On the role of polymeric hydrogels in the thermal response of gold nanorods under NIR laser irradiation.

Hydrogels are 3D cross-linked networks of polymeric chains designed to be used in the human body. Nowadays they find widespread applications in the biomedical field and are particularly attractive as drug delivery vectors. However, despite many good results, their release performance is sometimes very quick and uncontrolled, being forced by the high in vivo clearance of body fluids. In this direction, the development of novel responsive nanomaterials promises to overcome the drawbacks of common hydrogels, inducing responsive properties in three-dimensional polymeric devices. In this study, we synthesized and then loaded gold nanorods (Au NRs) within an agarose-carbomer (AC)-based hydrogel obtained from a microwave-assisted polycondensation reaction between carbomer 974P and agarose. The photothermal effect of the composite device was quantified in terms of maximum temperature and spatial-temporal temperature distribution, also during consecutive laser irradiations. This work shows that composite Au NRs loaded within AC hydrogels can serve as a stable photothermal treatment agent with enhanced photothermal efficiency and good thermal stability after consecutive laser irradiations. These results confirm that the composite system produced can exhibit an enhanced thermal effect under NIR laser irradiation, which is expected to lead to great therapeutic advantages for the localized treatment of different diseases.

Turn-Mimic Hydantoin-Based Loops Constructed by a Sequential Multicomponent Reaction.

A collection of peptidomimetics characterized by having an aspartic acid motif embedded in a rigid hydantoin heterocycle are synthesized through a sequential multicomponent domino process followed by standard regioselective deprotection/coupling reactions based on acid-base liquid/liquid purification protocols. 1H nuclear magnetic resonance experiments, molecular modeling, and X-ray analysis showed that the resulting hydantoin-based loops I (in particular) and II (to a lesser extent) can be considered novel ß-turn inducer motifs being able to project two peptide-like strands in a U-shaped conformation driven by the formation of intermolecular hydrogen bonds.

Synthesis and Characterization of New Triazole-Bispidinone Scaffolds and Their Metal Complexes for Catalytic Applications.

Bispidines are a family of ligands that plays a pivotal role in various areas of coordination chemistry, with applications in medicinal chemistry, molecular catalysis, coordination polymers synthesis, and molecular magnetism. In the present work, triazole moieties were introduced using the CuAAC click-reaction, with the aim of expanding the number of coordination sites on the bispidine core. The 1,2,3-triazole rings were thus synthesized on propargyl-derived bispidines after reaction with different alkyl azides. The new class of triazole-bispidines was characterized, and their chelation capabilities were evaluated with different metals through NMR titration, ESI-MS spectrometry, and single-crystal X-ray diffraction (SC-XRD). Finally, the suitability of these molecules as metal ligands for the catalytic Henry reaction was demonstrated with copper and zinc.

ß-Cyclodextrin functionalized agarose-based hydrogels for multiple controlled drug delivery of ibuprofen.

Agarose hydrogels are three-dimensional hydrophilic polymeric frameworks characterised by high water content, viscoelastic properties, and excellent ability as cell and drug delivery systems. However, their hydrophilicity as gel systems makes loading of hydrophobic drugs difficult and often ineffective. The incorporation of amphiphilic molecules (e.g. cyclodextrins) into hydrogels as hosts able to form inclusion complexes with hydrophobic drugs could be a possible solution. However, if not properly confined, the host compounds can get out of the network resulting in uncontrolled release. Therefore, in this work, ß-cyclodextrins-based host-guest supramolecular hydrogel systems were synthesised, with ß-cyclodextrins (ß-CD) covalently bound to the polymeric network, preventing leakage of the host molecules. Hydrogels were prepared at two different ß-CD-functionalized polyvinyl alcohol (PVA)/agarose ratios, and characterised chemically and physically. Then ibuprofen, a drug often used as a gold standard in studies involving ß-CD both in its hydrophilic and hydrophobic forms, was selected to investigate the release behavior of the synthesised hydrogels and the influence of ß-CD on the release. The presence of ß-CD linked to the polymeric 3D network ensured a higher and prolonged release profile for the hydrophobic drug and also seemed to have some influence on the hydrophilic one.

Recycling of used vegetable oils by powder adsorption.

The treatment of used vegetable oil (UVO) with seven different adsorbents and through two different procedures (stirring and gravity filtration) was explored. Important differences in terms of density, turbidity, electrical resistance, free fatty acids (FFAs) content and relative fatty acid distribution were observed. Different outcomes were shown depending both on the adsorbent and on the procedure. Lower values of density and FFAs were registered for oils treated by gravity filtration with portland (respectively 0.6% and 0.81 g/ml) and celite (respectively 0.7% and 0.72 g/ml). Considering the undesired leaching from the powder to the oil, related to the turbidity, the celite resulted more suitable for the oil recycling (241 Nephelometric Turbidity Unit (NTU) for portland vs 184 NTU for celite). In addition, Fourier-transform infrared spectroscopy combined with multivariate analysis allowed to determine a chemical fingerprint relative characteristic of vegetable oils recycled by gravity or by adsorption by stirring.

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics.

The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and N-alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid-liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the α carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies in silico (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as α-helix and ß-turn, being the open α-helix conformation slightly favorable according to molecular modeling, while the closed ß-turn conformation preferred in solution and in solid state.

Pd-Loaded Cellulose NanoSponge as a Heterogeneous Catalyst for Suzuki-Miyaura Coupling Reactions.

The (eco)design and synthesis of durable heterogeneous catalysts starting from renewable sources derived from biomass waste represents an important step for reducing environmental impacts of organic transformations. Herein, we report the efficient loading of Pd(II) ions on an eco-safe cellulose-based organic support (CNS), obtained by thermal cross-linking between TEMPO-oxidized cellulose nanofibers and branched polyethyleneimine in the presence of citric acid. A 22.7% w/w Pd-loading on CNS was determined by the ICP-OES technique, while the metal distribution on the xerogel was evidenced by SEM-EDS analysis. XPS analysis confirmed the direct chelation of Pd(II) ions by means of the high number of amino groups present in the network, so that further functionalization of the support with specific ligands was not necessary. The new composite turned to be an efficient heterogeneous pre-catalyst for promoting Suzuki-Miyaura coupling reactions between aryl halides and phenyl boronic acid in water, obtaining yields higher than 90% in 30 min, by operating in a microwave reactor at 100 °C and with just 2% w/w of CNS-Pd catalyst with respect to aryl halides (4.5‱ for Pd). At the end of first reaction cycle, Pd(II) ions on the support resulted in being reduced to Pd(0) while maintaining the same catalytic efficiency. In fact, no leaching was observed at the end of reactions, and five cycles of recycling and reusing of CNS-Pd catalyst provided excellent results in terms of yields and selectivity in the desired products.

Zinc- and Copper-Loaded Nanosponges from Cellulose Nanofibers Hydrogels: New Heterogeneous Catalysts for the Synthesis of Aromatic Acetals.

Herein we report the synthesis of cellulose-based metal-loaded nano-sponges and their application as heterogeneous catalysts in organic synthesis. First, the combination in water solution of TEMPO-oxidized cellulose nanofibers (TOCNF) with branched polyethyleneimine (bPEI) and citric acid (CA), and the thermal treatment of the resulting hydrogel, leads to the synthesis of an eco-safe micro- and nano-porous cellulose nano-sponge (CNS). Subsequently, by exploiting the metal chelation characteristics of CNS, already extensively investigated in the field of environmental decontamination, this material is successfully loaded with Cu (II) or Zn (II) metal ions. Efficiency and homogeneity of metal-loading is confirmed by scanning electron microscopy (SEM) analysis with an energy dispersive X-ray spectroscopy (EDS) detector and by inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis. The resulting materials perform superbly as heterogeneous catalysts for promoting the reaction between aromatic aldehydes and alcohols in the synthesis of aromatic acetals, which play a fundamental role as intermediates in organic synthesis. Optimized conditions allow one to obtain conversions higher than 90% and almost complete selectivity toward acetal products, minimizing, and in some cases eliminating, the formation of carboxylic acid by-products. ICP-OES analysis of the reaction medium allows one to exclude any possible metal-ion release, confirming that catalysis undergoes under heterogeneous conditions. The new metal-loaded CNS can be re-used and recycled five times without losing their catalytic activity.

Mechanochemical synthesis of mechanical bonds in M12L8 poly-[n]-catenanes.

Using mechanochemistry by grinding TPB and ZnBr2, an amorphous poly-[n]-catenane of interlocked M12L8 nanocages is obtained in good yields (∼80%) and within 15 minutes. The mechanical bond among the icosahedral M12L8 cages in the amorphous phase has been demonstrated by single crystal XRD, powder XRD and FT-IR spectroscopy following an amorphous-to-crystalline transformation by guest uptake of the amorphous phase. High-resolution solid-state 13C NMR spectroscopy gives insights into the local structure of the amorphous catenane focusing on TPB aromatic-aromatic interactions.

Synthesis and Characterization of a "Clickable" PBR28 TSPO-Selective Ligand Derivative Suitable for the Functionalization of Biodegradable Polymer Nanoparticles.

Reactive microgliosis is a pathological hallmark that accompanies neuronal demise in many neurodegenerative diseases, ranging from acute brain/spinal cord injuries to chronic diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and age-related dementia. One strategy to assess and monitor microgliosis is to use positron emission tomography (PET) by exploiting radioligands selective for the 18 kDa translocator protein (TSPO) which is highly upregulated in the brain in pathological conditions. Several TSPO ligands have been developed and validated, so far. Among these, PBR28 has been widely adopted for PET imaging at both preclinical and clinical levels, thanks to its high brain penetration and high selectivity. For this reason, PBR28 represents a good candidate for functionalization strategies, where this ligand could be exploited to drive selective targeting of TSPO-expressing cells. Since the PBR28 structure lacks functional moieties that could be exploited for derivatization, in this work we explored a synthetic pathway for the synthesis of a PBR28 derivative carrying an alkyne group (PBR-alkyne), enabling the fast conjugation of the ligand through azide-alkyne cycloaddition, also known as click-chemistry. As a proof of concept, we demonstrated in silico that the derivatized PBR28 ligand maintains the capability to fit into the TSPO binding pocked, and we successfully exploited PBR-alkyne to decorate zwitterionic biodegradable polymer nanoparticles (NPs) resulting in efficient internalization in cultured microglia-like cell lines.

Deep Eutectic Solvents: Promising Co-solvents to Improve the Extraction Kinetics of CyMe4-BTBP.

In this communication, we report on the use of deep eutectic solvents (DESs) for processing nuclear waste, with a view to selectively recovering minor actinides (MA) from highly active raffinate solutions. DESs are an interesting new class of green and eco-sustainable solvents. Herein, a representative family of DES was tested as a co-solvent for MA/lanthanides partitioning based on Selective ActiNide EXtraction (SANEX)-like hydrometallurgical processes. The reference system exploits the CyMe4-BTBP lipophilic extractant for selective MA recovery, but the slow kinetics is the main limitation toward the industrial implementation. A selection of hydrophilic DESs has been proposed as a phase transfer catalyst and tested to improve the process performances. In this work, the radiochemical stability and the extraction behavior of these DESs have been ascertained. Moreover, a preliminary optimization of system composition has been achieved. This study underlines a catalytic effect of DES that can be proficiently exploited to enhance CyMe4-BTBP extraction and selectivity.

Functionalized nanogel for treating activated astrocytes in spinal cord injury.

Astrogliosis has a unique reaction during spinal cord damage, with helpful or adverse impacts on recovery. There is consequently a pressing need for treatment to target activated astrocytes and their unsafe response after injury to ensure some preservative effect during the progressive damage. We specifically developed and characterized a functionalized nanogel-based nanovector in vitro and in vivo, demonstrating its selectivity towards astrocytes, and limited uptake by macrophages when functionalized with both NH2 and Cy5 groups. In vitro experiments showed that the internalization was mediated by a clathrin-dependent endocytic pathway. After internalization into the cytoplasm of astrocytes, nanogels undergo lysosomal degradation and release compounds with potential therapeutic efficacy.

Influence of the Core Formulation on Features and Drug Delivery Ability of Carbamate-Based Nanogels.

In the last years, nanogels have emerged as one of the most promising classes of novel drug delivery vehicles since they can be employed in multiple fields, such as various therapeutics or diagnostics, and with different classes of compounds and active molecules. Their features, such as a high volume to surface ratio, excellent drug loading and release ability, as well as biocompatibility and tunable behavior, are unique, and, nowadays, great efforts are made to develop new formulations that can be employed in a wider range of applications. Polyethylene glycol (PEG)-polyethylenimine (PEI) nanogels probably represent the baseline of this class of biomaterials and they are still largely employed and studied. In any way, the possibility to exploit new core formulations for nanogels is certainly very interesting in order to understand the influence of different polymer chains on the final properties of the system. In this research, we explore and make a comparison between PEG-PEI nanogels and two other different formulations: pluronic F127-PEI nanogels and PEG-Jeffamine nanogels. We propose nanogels synthesis methods, their chemical and physical characterization, as well as their stability analysis, and we focus on the different drug delivery ability that these structures exhibit working with different typologies of drug mimetics.

Deep eutectic solvent as solvent and catalyst: one-pot synthesis of 1,3-dinitropropanes via tandem Henry reaction/Michael addition.

The Henry reaction was performed using microwave heating within the deep eutectic solvent (DES) choline chloride/urea (ChCl/urea) which acted as both the catalyst and solvent for the reaction. The optimisation of the conditions (temperature, heating mode, time, DES) allowed 1,3-dinitropropane derivatives to be obtained via tandem Henry reaction/Michael addition, in one step from a range of different aromatic aldehydes in high yields and under mild reaction conditions.

Ecdysteroid Derivatives that Reverse P-Glycoprotein-Mediated Drug Resistance.

The expression of multidrug resistance P-glycoprotein (P-gp) by cancer cells represents one of the major drawbacks to successful cancer therapy. Accordingly, the development of drugs that inhibit the activity of this transporter remains a major challenge in cancer drug discovery. In this context, several new ecdysteroid derivatives have been synthesized and evaluated as P-gp inhibitors. Two of them (compounds 9 and 14) were able to resensitize CEMVbl100 and LoVoDoxo resistant cell lines to vinblastine and doxorubicin, respectively. Indeed, both compounds 9 and 14 increased the cellular accumulation of rhodamine 123 in cells expressing P-gp and stimulated basal P-glycoprotein-ATPase activity at a 1 µM concentration, demonstrating their interference with the transport of other substrates in a competitive mode. Moreover, in a medulloblastoma cell line (DAOY), compounds 9 and 14 reduced the side population representing cancer stem cells, which are characterized by a high expression of ABC drug transporters. Further, in DAOY cells, the same two compounds synergized with cisplatin and vincristine, two drugs used commonly in the therapy of medulloblastoma. Molecular docking studies on the homology-modeled structure of the human P-glycoprotein provided a rationale for the biological results, validating the binding mode within the receptor site, in accordance with lipophilicity data and observed structure-activity relationship information. Altogether, the present results endorse these derivatives as promising P-gp inhibitors, and they may serve as candidates to reverse drug resistance in cancer cells.

Combined structural and theoretical investigation on differently substituted bispidine ligands: predicting the properties of their corresponding coordination polymers.

Pyridine-based bispidine ligands L1-L7, which differ in the substituent at the N7 position of the bispidine scaffold, have been studied by single crystal X-ray diffraction and density functional theory (DFT) calculations, also including solid-state algorithms. Qualitative description of the packing interactions and quantitative data on the stability of each ligand in the solid-state have been employed to draw reasonable predictions on the ligand potential for the formation of linear 1D coordination polymers (CPs) with Mn(ii)Cl2 and on their resulting dynamic properties, in terms of adsorption and solvent exchange capabilities. The basic assumption lies in the fact that volume and polarizability of the ligands would similarly affect packing energies in both molecular solids and CP materials. The results here obtained confirm the data previously reported on CPs (those made from L4 are less dynamic than the ones with L1), but they also allow the prediction that CPs made with L2 and L5 should be more dynamic than expected, while CPs with L6 and L7 should not form altogether. This latter prediction was derived from the analysis of the steric and electronic factors of the ligand substituents on the N7 position and it is further substantiated by the obtainment of a 2 : 1 molecular complex, and not a CP, by crystallization of L6 with MnCl2.

Structural properties of the chelating agent 2,6-bis(1-(3-hydroxypropyl)-1,2,3-triazol-4-yl)pyridine: a combined XRD and DFT structural study.

The conformational isomerism of the chelating agent 2,6-bis(1-(3-hydroxypropyl)-1,2,3-triazol-4-yl)pyridine (PTD), exploited in fuel reprocessing in spent nuclear waste, has been studied by single crystal X-ray diffraction analysis in combination with an extensive DFT conformational investigation. In the solid-state, the elucidated crystal structure (i.e., not yet published) shows that by thermal treatment (DSC) no other phases are observed upon crystallization from the melt, indicating that the conformation observed by X-ray data is rather stable. Mapping of intermolecular and intramolecular noncovalent interactions has been used to elucidate the unusual arrangement of the asymmetric unit. Considerations relating to the stability of different conformational isomers in aqueous and non-aqueous solutions are also presented. The accurate structural description reported here might open various research topics such as the potential of PTD to act as an outer sphere ligand in the formation of second sphere coordination complexes and their interconversion by mechanochemical means.

Selective Modulation of A1 Astrocytes by Drug-Loaded Nano-Structured Gel in Spinal Cord Injury.

Astrogliosis has a very dynamic response during the progression of spinal cord injury, with beneficial or detrimental effects on recovery. It is therefore important to develop strategies to target activated astrocytes and their harmful molecular mechanisms so as to promote a protective environment to counteract the progression of the secondary injury. The challenge is to formulate an effective therapy with maximum protective effects, but reduced side effects. In this study, a functionalized nanogel-based nanovector was selectively internalized in activated mouse or human astrocytes. Rolipram, an anti-inflammatory drug, when administered by these nanovectors limited the inflammatory response in A1 astrocytes, reducing iNOS and Lcn2, which in turn reverses the toxic effect of proinflammatory astrocytes on motor neurons in vitro, showing advantages over conventionally administered anti-inflammatory therapy. When tested acutely in a spinal cord injury mouse model, it improved motor performance, but only in the early stage after injury, reducing the astrocytosis and preserving neuronal cells.

Effects of primary amine-based coatings on microglia internalization of nanogels.

Nanogels represent a pivotal class of biomaterials in the therapeutic intracellular treatment of many diseases, especially those involving the central nervous system (CNS). Their biocompatibility and synergy with the biological environment encourage their cellular uptake, releasing the curative cargo in the desired area. As a main drawback, microglia are generally able to phagocytize any foreign element overcoming the blood brain barrier (BBB), including these materials, drastically limiting their bioavailability for the target cells. In this work, we investigated the opportunity to tune and therefore reduce nanogel internalization in microglia cultures, exploiting the orthogonal chemical functionalization with primary amine groups, as a surface coating strategy. Nanogels are designed by following two methods: the direct grafting of aliphatic primary amines and the linkage of -NH2 modified PEG on the nanogel surface. The latter synthesis was proposed to evaluate the combination of PEGylation with the basic nitrogen atom. The achieved results indicate the possibility of effectively modulating the uptake of nanogels, in particular limiting their internalization using the PEG-NH2 coating. This outcome could be considered a promising strategy for the development of carriers for drugs or gene delivery that could overcome microglia scavenging.