Lutetium Texaphyrin-Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent.

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2-•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

Noncovalent and Covalent O-H···O Interactions in PPh3O Cocrystals: A Correlation Study Involving QTAIM, SAPT, NBO, and IBSI Methods.

PPh3O.hemihydrate polymorphs and 11 assorted PPh3O cocrystals collectively constitute a reliable stock to pursue a systematic analysis aiming to investigate the impacts of some vital issues on the TPPO.H-bond donor aggregates. The issues highlighted herein are (i) effect of varying acidity of H-bond donors on the degeneracy of lone pairs of the H-bond acceptor (PPh3O), (ii) effectiveness of the |V(r)|/G(r) and H(r)/ρ(r) parameters as a covalency metric, (iii) 3c-4e bonding in the covalent PPh3O.nitric acid cocrystal, (iv) salient features of H-bond interaction energy and an interplay of its components, (v) an intrinsic bond strength scale for the PPh3O cocrystals, and (vi) reliable empirical relations between several bond descriptors for a quick estimation of interaction energy. To be specific about point (vi), we have propounded two promising avenues for a fast semiquantitative calculation of interaction energy from an endearing nonenergetic parameter, viz., bond length: dO-H···O → ρBCP (MAPE = 2.36%) → ESAPT0 (MAPE = 9.26%), and dO-H···O → IBSI (MAPE = 1.87%) → ESAPT0 (MAPE = 9.66%). All the aforesaid issues have been explored in detail through the QTAIM, NBO, and IBSI analyses (M06-2X-D3/def2-TZVP level), as well as by the SAPT study at the SAPT0/aug-cc-pVDZ platform. The statistically valid correlation studies can be particularly conducive for practical purposes as a transformative extension of the established facts into postulates for the unknown cocrystals.

Luciferase-Decorated Gold Nanorods as Dual-Modal Contrast Agents for Tumor-Targeted High-Performance Bioluminescence/Photoacoustic Imaging.

Gold nanorods (AuNRs) have been considered highly compelling materials for early cancer diagnosis and have aroused a burgeoning fascination among the biomedical sectors. By leveraging the versatile tunable optical properties of AuNRs, herein, we have developed a novel tumor-targeted dual-modal nanoprobe (FFA) that exhibits excellent bioluminescence and photoacoustic imaging performance for early tumor diagnosis. FFA has been synthesized by anchoring the recombinant bioluminescent firefly luciferase protein (Fluc) on the folate-conjugated AuNRs via the PEG linker. TEM images and UV-vis studies confirm the nanorod morphology and successful conjugation of the biomolecules to AuNRs. The nanoprobe FFA relies on the ability of the folate module to target the folate receptor-positive tumor cells actively, and simultaneously, the Fluc module facilitates excellent bioluminescent properties in physiological conditions. The success of chemical engineering in the present study enables stronger bioluminescent signals in the folate receptor-positive cells (Skov3, Hela, and MCF-7) than in folate receptor-negative cells (A549, 293T, MCF-10A, and HepG2). Additionally, the AuNRs induced strong photoacoustic conversion performance, enhancing the resolution of tumor imaging. No apparent toxicity was detected at the cellular and mouse tissue levels, manifesting the biocompatibility nature of the nanoprobe. Prompted by the positive merits of FFA, the in vivo animal studies were performed, and a notable enhancement was observed in the bioluminescent/photoacoustic intensity of the nanoprobe in the tumor region compared to that in the folate-blocking region. Therefore, this synergistic dual-modal bioluminescent and photoacoustic imaging platform holds great potential as a tumor-targeted contrast agent for early tumor diagnosis with high-performance imaging information.

A Water-Soluble Wavy Coordination Polymer of Cu(II) as a Turn-On Luminescent Probe for Histidine and Histidine-Rich Proteins/Peptides.

Histidine plays an essential role in most biological systems. Changes in the homeostasis of histidine and histidine-rich proteins are connected to several diseases. Herein, we report a water-soluble Cu(II) coordination polymer, labeled CuCP, for the fluorimetric detection of histidine and histidine-rich proteins and peptides. Single-crystal structure determination of CuCP revealed a two-dimensional wavy network structure in which a carboxylate group connects the individual Cu(II) dimer unit in a syn-anti conformation. The weakly luminescent and water-soluble CuCP shows turn-on blue emission in the presence of histidine and histidine-rich peptides and proteins. The polymer can also stain histidine-rich proteins via gel electrophoresis. The limits of quantifications for histidine, glycine-histidine, serine-histidine, human serum albumin (HSA), bovine serum albumin, pepsin, trypsin, and lysozyme were found to be 300, 160, 600, 300, 600, 800, 120, and 290 nM, respectively. Utilizing the fluorescence turn-on property of CuCP, we measured HSA quantitatively in the urine samples. We also validated the present urinary HSA measurement assay with existing analytical techniques. Job's plot, 1H NMR, high-resolution mass spectrometry (HRMS), electron paramagnetic resonance (EPR), fluorescence, and UV-vis studies confirmed the ligand displacement from CuCP in the presence of histidine.

Label-Free Detection of Unbound Bilirubin and Nitrophenol Explosives in Water by a Mechanosynthesized Dual Functional Zinc Complex: Recognition of Picric Acid in Various Common Organic Media.

High levels of unconjugated bilirubin (UB) in serum lead to asymptomatic and neonatal jaundice and brain dysfunctions. Herein, we have reported the detection of UB at as low as 1 µM in an aqueous alkaline medium using a Zn(II) complex. The specificity of the complex has been validated by the HPLC in the concentration window 6-90 µM, which is rare. The sensory response of the probe at physiological pH against nitro explosives developed it as an instant-acting fluorosensor for picric acid (PA) and 2,4-dinitrophenol (2,4-DNP). Spectroscopic titration provided a binding constant of 4×105  M-1 with PA. The naked eye detection was found to be 15 µM. The solid-state photoluminescent nature of the complex enabled it for PA sensing in the solid phase. Interestingly, the probe remained fluorescent in various volatile and non-volatile organic solvents. As a result, it can also detect PA and 2,4-DNP in a wide range of common organic media. NMR studies revealed the coordination of PA, 2,4-DNP, and UB to the Zn(II) center of the probe, which is responsible for the observed quenching of the probe with the analytes.

Fabrication of a paper-based facile and low-cost microfluidic device and digital imaging technique for point-of-need monitoring of hypochlorite.

Lab-on-a-paper-based devices are promising alternatives to the existing arduous techniques for point-of-need monitoring. The present work reports an instant and facile method to produce a microfluidic paper-based analytical device (µPAD). The fabricated µPAD has been used to detect hypochlorite (OCl-) by incorporating newly synthesized chromo-fluorogenic ratiometric probes 1 and 2 into the sample reception zone. The probes showed high selectivity and fast response (<10 s) toward OCl- with an excellent linear relationship in the concentration range of 0-100 µM. The concentration-dependent fluorometric change driven by the reaction of 1@µPAD with OCl- has been monitored using gel-doc imaging systems, which is unprecedented. Digitizing the intensity of the colour solution with different mathematical models of colour has developed a straightforward method for monitoring OCl- without any interference from its competitors. 1@µPAD can detect OCl- at ∼10 times lower than the WHO recommended limit. The detection limit of 1@µPAD via a digital camera-based fluorescence technique was found to be better over digital camera-based cuvette assays. Therefore, 1@µPAD has been successfully utilized to monitor OCl- in actual environmental water samples with portability, ease of use, and sensitivity. The analytical RSD was found to be ≤3% based on fluorimetric detection using 1@µPAD. The chemodosimetric reaction between OCl- and the probe was evidenced by UV-vis and fluorescence spectroscopy, 1H NMR, and ESI-MS. The rapid response time, biocompatibility, low cytotoxicity, 100% aqueous solubility, ratiometric feature, and exclusive OCl- selectivity over other competitive ROS/RNS successfully lead to the application of the probes for bioimaging of exogenous as well as endogenous OCl- in normal cells (HEK293) and cancerous cells (HeLa).

Copper(II)-Incorporated Porphyrin-Based Porous Organic Polymer for a Nonenzymatic Electrochemical Glucose Sensor.

To date, the fabrication of multifunctional nanoplatforms based on a porous organic polymer for electrochemical sensing of biorelevant molecules has received considerable attention in the search for a more active, robust, and sensitive electrocatalyst. Here, in this report, we have developed a new porous organic polymer based on porphyrin (TEG-POR) from a polycondensation reaction between a triethylene glycol-linked dialdehyde and pyrrole. The Cu(II) complex of the polymer Cu-TEG-POR shows high sensitivity and a low detection limit for glucose electro-oxidation in an alkaline medium. The characterization of the as-synthesized polymer was done by thermogravimetric analysis (TGA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, and 13C CP-MAS solid-state NMR. The N2 adsorption/desorption isotherm was carried out at 77 K to analyze the porous property. TEG-POR and Cu-TEG-POR both show excellent thermal stability. The Cu-TEG-POR-modified GC electrode shows a low detection limit (LOD) value of 0.9 µM and a wide linear range (0.001-1.3 mM) with a sensitivity of 415.8 µA mM-1 cm-2 toward electrochemical glucose sensing. The interference of the modified electrode from ascorbic acid, dopamine, NaCl, uric acid, fructose, sucrose, and cysteine was insignificant. Cu-TEG-POR exhibits acceptable recovery for blood glucose detection (97.25-104%), suggesting its scope in the future for selective and sensitive nonenzymatic glucose detection in human blood.

Affinity Studies of Hemicyanine Derived Water Soluble Colorimetric Probes with Reactive Oxygen/Nitrogen/Sulfur Species.

Peroxynitrite (ONOO- ) is an essential endogenous reactive oxygen species (ROS) generated in mitochondria under various pathological and physiological conditions. An increase in its level in mitochondria is related to numerous diseases. Herein, we report a series of hemicyanine-derived water-soluble colorimetric probes (1-4) and the reactivity of which was studied with various reactive oxygen, nitrogen, and sulfur species. Probes 1-4 are formed by conjugating 1,2,3,3-tetramethyl-3H-indolium iodide and 4-hydroxybenzaldehyde or its derivatives through an alkene linkage formed by the Knoevenagel reaction. Oxidative cleavage of the electron-rich double bond of the conjugated hemicyanine dye revealed a discerning affinity of probe 3 towards peroxynitrite among all reactive oxygen species. The rapid change in color of 3 provides a sensitive and selective method for detecting peroxynitrite with a low detection limit of 180 nM. Notably, the water solubility of the probe displays excellent performance for the selective detection of peroxynitrite among ROS and reactive nitrogen (RNS)/sulfur species (RSS). UV-vis, 1 H NMR, and 13 C NMR spectroscopic data and results from theoretical calculations provide further information on the interaction of peroxynitrite with probe 3.

Coumarin-Ensembled Vanadium(V) Compounds and Their Affinity Studies Toward Biological Thiols Probed by Fluorescence Spectroscopy.

Fluorescence spectroscopic studies of a pair of new oxido-vanadium(V) compounds with biological thiols, such as homocysteine (Hcy), cysteine (Cys), and glutathione (GSH), have been investigated in this article. Despite notable progress in vanadium-thiol chemistry, no attention has been paid to exploring vanadium-based optical probes to study their interaction with biothiols. For this purpose, two oxido-vanadium(V) compounds, 1 and 2, have been prepared involving a tridentate ONO donor-based luminescent coumarin-derived ligand. Single crystal X-ray diffraction analysis, NMR (1 H, 13 C, and 51 V) spectroscopy, XPS, and DFT calculations have been used to establish their identities. The vanadium center in these compounds has a distorted octahedral environment. In compound 2, a methanol molecule is coordinated to the vanadium(V) center in the trans position of the terminal oxido moiety. The latter exerts a strong trans-labilizing influence on the coordinating methanol. Both 1 and 2 are weakly fluorescent. Photophysical investigations of the vanadium complexes in aqueous media at physiological pH (7.4) in the presence of various biothiols and amino acids showed significant fluorescence enhancement (83-fold) of the vanadium complexes, specifically with Hcy. The specific affinity of the complexes for Hcy remained unchanged even in the presence of other biothiols and amino acids. Kinetic investigation reveals pseudo-first order behavior of the compound with Hcy. Mechanistic studies have manifested that Hcy-induced reduction triggers the decomplexation of the vanadium compound, followed by hydrolysis and subsequent cyclization. Time-correlated single photon counting suggested that the radiative rate constant (kr ) of 1 and 2 in the presence of Hcy serves as the prime factor for the fluorescence enhancement of the medium. Compound 1 has been tested efficiently for Hcy measurement in blood plasma rendering it suitable for practical applications.

Advances in the Development of Water-Soluble Fluorogenic Probes for Bioimaging of Hypochlorite/Hypochlorous Acid in Cells and Organisms.

This mini-review summarizes the development of intracellular fluorogenic probes for biological investigations of hypochlorous acid/hypochlorite (HOCl/OCl-) in living cells and tissues. Monitoring the formation or effects of reactive oxygen species (ROS) inside living systems is critical in determining their roles in human physiology. HOCl/OCl- is considered as an important member of the nonradical ROS family for its decisive microbicidal action in the innate immune system. Even though HOCl/OCl- plays a defensive role in human health, abnormal or overexpression may have detrimental effects on the host physiology leading to many diseases, including neurodegeneration and cancer. In recent years, progress in the development of fluorescent imaging probes for observing HOCl/OCl- levels in live cells and tissues has been made. Despite considerable advancement, challenges still exist in areas like working solvent/media, pH, response time, buffer selection, emission region, and others. In addition, this account aims to discuss the design strategies and sensing mechanisms of the representative fluorogenic probes for bioimaging of HOCl/OCl-, endogenously and exogenously. Herein, we also have tried to provide the future direction to develop HOCl/OCl- specific probes for disease diagnosis with particular attention to the requirement of the recognition group, solvent, and buffer media, which will be beneficial for those working in the domain of biomedical research.

Enantiopure chiroptical probes for circular dichroism and absorbance based detection of nerve gas simulants.

A series of oxovanadium(V) compounds 1-4 were prepared and explored as stereodynamic chiroptical probes to detect a simulant of sarin known as diethyl chlorophosphate (DCP) without any interference from the competing analytes. Simultaneous CD cum UV/vis based bimodal instant recognition of DCP using optically active probes is unprecedented. Upon fabricating the vanadium compound with a polymer has yielded a chiroptical membrane, which showed a change in its dichroic as well as colorimetric signals on interaction with DCP vapour at 1 ppm. EPR and UV/vis studies revealed an irreversible change of the CD-active V(V) to the CD-silent ternary V(V) species in presence of DCP via a transient V(IV) species. Nucleophilic attack of the alkoxo oxygen of 1-4 to the electrophilic P atom of DCP resulted in the formation of ternary V(V) compounds as confirmed by 51V/31P NMR.

A unique water soluble probe for measuring the cardiac marker homocysteine and its clinical validation.

A series of copper(II) compounds 1-4 were synthesized and developed as fluorogenic probes to measure the cardiac marker homocysteine (Hcy) without any interference from other bioanalytes prevalent in human blood plasma including, cysteine and glutathione. UV-vis and EPR studies have provided confirmatory evidence for reduction-induced-emission-enhancement of the probe, which is responsible for the observed "off-to-on" behaviour towards Hcy. Water solubility, remarkable fluorescence enhancement (55-111 fold), and low detection ability (nearly 2.5 µM) make the probe suitable for clinical testing of cardiac samples. Investigation of 1 against a few reductive interferents testifies its specificity for Hcy. Results from clinical examination of cardiac samples by 1 when combined with the outcome of the reliability testing involving a clinically approved commercial immunoassay kit, validates the prospect of the molecular probe for direct measurement of Hcy in human plasma, which is unprecedented.

Studies on the interaction between oxido/dioxidovanadium(V) compounds and reactive oxygen species: Synthesis, characterization, and photophysical investigation.

Singlet oxygen (1O2) and hypochlorite (OCl-) are two principal non-radical reactive oxygen species (ROS) which, are produced in a number of biochemical processes. In cellular systems, these analytes play various important roles. In this article, we report two mononuclear oxido- and dioxidovanadium(V) compounds 1 and 2 of an intramolecularly hydrogen bonded luminescent zwitterion ligand (HL). Single crystal X-ray diffraction analysis and multinuclear (1H and 51V) NMR spectroscopy provided the identities of 1 and 2 in the solid and solution states, respectively. Both 1 and 2 are water soluble and fluorescent. Fluorescence of the ligand HL is responsible for the fluorescent nature of 1 and 2. Protonation of the hanging amine moiety of the ligand remained unchanged in the vanadium complexes 1 and 2. However, the intramolecular H-bonding is not present in 1 and 2. Hydrophilicity and luminescent nature of the vanadium complexes provided us the opportunity to study the interaction of 1 and 2 with different ROS. Excited state photophysical investigations revealed highly selective instant response of the probes 1 and 2 for singlet oxygen and hypochlorite. Specific response of the dioxidovanadium(V) complex 1 towards singlet oxygen/hypochlorite remained unchanged in presence of other challenging ROS. Spectrofluorimetric titration provided limit of detection around 180 nM for 1O2. 1H NMR and theoretical calculations provided further information on the interactions between vanadium compound and analyte.

Concurrent detection and treatment of cyanide-contaminated water using mechanosynthesized receptors.

The development of receptors that can detect as well as treat cyanide ions in aqueous samples is indispensable for environmental protection. Herein, we present the bulk solvent-free and instant green synthesis of a series of turn-on fluorimetric probes that can specifically detect the deadly poison cyanide among various anions and metal ions in water. Selective recognition of cyanide by the mechanosynthesized compounds is even observable by the naked eyes, which remained unaffected in the presence of various challenging species. NMR spectroscopic investigation supports the chemodosimetric sensing of cyanide by the receptors. A remarkable 55-83 fold fluorescence enhancement by the probes enabled us to reach a limit of detection (LOD) in the range of 8-26 ppb, well below the permissible limit of cyanide in drinking water. Being minuscule soluble in water, cyanide treatment studies with the ionophores showed greater than 99% reduction in the free cyanide concentration after three consecutive cycles of operation. Furthermore, the compounds can be used as sensitive probes for the estimation of cyanide in human blood serum in physiological conditions. Overall, the results presented in this article will certainly find great use in the area of cyanide pollution with regard to simultaneous sensing and treatment of free cyanide, which is heretofore unprecedented.

A Highly Selective Turn-On Biosensor for Measuring Spermine/Spermidine in Human Urine and Blood.

Spermine and spermidine serve as the key biomarkers for early-stage cancer diagnosis. This work reports a rapid, highly selective, and noninvasive sensing platform for spermine/spermidine. The hybrid material, developed in this work, has been characterized by UV-vis, IR, powder XRD, SEM, EDX, and rheological studies. Storage modulus (G') and loss modulus (G″) measurements infer that embedding boronic acid integrated coumarin softens the agarose gel fibers at room temperature. Stress resistance measurement and subsequent imaging further confirms the softness of the hybrid hydrogel over pure agarose gel and homogeneous distribution of the dye in the hybrid matrix as well. The soft hydrogel with a limit-of-detection (LOD) value of 6 µM showed a nearly 27-fold fluorescence enhancement for spermine. The hybrid hydrogel matrix can be useful within a wide concentration window (6 µM-2.5 mM spermine). Response time (≤7 s) confirms rapid detection ability of the material. Noninterference from various metal ions, common anions, monosaccharides, nucleobases, and amino acids, particularly, histidine, arginine, lysine, ornithine, glutamine, etc.,  makes the hybrid hydrogel suitable for the real-time measurement of spermine in human urinary and blood samples. Furthermore, noninterference from other biogenic amines supports the highly selective nature of the hybrid gel. The ability to measure spermine in urinary samples by the probe offers a noninvasive nature of the sensing platform. Overall, we envisioned that the hybrid material formulation would be useful for diagnosing early-stage tumors and assessing the recovery of patients undergoing chemotherapeutic treatment.

Affinity Directed Surface Functionalization of Two Different Metal Nanoparticles by a Natural Ionophore: Probing and Removal of Hg2+ and Al3+ Ions from Aqueous Solutions.

In this work, we report affinity controlled surface modifications of two different metal nanoparticles (MNPs) using a hydrophilic natural ionophore (microbial chelator) aeruginic acid (abbreviated as H2L) that possesses two different types of binding pockets viz. O/O from carboxylic acid group and N/O from a phenol-thiazole moiety. Preferred binding of the former donor set (i.e., O/O) on to the surface of silver nanoparticles (AgNPs) has resulted in a colorimetric nanomaterial HL@AgNPs, which showed naked eye observable easy detection of Hg2+ in aqueous HEPES buffer at pH 7.4, even in the presence of other metal ions. On the other hand, excellent affinity of the phenol-thiazole moiety (i.e., N/O) for iron nanosurfaces (FeNPs) develops a fluorogenic nanomaterial HL@FeNPs. Brilliant emission behavior of this nanomaterial enabled it to be useful for highly selective recognition of Al3+ under identical experimental conditions. Remarkable fluorescence enhancement (122-folds) of HL@FeNPs upon addition of Al3+ remain unchanged even in the presence of other competing metal ions. The nanomaterials HL@AgNPs and HL@FeNPs could even detect the target analytes instantly offering lower detection limits of 2 and 80 nM, respectively. Presence of toxic metal ions as environmental pollutant demands for dual-functional materials capable of performing the task of probing cum removal. Surface functionalizations of the nanomaterials of silver and iron with H2L have also resulted two removal agents that can efficiently and easily extract Hg2+ and Al3+ ions from contaminated water, respectively. We are not aware of any work that highlights the manifold utilization of a microbial chelator (i.e., natural ionophore) in the facile construction of different metal nanoparticles for environmental applications such as detection cum removal of toxic metal ions from aqueous solutions.