Glucose-Triggered Gelation of Supramolecular Peptide Nanocoils with Glucose-Binding Motifs.

Peptide self-assembly is a powerful tool to prepare functional materials at the nanoscale. Often, the resulting materials have high aspect-ratio, with intermolecular ß-sheet formation underlying 1D fibrillar structures. Inspired by dynamic structures in nature, peptide self-assembly is increasingly moving toward stimuli-responsive designs wherein assembled structures are formed, altered, or dissipated in response to a specific cue. Here, a peptide bearing a prosthetic glucose-binding phenylboronic acid (PBA) is demonstrated to self-assemble into an uncommon nanocoil morphology. These nanocoils arise from antiparallel ß-sheets, with molecules aligned parallel to the long axis of the coil. The binding of glucose to the PBA motif stabilizes and elongates the nanocoil, driving entanglement and gelation at physiological glucose levels. The glucose-dependent gelation of these materials is then explored for the encapsulation and release of a therapeutic agent, glucagon, that corrects low blood glucose levels. Accordingly, the release of glucagon from the nanocoil hydrogels is inversely related to glucose level. When evaluated in a mouse model of severe acute hypoglycemia, glucagon delivered from glucose-stabilized nanocoil hydrogels demonstrates increased protection compared to delivery of the agent alone or within a control nanocoil hydrogel that is not stabilized by glucose.

Designing a vehicle-free anti-bacterial topical hydrogel from Fmoc-diphenylalanine.

A supramolecular synthon-based salt formation strategy has been employed to afford an anti-bacterial topical hydrogel from Fmoc-diphenylalanine (FmocFF). The nontrivial steps (pH/solvent switch along with heat-cool protocol) required for making the hydrogel from FmocFF were successfully avoided following this strategy.

Phenylalanine conjugated supramolecular hydrogels developed from the mafenide and flurbiprofen multidrug for biological applications.

A well-known nonsteroidal anti-inflammatory drug (NSAID), flurbiprofen (FLR), was first conjugated individually with two naturally occurring amino acids such as L-phenylalanine (PHE) and L-alanine (ALA). These covalent amidic bioconjugates were further reacted individually with mafenide (a drug for treating burn wounds) and amantadine (an antiviral drug) to develop primary ammonium monocarboxylate (PAM) salts. Interestingly, both the PHE-containing multidrug salts exhibited significant gelation ability with various solvents including biologically potent water or methyl salicylate (MS). The isolated hydrogel (HG) as well as all the organogels obtained from multidrug gelators were extensively characterized by dynamic rheology and rheoreversibility studies. The hydrogel of FLR·PHE·MAF and MS gels of FLR·PHE·AMN/FLR·AMN were also selectively characterized by table-top and FEG-TEM analyses. The temperature-dependent 1H-NMR spectroscopy of the selected HG further provided insights into the gelation mechanism and the only isolated single-crystal of the weakly diffracted gelator FLR·AMN also revealed the presence of 1D hydrogen-bonded networks. The pure hydrogelator FLR·PHE·MAF salt (which is also an ambidextrous gelator) was found to be promising in both mechanical (rheoreversible) and biological applications and was found to be effective in cytotoxicity, biocompatibility, anti-cancer activity (MTT and cell migration assay), antibacterial response (zone inhibition, turbidity, INT, and resazurin assay) and haemolysis studies.

Supramolecular Gels from Bis-amides of L-Phenylalanine: Synthesis, Structure and Material Applications.

A series of small organic molecules having a bis-amide backbone containing hydrogen-bond functionalities were rationally designed, synthesized and characterized to examine their ability to act as potential low-molecular-weight gelators (LMWGs). All the bis-amides were decorated with identical 3-pyridyl amide of L-phenylalanine moieties along with variously substituted terminal benzoyl groups. Gelation studies revealed that only 4-methylphenyl substituted bis-amide (PME) was capable of gelling both aqueous (DMSO/water) and methyl salicylate (MS) (an important solvent for topical formulation for medical applications) solvents; whereas 4-chlorophenyl and 4-bromophenyl substituted bis-amides (PCL, PBR, respectively) acted as organogelator for various organic solvents. On the contrary, 4-nitrophenyl as well as 3,5-dinitrophenyl substituted bis-amides (PNI, DNI, respectively) were unable to gel any solvents studied herein. The corresponding aqueous gel namely PME-HG and three methyl salicylate gels PME-MS, PCL-MS and PBR-MS were characterized by dynamic and table top rheology followed by electron microscopy. Single crystal X-ray diffraction (SXRD) data revealed crucial insights into the supramolecular assembly of all the gelator and nongelator bis-amides. Both PME-HG and PME-MS were rheoreversible - an important property in material applications. Interestingly, PME-MS displayed remarkable material properties such as shape-sustaining, loadbearing and self-healing. Selected MS and aqueous gels loaded with nano-molar iodine were found to possess anti-bacterial property as revealed by zone inhibition assay.

Supramolecular Hydrogels Developed from Mafenide and Indomethacin as a Plausible Multidrug Self-Delivery System as Antibacterial and Anti-inflammatory Topical Gels.

Following a structural rationale, a series of simple organic salts derived from mafenide (a drug for treating burn wounds) and n-alkyl carboxylic acids (Me-(CH2)n-COOH; n = 1-3, 10-15) and various nonsteroidal anti-inflammatory drugs (NSAIDs), namely, indomethacin (IND), diclofenac (DIC), meclofenamic acid (MEC), tolfenamic acid (TOL), and flufenamic acid (FLU) (designated as salts 1-14, respectively) were synthesized as potential hydrogelators. Gelation studies revealed that mafenide n-alkyl carboxylates with n = 11-14, i.e., salts 5-8, and the indomethacin salt of mafenide, i.e., salt 10, were hydrogelators. The corresponding hydrogels, namely, 5(HG)-8(HG) and 10(HG), were characterized by table-top and dynamic rheology and high-resolution transmission electron microscopy (HR-TEM). Single-crystal structures of the nongelator salts 1-3 and the gelator salt 10 were determined by X-ray diffraction. The results obtained from various studies, which included the solubility, biostability, biocompatibility (MTT assay), and anti-inflammatory (PGE2 assay) response of salt 10, the antibacterial response (zone inhibition assay) of salt 10, its components, and 10(HG), and the release of salt 10in vitro from the corresponding hydrogel bed to the bulk solvent at 37 °C in 24 h, suggested their plausible use in developing multidrug-derived topical hydrogels for self-delivery applications.

Supramolecular Gels Derived from the Salts of Variously Substituted Phenylacetic Acid and Dicyclohexylamine: Design, Synthesis, Structures, and Dye Adsorption.

A well-studied supramolecular synthon, namely, secondary ammonium monocarboxylate (SAM), was exploited to generate a new series of organic salts derived from variously substituted phenylacetic acid and dicyclohexylamine as potential low-molecular-weight gelators. As much as 25 % of the SAM salts under study were gelators. The gels were characterized by rheology, and the morphology of the gel networks was studied by high-resolution electron microscopy. Single-crystal and powder XRD data were employed to study structure-property (gelation) correlations. One of the gels could adsorb a hydrophobic dye (Nile Red) more efficiently than that of a hydrophilic dye (Calcein) from dimethyl sulfoxide; this might provide useful clues towards the development of stain-removing gels.

Supramolecular Synthon Approach in Developing Anti-Inflammatory Topical Gels for In†Vivo Self-Delivery.

A new series of tertiary-butyl ammonium (TBA) salts of various nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized and characterized. Nearly 90 % of the NSAID-derived primary ammonium monocarboxylate (PAM) salts displayed remarkable gelation ability with various solvents including methyl salicylate. Single crystal X-ray diffraction data (SXRD) revealed the existence of 1D PAM synthon in the gelator salts. Structure-property correlation studies based on SXRD and powder X-ray diffraction (PXRD) data established the presence of the 1D PAM synthon in the bulk salts as well as in the corresponding xerogels. A parallel series of salts derived from TRIS (2-amino-2-(hydroxymethyl)-1,3-propanediol) and the same set of NSAIDs displayed poor gelation ability; only 33 % of the salts in the series displayed gelation ability. A few selected gelator salts of both TBA and TRIS were found to be biocompatible (MTT assay with RAW 264.7 cell line) and two of the selected salts (FLR.TBA and FLR.TRIS) possessed anti-inflammatory properties equal to the parent drug FLR (flurbiprofen). Finally a methyl salicylate topical gel derived from FLR.TRIS was successfully delivered in a self-delivery fashion to treat inflamed skin conditions in the mice model. Histological studies of the dorsal tissues of the untreated and treated mice clearly demonstrated the effect of topical gels in such treatment.

Salt metathesis for developing injectable supramolecular metallohydrogelators as a multi-drug-self-delivery system.

Salt metathesis has been exploited to generate a series of non-steroidal anti-inflammatory drug (NSAID) based Zn(ii) metallohydrogels displaying both anti-inflammatory and anti-bacterial properties. Relatively low cytotoxicity, rheoreversibility and injectibility of one of these hydrogels make it suitable for multi-drug-self-delivery application.

Multidrug-Containing, Salt-Based, Injectable Supramolecular Gels for Self-Delivery, Cell Imaging and Other Materials Applications.

Both molecular and crystal-engineering approaches were exploited to synthesize a new class of multidrug-containing supramolecular gelators. A well-known nonsteroidal anti-inflammatory drug, namely, indomethacin, was conjugated with six different l-amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table-top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature-dependent 1 H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single-crystal X-ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen-bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self-delivery) applications for future multidrug-containing injectable delivery vehicles.

Exploiting supramolecular synthons in designing gelators derived from multiple drugs.

A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well-studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications.

Peptide conjugates of a nonsteroidal anti-inflammatory drug as supramolecular gelators: synthesis, characterization, and biological studies.

Indomethacin (IND), which is a well-known nonsteroidal anti-inflammatory drug (NSAID), was conjugated with various naturally occurring amino acids. Most of these bioconjugates were capable of gelling pure water, a solution of NaCl (0.9 wt%), and phosphate-buffered saline (pH 7.4), as well as a few organic solvents. The gels were characterized by table-top and dynamic rheology, and electron microscopy. Variable-temperature (1)H NMR spectroscopy studies on a selected gel were performed to gain insights into the self-assembly process during gel formation. Both 1D and 2D hydrogen-bonded networks were observed in the single-crystal structures of two of the gelators. Plausible biological applications of the hydrogelators were evaluated with the ultimate aim of drug delivery in a self-delivery fashion. All hydrogelators were stable in phosphate-buffered saline at pH 7.4 at 37 °C, and biocompatible in mouse macrophage RAW 264.7 cell line (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Two of the most biocompatible hydrogelators displayed an anti-inflammatory response comparable to that of the parent drug IND in prostaglandin E2 assay. Release of the bioconjugates into the bulk solvent interfaced with the corresponding hydrogels indicated their plausible future application in drug delivery.

A direct synthesis of selenophenes by Cu-catalyzed one-pot addition of a selenium moiety to (E,E)-1,3-dienyl bromides and subsequent nucleophilic cyclization.

An efficient protocol for the synthesis of selenophenes and selanyl selenophenes has been achieved by a simple one-pot reaction of 1,3-dienyl bromides and 1,3-dienyl-gem-dibromides respectively with KSeCN catalyzed by CuO nanoparticles. Several aryl, alkenyl, heteroaryl, and alkyl substituted selenophenes were obtained with a broad array of functional group tolerance. This is found to be a general methodology for chalcogenophenes being effective for the synthesis of thiophenes too.