Sulfonamide as amide isostere for fine-tuning the gelation properties of physical gels.

(S)-2-Stearamidopentanedioic acid (C18-Glu) is a known LMW gelator that forms supramolecular gels in a variety of solvents. In this work, we have carried out the isosteric substitution of the amide group by a sulfonamide moiety yielding the new isosteric gelator (S)-2-(octadecylsulfonamido)pentanedioic acid (Sulfo-Glu). The gelation ability and the key properties of the corresponding gels were compared in terms of gelation concentration, gel-to-sol transition temperature, mechanical properties, morphology, and gelation kinetics in several organic solvents and water. This comparison was also extended to (S)-2-(4-hexadecyl-1H-1,2,3-triazol-4-yl)pentanedioic acid (Click-Glu), which also constitutes an isostere of C18-Glu. The stabilizing interactions were explored through computational calculations. In general, Sulfo-Glu enabled the formation of non-toxic gels at lower concentrations, faster, and with higher thermal-mechanical stabilities than those obtained with the other isosteres in most solvents. Furthermore, the amide-sulfonamide isosteric substitution also influenced the morphology of the gel networks as well as the release rate of an embedded antibiotic (vancomycin) leading to antibacterial activity in vitro against Staphylococcus aureus.

Release of small bioactive molecules from physical gels.

Pharmaceutical drugs with low water solubility have always received great attention within the scientific community. The reduced bioavailability and the need of frequent administrations have motivated the investigation of new drug delivery systems. Within this context, drug carriers that release their payload in a sustained way and hence reduce the administration rate are highly demanded. One interesting strategy to meet these requirements is the entrapment of the drugs into gels. So far, the most investigated materials for such drug-loaded gels are derived from polymers and based on covalent linkages. However, over the last decade the use of physical (or supramolecular) gels derived from low molecular weight compounds has experienced strong growth in this field, mainly due to important properties such as injectability, stimuli responsiveness and ease of synthesis. This review summarizes the use of supramolecular gels for the encapsulation and controlled release of small therapeutic molecules.

Ultrasonication-enhanced gelation properties of a versatile amphiphilic formamidine-based gelator exhibiting both organogelation and hydrogelation abilities.

We describe the preparation of a novel amphiphilic gelator built from a formamidine core, which is able to form a variety of physical organogels and hydrogels at concentrations ranging from 15 to 150 mg mL-1. Interestingly, ultrasound treatment of isotropic solutions (i.e., gel-precursor) resulted in a remarkable enhancement of the gelation kinetics as well as the gelation scope and characteristic gel properties (e.g., critical gelation concentration, gel-to-sol transition temperature, viscoelastic moduli) in comparison to the heating-cooling protocol typically used to obtain supramolecular gels. Thermoreversibility, thixotropy, injectability and multistimuli responsiveness are some of the most relevant functionalities of these gels. Electron microscopy imaging revealed the formation of entangled networks made of fibers of nanometer diameters and micrometer lengths, with different morphological features depending on the solvent. Insights into the driving forces for molecular aggregations were obtained from FTIR, NMR, PXRD and computational studies. The results suggest a major stabilization of the fibers through additive N-HO hydrogen bonds, in combination with hydrophobic interactions, over π-π stacking interactions.

Transfection of Antisense Oligonucleotides Mediated by Cationic Vesicles Based on Non-Ionic Surfactant and Polycations Bearing Quaternary Ammonium Moieties.

Three different ionene polymers with varying quaternary ammonium moieties were used as a proof of concept for the formulation of antisense oligonucleotides, which are capable of inhibiting Renilla luciferase messenger ribonucleic acid (mRNA). Cationic vesicles, consisting of cationic polymer, antisense oligonucleotide (Luc) and non-ionic surfactant polysorbate 80, were investigated regarding their ζ potential, cytotoxicity and transfection efficiency. Deoxyribonucleic acid- (DNA) forming complexes in the presence of cationic vesicles were also investigated in terms of small-angle X-ray scattering (SAXS). The studied cationic vesicles showed very little, if any, toxicity against HeLa cells. Transfection abilities proved to vary strongly depending on the present quaternary ammonium moiety.

Aromatic ionene topology and counterion-tuned gelation of acidic aqueous solutions.

Unusual gelation of acidic solutions was achieved using polycations bearing quaternary ammonium moieties. These ionene polymers are based on a disubstituted phenylene dibenzamide core, which allows the construction of different topomers (i.e. ortho-1, meta-2 and para-3). The topology of the polymers was found to play a key role on their aggregation behaviour both in pure water and in a variety of aqueous acidic solutions leading to the formation of stable acidic gels. Specifically, ortho-1 showed superior gelation ability than the analogues meta-2 and para-3 in numerous solutions of different pH and ionic strengths. Lower critical gelation concentrations, higher gel-to-sol transition temperatures and faster gelation were usually observed for ortho-1 regardless the solvent system. Detailed computational molecular dynamic simulations revealed a major role of the counterion (Cl-) and specific polymerpolymer interactions. In particular, hydrogen bonds, N-Hπ interactions and intramolecular π-π stacking networks are distinctive in ortho-1. In addition, counterions located at internal hydration regions also affect to such polymerpolymer interactions, acting as binders and, therefore, providing additional stability.

Antimicrobial and Hemolytic Studies of a Series of Polycations Bearing Quaternary Ammonium Moieties: Structural and Topological Effects.

A series of polycations bearing quaternary ammonium moieties have shown antimicrobial activity against the Gram-negative bacterium Escherichia coli. Different polymer topologies governed by a disubstituted aromatic core as well as different diamine-based linkers were found to influence the antimicrobial properties. Moreover, the hemolytic activity against human red blood cells was measured and demonstrated good biocompatibility and selectivity of these polycations for bacteria over mammalian cells.

Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2R Affinity and Selectivity.

In search for selective ligands for the muscarinic acetylcholine receptor (MR) subtype M2, the dimeric ligand approach, that is combining two pharmacophores in one and the same molecule, was pursued. Different types (agonists, antagonists, orthosteric, and allosteric) of monomeric MR ligands were combined by various linkers with a dibenzodiazepinone-type MR antagonist, affording five types of heterodimeric compounds ("DIBA-xanomeline," "DIBA-TBPB," "DIBA-77-LH-28-1," "DIBA-propantheline," and "DIBA-4-DAMP"), which showed high M2R affinities (pKi > 8.3). The heterodimeric ligand UR-SK75 (46) exhibited the highest M2R affinity and selectivity [pKi (M1R-M5R): 8.84, 10.14, 7.88, 8.59, and 7.47]. Two tritium-labeled dimeric derivatives ("DIBA-xanomeline"-type: [3H]UR-SK71 ([3H]44) and "DIBA-TBPB"-type: [3H]UR-SK59 ([3H]64)) were prepared to investigate their binding modes at hM2R. Saturation-binding experiments showed that these compounds address the orthosteric binding site of the M2R. The investigation of the effect of various allosteric MR modulators [gallamine (13), W84 (14), and LY2119620 (15)] on the equilibrium (13-15) or saturation (14) binding of [3H]64 suggested a competitive mechanism between [3H]64 and the investigated allosteric ligands, and consequently a dualsteric binding mode of 64 at the M2R.

Cationic nioplexes-in-polysaccharide-based hydrogels as versatile biodegradable hybrid materials to deliver nucleic acids.

Two polysaccharide-based hydrogels made of only κ-carrageenan (4%; w/v) or of a mixture of methylcellulose:κ-carrageenan (2%; w/v) were used to encapsulate cationic nioplexes. These vesicular particles were made of a synthetic aminolipid and polysorbate-80 (Tween-80), as a non-ionic surfactant agent. According to oscillatory rheological measurements, the presence of nioplexes did not compromise the mechanical integrity of the gels. In vitro niosomal release experiments demonstrated the liberation of nioplexes up to 24 h, and the curves were fitted according to Higuchi, Korsmeyer-Peppas and Weibull equation models, which indicated Fickian-diffusion controlled mechanisms. Besides nioplexes, cervical cancer cells were also entrapped within the biohydrogels. Cell release confirmed that these materials did not affect the cell viability, allowing cells to spread and proliferate after 24 h. The applicability of these biocompatible hydrogels was also extended to gene delivery. In this regard, the best silencing activities were found when cationic niosomes were complexed with antisense oligonucleotides in KC hydrogels. Nioplexes were able to release through the hydrogel and promoted silencing of luciferase expression in the presence of serum without using commercially available cationic lipids. Overall, the formation of such hybrid materials by integrating cationic nioplexes within biodegradable hydrogels provides a new perspective for the delivery of macromolecular therapeutics.

Spectroscopic Characterization of Azo Dyes Aggregation Induced by DABCO-Based Ionene Polymers and Dye Removal Efficiency as a Function of Ionene Structure.

The aggregation mode of three azo dyes, methyl orange (MO), ponceau SS (PSS), and direct blue 1 (DB1) induced by three 1,4-diazabicyclo[2.2.2]octane (DABCO)-based ionene polymers having different topologies (i.e., 1,2-ionene, 1,3-ionene, and 1,4-ionene) was investigated in this work. Metachromatic behavior of the dyes in the presence of ionenes, and the stability of the ionene/dye complex were discussed as a function of ionene structure. It was demonstrated that the association of the dye molecules with the ionenes and the metachromasy were strongly influenced by both the dye structure and the ionene topology. Thus, MO, having one -SO3Na group per molecule, was almost stoichiometrically bound to all ionenes regardless of their topology, showing also a metachromatic effect. In sharp contrast, the interaction of PSS and DB1 molecules with ionenes was strongly dependent on the polymer topology. It was found that PSS having two -SO3Na groups per molecule was preferentially bound onto both 1,2-ionene and 1,3-ionene, but DB1, having four -SO3Na groups per molecule and a more complex structure, was efficiently bound only onto 1,2-ionene. The dye removal efficiency with each ionene was evaluated in batch mode taking into account the affinity of ionenes for azo dyes. The experimental isotherms of the dye sorption were fitted with four isotherm models, i.e., Langmuir, Freundlich, Sips, and Dubinin-Radushkevich. It was found that the best fitting of the experimental data was given by the Langmuir, Sips, and Dubinin-Radushkevich isotherm models. The maximum equilibrium sorption capacity, qm, evaluated by the Langmuir model, at 35 °C, was as follows: 985.71 mg MO/g 1,3-ionene, 483.71 mg PSS/g 1,3-ionene, 1010.49 mg PSS/g 1,2-ionene, and 976.7 mg DB1/g 1,2-ionene. Kinetic study of the dye removal indicated chemisorption as the main mechanism of sorption.

Biodegradable liposome-encapsulated hydrogels for biomedical applications: a marriage of convenience.

Hydrogels are hydrophilic three-dimensional networks with demonstrated potential for medical and pharmaceutical applications. Specifically, biopolymer-based hydrogels offer certain advantages over synthetic polymers in terms of biocompatibility and biodegradability. Because of their inherent properties, hydrogels are able to efficiently encapsulate and liberate in a controlled release manner, different hydrophobic and hydrophilic therapeutic molecules, including nucleic acids, proteins and antibodies. Several strategies have been reported in the literature to minimize the potential burst release of encapsulated drugs, thus preventing their local accumulation and consequent toxic responses. Within this context, liposomes embedded in hydrogels have emerged as an attractive strategy to reduce this undesirable effect. This tutorial review covers a selection of the most promising cationic, neutral and anionic biopolymer-based hydrogels containing liposomes, niosomes or vesicles for drug delivery or tissue engineering applications.

Supramolecular phase-selective gelation by peptides bearing side-chain azobenzenes: effect of ultrasound and potential for dye removal and oil spill remediation.

Phase selective gelation (PSG) of organic phases from their non-miscible mixtures with water was achieved using tetrapeptides bearing a side-chain azobenzene moiety. The presence of the chromophore allowed PSG at the same concentration as the minimum gelation concentration (MGC) necessary to obtain the gels in pure organic phases. Remarkably, the presence of the water phase during PSG did not impact the thermal, mechanical, and morphological properties of the corresponding organogels. In the case of miscible oil/water mixtures, the entire mixture was gelled, resulting in the formation of quasi-hydrogels. Importantly, PSG could be triggered at room temperature by ultrasound treatment of the mixture or by adding ultrasound-aided concentrated solution of the peptide in an oil-phase to a mixture of the same oil and water. Moreover, the PSG was not affected by the presence of salts or impurities existing in water from natural sources. The process could be scaled-up, and the oil phases (e.g., aromatic solvents, gasoline, diesel fuel) recovered almost quantitatively after a simple distillation process, which also allowed the recovery and reuse of the gelator. Finally, these peptidic gelators could be used to quantitatively remove toxic dyes from aqueous solutions.

Non-invasive and continuous monitoring of the sol-gel phase transition of supramolecular gels using a fast (open-ended coaxial) microwave sensor.

An open coaxial re-entrant microwave sensor has been used for the non-invasive and continuous monitoring of the sol-gel transition of physical gels characterized by different gelation mechanisms, solvents, compositions, and stabilities. Comparison of measurements by differential scanning calorimetry allowed the identification of the phase transition by a change in the dielectric properties of the material over time.

Magnetic Gel Composites for Hyperthermia Cancer Therapy.

Hyperthermia therapy is a medical treatment based on the exposition of body tissue to slightly higher temperatures than physiological (i.e., between 41 and 46 °C) to damage and kill cancer cells or to make them more susceptible to the effects of radiation and anti-cancer drugs. Among several methods suitable for heating tumor areas, magnetic hyperthermia involves the introduction of magnetic micro/nanoparticles into the tumor tissue, followed by the application of an external magnetic field at fixed frequency and amplitude. A very interesting approach for magnetic hyperthermia is the use of biocompatible thermo-responsive magnetic gels made by the incorporation of the magnetic particles into cross-linked polymer gels. Mainly because of the hysteresis loss from the magnetic particles subjected to a magnetic field, the temperature of the system goes up and, once the temperature crosses the lower critical solution temperature, thermo-responsive gels undergo large volume changes and may deliver anti-cancer drug molecules that have been previously entrapped in their networks. This tutorial review describes the main properties and formulations of magnetic gel composites conceived for magnetic hyperthermia therapy.

Amide-triazole isosteric substitution for tuning self-assembly and incorporating new functions into soft supramolecular materials.

The proof-of-concept for the modular synthesis of new functional soft gel materials based on amide-triazole isosteric replacement has been demonstrated. A coassembly approach of isosteric amino acid-based hydrogelators was fruitfully applied for fine-tuning the release of entrapped drugs.