherichia coli 780, and gram-positive bacteria, Staphylococcus aureus 1466. The results exhibit a satisfactory bactericidal effect against bacteria, with a killing efficiency of up to 100 % upon laser irradiation. As a result, PY-AZB may provide a viable option for photothermal treatment.

Heavy Atom Effect on the Intersystem Crossing of a Boron Difluoride Formazanate Complex-Based Photosensitizer: Experimental and Theoretical Studies.

Photodynamic therapy (PDT) is a photochemical-based treatment approach that involves using light to activate photosensitizers (PSs). Attractively, PDT is one of the alternative cancer treatments due to its noninvasive technique. By utilizing the heavy atom effect, this work modified a class of formazan dyes to improve intersystem crossing (ISC) to improve reactive oxygen species (ROS) generation for PDT treatment. Two methods were used to observe the ROS generation enhanced by ISC of the synthesized complexes including, (1) recording DPBF decomposition caused by the ROS, and (2) calculating the potential energy curves for photophysical mechanisms of BF2 -formazanate dyes using the DFT and nudged elastic band (NEB) methods. The photophysical properties of the dyes were studied using spectroscopic techniques and X-ray crystallography, as well as DFT calculations. The experimental and theoretical results and in vitro cellular assays confirmed the potential use of the newly synthesized iodinated BF2 -formazanate dyes in PDT.

Unraveling the photophysical characteristics and biological applications of vinyl sulfones as viscosity sensors.

For the first time, a series of vinyl sulfone-NH2-based push-pull fluorophores (4a-4d) were introduced for their potential use in biological applications. The fluorophores 4a-4d were readily synthesized upon reduction of the corresponding vinyl sulfones-NO2 (3a-3d), which were prepared by sulfonylation of nitrostyrene. Both types of probes can be prepared in high yields through a few steps with minimal cost. In diverse solvents, probes 4a-4d exhibited fluorescence with strong emission peaking around 403-490 nm. Additionally, the fluorescence intensity of probe 4d rose approximately 85-fold with increasing viscosity. The probes 4a-4d demonstrated good stability and photostability in a broad pH range. Moreover, probes 4a-4d showed significantly improved biocompatibility compared to those derived from 3a-3d. For cell imaging applications, the developed probes 4a-4d exhibited much stronger blue fluorescence in cancer cells (HepG2) compared to 3a-3d. In addition, probes 4a-4d exhibited low cytotoxicity within 24 h toward both cancer and normal cells (HEK-293). Interestingly, probe 4d showed great sensitivity to viscosity in cancer cells. As a result, readily prepared vinyl sulfone-NH2-based push-pull fluorophores (4a-4d) offer a promising strategy for further development as cancer cell staining agents.

Quinoline-Malononitrile-Based Aggregation-Induced Emission Probe for Monoamine Oxidase Detection in Living Cells.

A quinoline-malononitrile (QM)-based aggregation-induced emission probe was developed to detect MAOs in cells through an enzymatic reaction followed by ß-elimination. After being incubated at 37 °C, QM-NH2 responded to the MAO enzymes with great specificity and within just 5 min. This 5 min responsive mechanism was fast, with the limit of detection (LOD) at 5.49 and 4.76 µg mL-1 for MAO-A and MAO-B, respectively. Moreover, QM-NH2 displayed high enzyme specificity even in the presence of high concentrations of biological interferences, such as oxidizing and reducing agents, biothiols, amino acids, and glucose. Furthermore, QM-NH2 demonstrated biocompatibility as the cells retained more than 70% viability when exposed to QM-NH2 at concentrations of up to 20 µM. As a result, QM-NH2 was used to detect MAO-A and MAO-B in SH-SY5Y and HepG2 cells, respectively. After 1h incubation with QM-NH2, the cells exhibited enhanced fluorescence by about 20-fold. Moreover, the signal from cells was reduced when MAO inhibitors were applied prior to incubating with QM-NH2. Therefore, our research recommends using a QM probe as a generic method for producing recognition moieties for fluorogenic enzyme probes.

Quercetin Nanoparticle-Based Hypoxia-Responsive Probe for Cancer Detection.

In this study, we developed functional nanomaterials via a phenolic-enabled nanotechnology strategy for hypoxia detection employing quercetin (QCT), an abundant flavonoid, as a polyphenolic system. The nano form of QCT was stabilized by coating it with polyethylene glycol (PEG) before loading it with a flavylium dye (Flav) as a pH indicator. The nanosystem, Flav@QCT-PEG, collapsed when it was in an acidic environment, i.e., pH 5, leading to the release of Flav, which activated the fluorescent signal. Therefore, Flav@QCT-PEG was applied to detect hypoxic tumors, known to be acidic, and responded to hypoxic environments in a dose- and time-dependent manner.

Hybrid Cyanine/Methotrexate Nanoparticles for Synergistic PDT/Chemotherapy of Breast Cancer.

Typically, nanomedicine was prepared using a nanocarrier to load cargo for specific purposes. In this work, a carrier-free nanosystem for imaging and photodynamic (PDT)/chemo combination therapy was developed using simple self-assembly of a dye and a chemotherapeutic agent. The resulting nanoparticles (I2-IR783/MTX@NPs) exhibited a spherical morphology with a size of 240.6 ± 2.5 nm. I2-IR783/MTX@NPs had substantial internalization in 4T1 murine breast cancer cells and showed a synergistic anticancer effect after NIR light irradiation. Additionally, the 3D tumor model exhibits the same phototoxicity of nanoparticles as a 2D cell culture. The PDT efficiency of the nanosystem in the physiological environment was confirmed by the detection of intracellular reactive oxygen species as well as the live/dead viability/cytotoxicity assay following NIR light exposure. In addition, optical coherence tomography (OCT) was used as an alternative tool to monitor the response after treatment. Therefore, I2-IR783/MTX@NPs show great potential use in theranostic application for breast cancer PDT-chemotherapy.

Aza-BODIPY based carbonic anhydrase IX: Strategy to overcome hypoxia limitation in photodynamic therapy.

Hypoxia caused by photodynamic therapy (PDT) is a major hurdle to cancer treatment since it can promote recurrence and progression by activating angiogenic factors, lowering therapeutic efficacy dramatically. In this work, AZB-I-CAIX2 was developed as a carbonic anhydrase IX (CAIX)-targeting NIR photosensitizer that can overcome the challenge by utilizing a combination of CAIX knockdown and PDT. AZB-I-CAIX2 showed a specific affinity to CAIX-expressed cancer cells and enhanced photocytotoxicity compared to AZB-I-control (the molecule without acetazolamide). Moreover, selective detection and effective cell cytotoxicity of AZB-I-CAIX2 by PDT in hypoxic CAIX-expressed murine cancer cells were achieved. Essentially, AZB-I-CAIX2 could minimize tumor size in the tumor-bearing mice compared to that in the control groups. The results suggested that AZB-I-CAIX2 can improve therapeutic efficiency by preventing PDT-induced hypoxia through CAIX inhibition.

BODIPY-Based Fluorescent Probes for Selective Visualization of Endogenous Hypochlorous Acid in Living Cells via Triazolopyridine Formation.

In this work, the two pyridylhydrazone-tethered BODIPY compounds (2 and 3) were synthesized. These compounds aimed to detect hypochlorous acid (HOCl) species via cyclic triazolopyridine formation. The open forms and the resulting cyclic forms of BODIPYs (2, 3, 4, and 5) were fully characterized by nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and single-crystal X-ray diffraction. These two probes can selectively detect HOCl through a fluorescence turn-on mechanism with the limit of detections of 0.21 µM and 0.77 µM for compounds 2 and 3, respectively. This fluorescence enhancement phenomenon could be the effect from C = N isomerization inhibition due to HOCl-triggered triazolopyridine formation. In cell imaging experiments, these compounds showed excellent biocompatibility toward RAW 264.7 murine live macrophage cells and greatly visualized endogenous HOCl in living cells stimulated with lipopolysaccharide.

A facile method for generating polypyrrole microcapsules and their application in electrochemical sensing.

A facile and rapid strategy to generate polypyrrole microcapsules is reported. The strategy is compatible with a vortex mixer and with a microfluidic chip for droplet generation, allowing a > 100-fold reduction in particle size. The sub-micron particle sizes obtained can also be tuned to some extent based on the chip geometry. The capsules can be kept stably in solution and can be transferred onto electrochemical devices. As an application example, we casted the polypyrrole capsules generated onto screen-printed electrodes, leading to a significant increase in their electroactive surface area and capacitance. The electrodes were further modified with glucose dehydrogenase (GDH) to fabricate glucose biosensors. The introduction of polypyrrole microcapsules increased the dynamic range of the glucose sensor to ca. 300% compared with that of the electrode without polypyrrole microcapsules. The resulting glucose sensor is operated at a constant applied potential of 0.20 V vs. Ag/AgCl (3 M KCl) in an air-equilibrated electrolyte. At this potential, the sensor showed a linear range from 1.0 to 9.0 mM glucose with a sensitivity of 3.23 µA cm-2 mM-1 (R2 = 0.993). The limit of detection obtained was 0.09 mM, and the reproducibility was 3.6%. The method allows generating polypyrrole microcapsules without surfactants or organic solvents and may enable new opportunities in the design of biosensors, electronic devices, and molecular delivery.

PEGylated Aza-BODIPY Nanoparticles for Photothermal Therapy.

Photothermal therapy is a promising treatment modality in the realm of cancer therapy. Photothermal nanomaterials that absorb and emit in the near-infrared range (750-900 nm) have drawn a lot of attention recently because of the deep penetration of NIR light in biological tissue. Most nanomaterials, however, are produced by encapsulating or altering the surface of a nanoplatform, which has limited loading capacity and long-term storage. Herein, we developed a stable polymer conjugated with aza-BODIPY that self-assembled to form nanoparticles (aza-BODIPY-mPEG) with better hydrophilicity and biocompatibility while retaining the dye's photothermal conversion characteristics. Aza-BODIPY-mPEG with a hydrodynamic size of around 170 nm exhibited great photostability and excellent photothermal therapy in vitro and in ovo. Aza-BODIPY-mPEG exhibits approximately 30% better anti-angiogenesis and antitumor activity against implanted xenograft human HCT116 tumor in the chick embryo compared to parent aza-BODIPY-A, altogether suggesting that aza-BODIPY-mPEG is a promising material for cancer photothermal therapy.

Hemicyanine-based pH-responsive probes for rapid hypoxia detection in cancer cells.

As pH-sensitive and hypoxia-responsive probes, three hemicyanine derivatives based on vanillin and the indole ring (Val-Hcys) were synthesized. The fluorescence of the probes can be activated at acidic pH using the amide functionalized sidechains. Furthermore, when Val-Hcys were incubated with hypoxic cells for 5 min, the fluorescent signals significantly increased when compared to normoxia cells (4-fold enhancement, maximum at 180 min). In addition, Val-Hcys tend to accumulate in lysosomes and mitochondria, two important organelles involved in cell mitophagy. Surprisingly, Val-Hcys improved cell viability in hypoxic conditions. As a result, this study demonstrates the utility of Val-Hcys as pH-responsive probes for detecting hypoxic areas.

Electrodeposition of Cobalt Oxides on Carbon Nanotubes for Sensitive Bromhexine Sensing.

We develop an electrochemical sensor for the determination of bromhexine hydrochloride (BHC), a widely use mucolytic drug. The sensor is prepared by electrodeposition of cobalt oxides (CoOx) on a glassy carbon electrode modified with carboxylated single-walled carbon nanotubes (SWCNT). A synergistic effect between CoOx and SWCNT is observed, leading to a significant improvement in the BHC electrooxidation current. Based on cyclic voltammetry studies at varying scan rates, we conclude that the electrochemical oxidation of BHC is under mixed diffusion-adsorption control. The proposed sensor allows the amperometric determination of BHC in a linear range of 10-500 µM with a low applied voltage of 0.75 V. The designed sensor provides reproducible measurements, is not affected by common interfering substances, and shows excellent performance for the analysis of BHC in pharmaceutical preparations.

Indomethacin-based near-infrared photosensitizer for targeted photodynamic cancer therapy.

Near-IR fluorescent sensitizers based on heptamethine cyanine (Cy820 and Cy820-IMC) were synthesized and their abilities to target and abolish tumor cells via photodynamic therapy (PDT) were explored. Some hepthamethine cyanine dyes can be transported into cancer cells via the organic anion transporting polypeptides (OATPs). In this study, we aimed to enhance the target ability of the sensitizer by conjugation Cy820 with indomethacin, a non-steroidal anti-inflammatory drug (NSAID), to obtain Cy820-IMC that aimed to target cyclooxygenase-2 (COX-2) which overexpresses in cancer cells. The results showed that Cy820-IMC internalized the cancer cells faster than Cy820 which was verified to be related to COX-2 level and OATPs. Based on PDT experiments, Cy820-IMC has higher photocytotoxicity index than Cy820, >7.13 and 4.90, respectively, implying that Cy820-IMC showed better PDT property than Cy820. However, Cy820 exhibits slightly higher normal-to-cancer cell toxicity ratio than Cy820-IMC, 6.58 and 3.63, respectively. Overall, Cy820-IMC has superior cancer targetability and enhanced photocytoxicity. These characteristics can be further improved towards clinically approved sensitizers for PDT.

Effect of morpholine and charge distribution of cyanine dyes on cell internalization and cytotoxicity.

To improve the potency of Heptamethine cyanines (Hcyanines) in cancer research, we designed and synthesized two novel Hcyanines based theranostic probes, IR794-Morph and IR794-Morph-Mpip, to enhance cancer cell internalization and targeting. In acidic conditions that resemble to tumour environment, both IR794 derivatives exhibited broad NIR absorption band (704‒794 nm) and fluorescence emission (798‒828 nm) that is suitable for deep seated tumour imaging. Moreover, in vitro study revealed that IR794-Morph-Mpip exhibited better cancer targetability towards various cancer cell lines under physiological and slightly acidic conditions compared to normal cells. IR794-Morph-Mpip was fast internalized into the cancer cells within the first 5 min and mostly localized in lysosomes and mitochondria. In addition, the internalized signal was brighter when the cells were in the hypoxic environment. Furthermore, cellular uptake mechanism of both IR794 dyes, investigated via flow cytometry, revealed that endocytosis through OATPs receptors and clathrin-mediated endocytosis were the main routes. Moreover, IR794-Morph-Mpip, displayed anti-cancer activity towards all tested cancer cell types with IC50 below 7 µM (at 6 h incubation), which is approximately three times lower than that of the normal cells. Therefore, increasing protonated cites in tumour environment of Hcyanines together with incorporating morpholine in the molecule can enhance structure-inherent targeting of these dyes.

Near-Infrared Fluorescent Heptamethine Cyanine Dyes for COX-2 Targeted Photodynamic Cancer Therapy.

We designed and synthesized two heptamethine cyanine-based theranostic probes that aimed to target COX-2 in cancer cells. One is I-IR799-CXB, in which I-IR799 is conjugated to the COX-2-specific inhibitor, celecoxib, and another is I-IR799-IMC, where the non-selective COX inhibitor, indomethacin, was used. I-IR799 is a heptamethine cyanine derivative that can be activated by near-infrared light for photodynamic therapy (PDT) purposes. I-IR799-CXB and I-IR799-IMC were tested for their cancer-targeting capacity and photodynamic efficiency toward hepatocellular carcinoma (HepG2) cells relative to normal liver cells, alpha mouse liver 12 (AML12) cells. Interestingly, after conjugation, I-IR799-IMC exhibited better tumour targetability and PDT efficiency than I-IR799-CXB.

Crystallographic and Spectroscopic Investigations on Oxidative Coordination in the Heteroleptic Mononuclear Complex of Cerium and Benzoxazine Dimer.

Among lanthanide-based compounds, cerium compounds exhibit a significant role in a variety of research fields due to their distinct tetravalency, high economic feasibility, and high stability of Ce(IV) complexes. Herein, a systematic investigation of crystallographic information, chemical properties, and mechanistic formation of the novel Ce(IV) complex synthesized from cerium(III) nitrate hexahydrate and 2,2'-(methylazanediyl)bis(methylene)bis(4-methylphenol) (MMD) ligand has been explored. According to the analysis of the crystallographic information, the obtained complex crystal consists of the Ce(IV) center coordinated with two nitrate ligands and two bidentate coordinated (N-protonated and O,O-deprotonated) MMD ligands. The fingerprint plots and the Hirshfeld surface analyses suggest that the C-H⋯O and C-H⋯π interactions significantly contribute to the crystal packing. The C-H⋯O and C-H⋯π contacts link the molecules into infinite molecular chains propagating along the [100] and [010] directions. Synchrotron powder X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) techniques have been employed to gain an understanding of the oxidative complexation of Ce(IV)-MMD complex in detail. This finding would provide the possibility to systematically control the synthetic parameters and wisely design the precursor components in order to achieve the desired properties of novel materials for specific applications.