Micropores in Hollow Organic Cage Nanocapsule as a Size Exclusion Gate: Cage Entrapped Pd(II)-Catalyst for Efficient Cross-Coupling Reaction.

Hollow porous organic capsules (HPOCs) with an entrapped active catalyst have nanosized cavities, providing the benefits of a nanoreactor, as well as separation of the catalysts from the reaction medium via pores acting as a size-exclusion gate. Such purpose-built HPOCs with desired molecular weight cutoffs offer the advantages of semipermeable membrane separation and a sustainable chemical process that excludes energy-extensive separation. Here, we report a newly synthesized HPOC with an entrapped Pd(PPh3)2Cl2 as the catalyst for demonstrating a Suzuki-Miyaura coupling reaction as a proof of concept.

Efficient Iodine Uptake of Ultra Thermally Stable Conjugated Copolymers Bearing Biaceanthrylenyl Moieties and Contorted Aromatic Units Using a [3 + 2] Palladium-Catalyzed Cyclopolymerization Reaction.

A novel series of copolymers made from alternating aromatic surrogates with contorted and spiro compounds, denoted as BCP1-3, was successfully synthesized employing a palladium-catalyzed one-pot [3 + 2] cyclopentannulation reaction. The resulting copolymers BCP1-3, which were isolated in high yields, exhibited weight-average molecular weights (Mw) ranging from 11.0 to 61.5 kg mol-1 (kDa) and polydispersity index (Mw/Mn) values in the range of 1.7 and 2.0, which suggest a narrow molecular weight distribution, thus indicating the formation of uniform copolymer chains. Investigation of the thermal properties of BCP1-3 by thermogravimetric analysis disclosed outstanding stability with 10% weight loss temperature values reaching 800 °C. Iodine adsorption tests revealed remarkable results, particularly for BCP2, which demonstrated a strong affinity toward iodine reaching an uptake of 2900 mg g-1. Additionally, recyclability tests showcased the effective regeneration of BCP2 after several successive iodine adsorption-desorption cycles.

Efficient Removal of Carcinogenic Azo Dyes from Water Using Iron(II) Clathrochelate Derived Metalorganic Copolymers Made from a Copper-Catalyzed [4 + 2] Cyclobenzannulation Reaction.

A novel synthetic strategy is disclosed to prepare a new class of metalorganic copolymers that contain iron(II) clathrochelate building blocks by employing a mild and cost-effective copper-catalyzed [4 + 2] cyclobenzannulation reaction, using three specially designed diethynyl iron(II) clathrochelate synthons. The target copolymers CBP1-3 were isolated in high purity and excellent yields as proven by their structural and photophysical characterization, namely, Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS) and UV-VIS absorption and emission spectroscopies. The thermogravimetric analysis (TGA) of CBP1-3 revealed an excellent chemical stability. Investigation of the adsorption properties of the target copolymers towards the carcinogenic methyl red dye from aqueous solution revealed a quantitative uptake in 30 min. Isothermal adsorption studies disclosed that methyl red uptake from aqueous solution followed the Langmuir model for all of the target copolymers, reaching a maximum adsorption capacity (qm) of 431 mg g-. Kinetic investigation revealed that the adsorption followed pseudo-first-order with an equilibrium adsorption capacity (qe,cal) of 79.35 mg g- and whose sorption property was sustained even after its reuse several times.

Stimuli-Responsive Prodrug Chemistries for Cancer Therapy.

Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs through chemical or enzymatic cleavage. The prodrug approach holds tremendous potential to create the enhanced version of an existing pharmacological agent and leverage those improvements to augment the drug molecules' bioavailability, targeting ability, therapeutic efficacy, safety, and marketability. Especially in cancer therapy, prodrug application has received substantial attention. A prodrug can effectively broaden the therapeutic window of its parent drug by enhancing its release at targeted tumor sites while reducing its access to healthy cells. The spatiotemporally controlled release can be achieved by manipulating the chemical, physical, or biological stimuli present at the targeted tumor site. The critical strategy comprises drug-carrier linkages that respond to physiological or biochemical stimuli in the tumor milieu to yield the active drug form. This review will focus on the recent advancements in the development of various fluorophore-drug conjugates that are widely used for real-time monitoring of drug delivery. The use of different stimuli-cleavable linkers and the mechanisms of linker cleavage will be discussed. Finally, the review will conclude with a critical discussion of the prospects and challenges that might impede the future development of such prodrugs.

Multimodal Biofilm Inactivation Using a Photocatalytic Bismuth Perovskite-TiO2-Ru(II)polypyridyl-Based Multisite Heterojunction.

Infectious bacterial biofilms are recalcitrant to most antibiotics compared to their planktonic version, and the lack of appropriate therapeutic strategies for mitigating them poses a serious threat to clinical treatment. A ternary heterojunction material derived from a Bi-based perovskite-TiO2 hybrid and a [Ru(2,2'-bpy)2(4,4'-dicarboxy-2,2'-bpy)]2+ (2,2'-bpy, 2,2'-bipyridyl) as a photosensitizer (RuPS) is developed. This hybrid material is found to be capable of generating reactive oxygen species (ROS)/reactive nitrogen species (RNS) upon solar light irradiation. The aligned band edges and effective exciton dynamics between multisite heterojunctions are established by steady-state/time-resolved optical and other spectroscopic studies. Proposed mechanistic pathways for the photocatalytic generation of ROS/RNS are rationalized based on a cascade-redox processes arising from three catalytic centers. These ROS/RNS are utilized to demonstrate a proof-of-concept in treating two elusive bacterial biofilms while maintaining a high level of biocompatibility (IC50 > 1 mg/mL). The in situ generation of radical species (ROS/RNS) upon photoirradiation is established with EPR spectroscopic measurements and colorimetric assays. Experimental results showed improved efficacy toward biofilm inactivation of the ternary heterojunction material as compared to their individual/binary counterparts under solar light irradiation. The multisite heterojunction formation helped with better exciton delocalization for an efficient catalytic biofilm inactivation. This was rationalized based on the favorable exciton dissociation followed by the onset of multiple oxidation and reduction sites in the ternary heterojunction. This together with exceptional photoelectric features of lead-free halide perovskites outlines a proof-of-principle demonstration in biomedical optoelectronics addressing multimodal antibiofilm/antimicrobial modality.

High Uptake of the Carcinogenic Pararosaniline Hydrochloride Dye from Water Using Carbazole-Containing Conjugated Copolymers Synthesized from a One-Pot Cyclopentannulation Reaction.

Three conjugated copolymers CAP1-3 were synthesized in one-step via a typical [3+2] cyclopentannulation reaction using a specially designed diethynyl carbazole synthon with various dibrominated polycondensed aromatic hydrocarbons (PAHs). The desired copolymers CAP1-3 were obtained in excellent yields, and their structures were confirmed by 1H- and 13C- nuclear magnetic spectroscopy (NMR), whereas gel permeation chromatography revealed weight-average molar masses (Mw) up to 19.9 kDa with a polydispersity index (PDI) in the range of 2.2-2.6. Interestingly, CAP1-3 exhibits an outstanding capacity to adsorb the carcinogenic pararosaniline hydrochloride dye (Basic Red 9, BR9) from aqueous solutions. Isothermal adsorption studies were carried out following the linear models of Langmuir and Freundlich, divulging an adsorption capacity maximum (qm) toward BR9 of 483.09 mg g-1. Investigation of the dye uptake mechanism on CAP1-3 revealed a pseudo-second-order kinetic model for the target copolymer that showed the highest uptake capacity. Recyclability tests disclosed an excellent adsorption efficiency of BR 9 reaching 93% after six cycles.

Small-Molecule Cdc25A Inhibitors Protect Neuronal Cells from Death Evoked by NGF Deprivation and 6-Hydroxydopamine.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that are presently incurable. There have been reports of aberrant activation of cell cycle pathways in neurodegenerative diseases. Previously, we have found that Cdc25A is activated in models of neurodegenerative diseases, including AD and PD. In the present study, we have synthesized a small library of molecules targeting Cdc25A and tested their neuroprotective potential in cellular models of neurodegeneration. The Buchwald reaction and amide coupling were crucial steps in synthesizing the Cdc25A-targeting molecules. Several of these small-molecule inhibitors significantly prevented neuronal cell death induced by nerve growth factor (NGF) deprivation as well as 6-hydroxydopamine (6-OHDA) treatment. Lack of NGF signaling leads to neuron death during development and has been associated with AD pathogenesis. The NGF receptor TrkA has been reported to be downregulated at the early stages of AD, and its reduction is linked to cognitive failure. 6-OHDA, a PD mimic, is a highly oxidizable dopamine analogue that can be taken up by the dopamine transporters in catecholaminergic neurons and can induce cell death by reactive oxygen species (ROS) generation. Some of our newly synthesized molecules inhibit Cdc25A phosphatase activity, block loss of mitochondrial activity, and inhibit caspase-3 activation caused by NGF deprivation and 6-OHDA. Hence, it may be proposed that Cdc25A inhibition could be a therapeutic possibility for neurodegenerative diseases and these Cdc25A inhibitors could be effective treatments for AD and PD.

Modulating Resonance Energy Transfer with Supramolecular Control in a Layered Hybrid Perovskite and Chromium Photosensitizer Assembly.

Recently, the low-dimensional organic-inorganic halide perovskites (OIHP) have been exploited heavily for their favorable exciton dynamics, broad-band emission, remarkable stability, and tunable band-edge excited-state energy compared to their 3D counterparts for potential optoelectronic applications. Low-dimensional perovskites are generally good candidates for utilization as room-temperature photoluminescence (PL) materials. Further, doping divalent transition metals like Mn2+ into OIHP is expected to introduce a 4T1-6A1-based low-energy luminescence emission around 600 nm; an optical property that is favorable for biomedical optoelectronics. Doping Mn2+ in the perovskite lattice is also expected to induce the generation of cytotoxic singlet oxygen species (1O2), a ROS that is being exploited for various therapeutic applications. To integrate these optical and therapeutic properties of a 2D (PEA)2PbBr4 (Pb PeV; PEA = phenylethylammonium cation) perovskite alloyed with Mn2+ ions (Mn:PbPeV) and the option for a photoinduced energy transfer process involving a Cr(III)-based 1O2 generating photosensitizer (CrPS), we designed a unique purpose-built nanoassembly (Mn:PbPeV@PCD) using the encapsulation properties of a water-soluble polymer derived from ß-cyclodextrin (PCD). Here the PCD is observed to modulate the classical internal energy transfer of Pb2+ exciton to alloyed Mn2+ orange emission, resulting in the emergence of a new blue emission. The addition of CrPS into the Mn:PbPeV@PCD to generate the CrPS@Mn:PbPeV@PCD assembly results in restoring perovskite luminescence followed by the external energy transfer to CrPS. We have elucidated the mechanism of these cascade energy transfer processes between multiple components using steady-state and time-resolved luminescence techniques. Efficient ROS generation and its potential to induce an oxidation reaction of a biomolecule are realized using guanine as the target molecule. Further photoinduced cleavage studies with biomolecules confirmed the efficacy of the nanoassembly in inducing the cleavage of guanine-rich DNA. The study opens up a new direction in the field of perovskite for biomedical applications.

Aggregation-Induced Emission of Contorted Polycondensed Aromatic Hydrocarbons Made by Edge Extension Using a Palladium-Catalyzed Cyclopentannulation Reaction.

Contorted polycyclic aromatic hydrocarbons (PAHs), CPA1-2 and CPB1-2, bearing peripheral five-membered rings were synthesized employing a palladium-catalyzed cyclopentannulation reaction using specially designed diaryl acetylene synthons TPE and TPEN with commercially available dibromo- anthracene DBA and bianthracene DBBA derivatives. The resulting target compounds CPA1-2 and CPB1-2 were isolated in excellent yield and found to be highly soluble in common organic solvents, which allowed for their structural characterization and investigation of the photophysical properties, disclosing their aggregation-induced emission (AIE) properties in THF at selective concentration ranges of water fractions in the solvent mixture. Examination of the contorted PAH structures by means of density functional theory (DFT) revealed higher electronic conjugation in the more rigid and planar anthracene-containing CPA1-2 derivatives when compared to the twisted bianthracene-bearing moieties CBPA1-2 with HOMO-LUMO bandgaps (ΔE) of ∼2.32 eV for the former PAHs and ∼2.78 eV for the latter ones.

Nanoparticles for super-resolution microscopy: intracellular delivery and molecular targeting.

Following an overview of the approaches and techniques used to acheive super-resolution microscopy, this review presents the advantages supplied by nanoparticle based probes for these applications. The various clases of nanoparticles that have been developed toward these goals are then critically described and these discussions are illustrated with a variety of examples from the recent literature.

A combination therapy strategy for treating antibiotic resistant biofilm infection using a guanidinium derivative and nanoparticulate Ag(0) derived hybrid gel conjugate.

Bacteria organized in biofilms show significant tolerance to conventional antibiotics compared to their planktonic counterparts and form the basis for chronic infections. Biofilms are composites of different types of extracellular polymeric substances that help in resisting several host-defense measures, including phagocytosis. These are increasingly being recognized as a passive virulence factor that enables many infectious diseases to proliferate and an essential contributing facet to anti-microbial resistance. Thus, inhibition and dispersion of biofilms are linked to addressing the issues associated with therapeutic challenges imposed by biofilms. This report is to address this complex issue using a self-assembled guanidinium-Ag(0) nanoparticle (AD-L@Ag(0)) hybrid gel composite for executing a combination therapy strategy for six difficult to treat biofilm-forming and multidrug-resistant bacteria. Improved efficacy was achieved primarily through effective biofilm inhibition and dispersion by the cationic guanidinium ion derivative, while Ag(0) contributes to the subsequent bactericidal activity on planktonic bacteria. Minimum Inhibitory Concentration (MIC) of the AD-L@Ag(0) formulation was tested against Acinetobacter baumannii (25 µg mL-1), Pseudomonas aeruginosa (0.78 µg mL-1), Staphylococcus aureus (0.19 µg mL-1), Klebsiella pneumoniae (0.78 µg mL-1), Escherichia coli (clinical isolate (6.25 µg mL-1)), Klebsiella pneumoniae (clinical isolate (50 µg mL-1)), Shigella flexneri (clinical isolate (0.39 µg mL-1)) and Streptococcus pneumoniae (6.25 µg mL-1). Minimum bactericidal concentration, and MBIC50 and MBIC90 (Minimum Biofilm Inhibitory Concentration at 50% and 90% reduction, respectively) were evaluated for these pathogens. All these results confirmed the efficacy of the formulation AD-L@Ag(0). Minimum Biofilm Eradication Concentration (MBEC) for the respective pathogens was examined by following the exopolysaccharide quantification method to establish its potency in inhibition of biofilm formation, as well as eradication of mature biofilms. These effects were attributed to the bactericidal effect of AD-L@Ag(0) on biofilm mass-associated bacteria. The observed efficacy of this non-cytotoxic therapeutic combination (AD-L@Ag(0)) was found to be better than that reported in the existing literature for treating extremely drug-resistant bacterial strains, as well as for reducing the bacterial infection load at a surgical site in a small animal BALB/c model. Thus, AD-L@Ag(0) could be a promising candidate for anti-microbial coatings on surgical instruments, wound dressing, tissue engineering, and medical implants.

Ultrasensitive Reagent for Ratiometric Detection and Detoxification of iAsIII in Water and Mitochondria.

Toxicity induced by inorganic arsenic as AsO33- (iAsIII) is of global concern. Reliable detection of the maximum allowed contaminant level for arsenic in drinking water and in the cellular system remains a challenge for the water quality management and assessment of toxicity in the cellular milieu, respectively. A new Ir(III)-based phosphorescent molecule (AS-1; λExt = 415 nm and λEms = 600 nm, Φ = 0.3) is synthesized for the selective detection of iAsIII in an aqueous solution with a ratiometric luminescence response even in the presence of iAsV and all other common inorganic cations and anions. The relatively higher affinity of the thioimidazole ligand (HPBT) toward iAsIII led to the formation of a fluorescent molecule iAsV-HPBT (λExt = 415 nm and λEms = 466 nm, Φ = 0.28) for the reaction of iAsIII and AS-1. An improved limit of quantitation (LOQ) down to 0.2 ppb is achieved when AS-1 is used in the CTAB micellar system. Presumably, the cationic surfactants favor the localization of AS-1@CTABMicelle in mitochondria of MCF7 cells, and this is confirmed from the images of the confocal laser fluorescence scanning microscopic studies. Importantly, cell viability assay studies confirm that AS-1@CTABMicelle induces dose-dependent detoxification of iAsIII in live cells. Further, luminescence responses at 466 nm could be utilized for developing a hand-held device for the in-field application. Such a reagent that allows for ratiometric detection of iAsIII with LOQ of 2.6 nM (0.5 ppb) in water, as well as helps in visualizing its distribution in mitochondria with a detoxifying effect, is rather unique in contemporary literature.

Graphene quantum dots alleviate ROS-mediated gastric damage.

The gastrointestinal (GI) tract is one of the major sites for reactive oxygen species generation (ROS). Physiological ROS, lower than the threshold concentration, is beneficial for human physiology to preserve gut functional integrity. However, ROS generated in large quantities in presence of external stimuli overwhelms the cellular antioxidant defense mechanism and results in oxidative damage and associated physiological disorder. Graphene quantum dots (GQDs) are a class of carbon-based nanomaterials that have attracted tremendous attention not only for their tunable optical properties but also for their broad-spectrum antioxidant properties. In this report we have shown that GQDs are highly efficient in scavenging ROS and suppressing stress-induced gastric ulcers by targeting the MMP-9 pathway and reducing the inflammatory burden by suppressing excessive oxidative stress by inducing high caspase activity, overproduction of Bax, and downregulation of BCL2.

Interfacial synthesis of large-area ultrathin polyimine nanofilms as molecular separation membrane.

Thin film membranes of covalent organic frameworks are promising for high-permeance molecular separation. However, their synthesis needs a high temperature or longer reaction time, unsuitable for large-scale fabrication of thin film composite membranes. The ultrathin film of porous organic polymers as a separation layer of the composite membrane could be a close alternative to COF membranes. Here we report transition metal ion-catalyzed room temperature fabrication of the ultrathin (≈12 nm) polyimine nanofilms via interfacial polymerization of melamine and triformylphloroglucinol onto hydrolyzed polyacrylonitrile support within a short reaction time. Composite membranes exhibit high water permeance (≈78 L m-2 h-1 bar-1), high rejection (99.6%) of brilliant blue R (825.9 g mol-1), low rejection of NaCl (≈1.8%) and Na2SO4 (≈17%), and enable efficient molecular separation. The role of metal ion catalysts for large-area fabrication of the ultrathin polyimine nanofilm membranes used for molecular separation is demonstrated.

Chitosan/benzyloxy-benzaldehyde modified ZnO nano template having optimized and distinct antiviral potency to human cytomegalovirus.

Utilization of biomolecules encapsulated nano particles is currently originating ample attention to generate unconventional nanomedicines in antiviral research. Zinc oxide nanoparticle has been extensively studied for antimicrobial, antifungal and antifouling properties due to high surface to volume ratios and distinctive chemical as well as physical properties. Nevertheless, still minute information is available on their response on viruses. Here, in situ nanostructured and polysaccharide encapsulated ZnO NPs are fabricated with having antiviral potency and low cytotoxicity (%viability ~ 90%) by simply controlling the formation within interspatial 3D networks of hydrogels through perfect locking mechanism. The two composites ChH@ZnO and ChB@ZnO shows exceedingly effective antiviral activity toward Human cytomegalovirus (HCMV) having cell viability 93.6% and 92.4% up to 400 µg mL-1 concentration. This study brings significant insights regarding the role of ZnO NPs surface coatings on their nanotoxicity and antiviral action and could potentially guide to the development of better antiviral drug.

Fluorescent probes for imaging bioactive species in subcellular organelles.

Luminescent molecular probes and nanoscale materials have become important tools in biosensing and bioimaging applications because of their high sensitivity, fast response, specificity, and methodological simplicity. In recent years, there has been a notable advancement in fluorescent probes that respond to the subtle changes in subcellular microenvironments (e.g., polarity, pH, and viscosity) or distribution of certain crucial biomarkers (e.g., reactive oxygen species, ions, amino acids, and enzymes). The dynamic fluctuations of these bio-molecules in subcellular microenvironments control cellular homeostasis, immunity, signal conduction, and metabolism. Their abnormal expressions are linked to various biological disorders and disease states. Thus, the real-time monitoring of such bioactive species is intimately linked to clinical diagnostics. Appropriately designed luminescent probes are ideally suited for desired organelle specificity, as well as for reporting intracellular changes in biochemicals/microenvironmental factors with the luminescence ON response. In this perspective, we review our recent work on the development of fluorescent probes for sensing and imaging within sub-cellular organelles. We have also discussed the design aspects for developing a prodrug with a fluorescent probe as an integral part of possible theranostic applications. An overview of the design principles, photophysical properties, detection mechanisms, current challenges, and potential future directions of fluorescent probes is presented in this feature article. We have also discussed the limitations and challenges of developing the solution platform for sensing technologies in clinical diagnostics.

Redox-Responsive Nanocapsules for the Spatiotemporal Release of Miltefosine in Lysosome: Protection against Leishmania.

Leishmaniasis, a vector-borne disease, is caused by intracellular parasite Leishmania donovani. Unlike most intracellular pathogens, Leishmania donovani are lodged in parasitophorous vacuoles and replicate within the phagolysosomes in macrophages. Effective vaccines against this disease are still under development, while the efficacy of the available drugs is being questioned owing to the toxicity for nonspecific distribution in human physiology and the reported drug-resistance developed by Leishmania donovani. Thus, a stimuli-responsive nanocarrier that allows specific localization and release of the drug in the lysosome has been highly sought after for addressing two crucial issues, lower drug toxicity and a higher drug efficacy. We report here a unique lysosome targeting polymeric nanocapsules, formed via inverse mini-emulsion technique, for stimuli-responsive release of the drug miltefosine in the lysosome of macrophage RAW 264.7 cell line. A benign polymeric backbone, with a disulfide bonding susceptible to an oxidative cleavage, is utilized for the organelle-specific release of miltefosine. Oxidative rupture of the disulfide bond is induced by intracellular glutathione (GSH) as an endogenous stimulus. Such a stimuli-responsive release of the drug miltefosine in the lysosome of macrophage RAW 264.7 cell line over a few hours helped in achieving an improved drug efficacy by 200 times as compared to pure miltefosine. Such a drug formulation could contribute to a new line of treatment for leishmaniasis.

Mitochondriotropic lanthanide nanorods: implications for multimodal imaging.

Two-photon active mitochondriotropic lanthanide nanorods for high resolution fluorescence imaging. The presence of Gd in the nanorods also enabled us to utilize this material as a T1-T2 dual-mode contrast reagent for recording magnetic resonance images of the mouse brain.

Recent Advances in Fluorescent Probes for Detection of HOCl and HNO.

It is known that reactive oxygen (ROS) and nitrogen (RNS) species play a diverse role in various biological processes, such as inflammation, signal transduction, and neurodegenerative injury, apart from causing various diseases caused by oxidative and nitrosative stresses, respectively, by ROS and RNS. Thus, it is very important to quantify the concentration level of ROS and RNS in live cells, tissues, and organisms. Various small-molecule-based fluorescent/chemodosimetric probes are reported to quantify and map the effective distribution of ROS/RNS under in vitro/in vivo conditions with a great spatial and temporal resolution. Such reagents are now appreciated as an excellent tool for aiding breakthroughs in modern redox biology. This mini-review is a brief, but all-inclusive, account of such molecular probes that have been developed recently.