Multifunctional magneto-plasmonic lipogel based on peptide hydrogel for application in combined cancer therapy.

Supramolecular hydrogels, particularly low-molecular-weight peptide hydrogels, are promising drug delivery systems due to their ability to change the solubility, targeting, metabolism and toxicity of drugs. Magneto-plasmonic liposomes, in addition to being remotely controllable with the application of an external magnetic field, also increase the efficiency of encapsulated drug release through thermal stimulation, for example, with magnetic and optical hyperthermia. Thus, the combination of those two materials-giving magneto-plasmonic lipogels-brings together several functionalities, among which are hyperthermia and spatiotemporally controlled drug delivery. In this work, a novel dehydrodipeptide hydrogelator was synthesised, and the respective hydrogel was functionalized with magneto-plasmonic liposomes. After individually characterising the components with regard to their rheological, spectroscopic and magnetic properties, the magneto-plasmonic lipogel was equally characterised and evaluated concerning its ability to deliver drugs in a controlled fashion. To this end, the response of the 5(6)-carboxyfluorescein-loaded magneto-plasmonic lipogel to near-infrared light was assessed. The results showed that the system is a proper carrier of hydrophilic drugs and allows to envisage photo-responsive drug delivery. These facts, together with the magnetic guidance and hyperthermia capabilities of the developed composite gel, may pave the way to a new era in the treatment of cancer and other diseases.

Can Biomass Mastication Assist the Downstreaming of Polyhydroxyalkanoates Produced from Mixed Microbial Cultures?

Polyhydroxyalkanoates (PHAs) are natural polyesters which biodegrade in soils and oceans but have more than double the cost of comparable oil-based polymers. PHA downstreaming from its biomass represents 50% of its overall cost. Here, in an attempt to assist downstreaming, mastication of wet biomasses is tested as a new mechanical continuous biomass pretreatment with potential for industrial upscaling. Downstreaming conditions where both product recovery and purity are low due to the large amount of treated wet biomass (50% water) were targeted with the following process: extraction of 20 g in 100 mL solvent at 30 °C for 2 h, followed by 4.8 h digestion of 20 g in 0.3 M NaOH. Under the studied conditions, NaOH digestion was more effective than solvent extraction in recovering larger PHA amounts, but with less purity. A nearly 50% loss of PHA was seen during digestion after mastication. PHAs downstreamed by digestion with large amounts of impurities started to degrade at lower temperatures, but their melt elasticity was thermally stable at 170 °C. As such, these materials are attractive as fully PHA-compatible processing aids, reinforcing fillers or viscosity modifiers. On the other hand, wet biomass mastication before solvent extraction improves PHA purity and thermal stability as well as the melt rheology, which recovers the viscoelasticity measured with a PHA extracted from a dried biomass.

An injectable, naproxen-conjugated, supramolecular hydrogel with ultra-low critical gelation concentration-prepared from a known folate receptor ligand.

Short peptides capped on the N-terminus with aromatic groups are often able to form supramolecular hydrogels-self-assembled networks of fibrils able to trap water molecules. Typically, these hydrogelators can form stiff gels at concentrations of 0.1 to 1.0 wt%-i.e. they consist of mainly water. The properties of these soft materials mimic those of the extracellular matrix (ECM) of biological tissue and therefore they have found many biomedical uses in tissue engineering, wound healing, drug delivery, biosensing and bioprinting applications. In drug delivery strategies related to cancer therapy, injectable hydrogels can serve as a depot formulation, where a sustained release of the chemotherapeutic from near the tumour site allows reduced doses and, therefore, decreased side effects. To further target cancer cells, folic acid-conjugated hydrogels and nanostructures are often sought, to exploit the overexpression of folate receptors on cancer cells-an approach which can allow the selective cellular uptake of an encapsulated drug. In this present study, two known dipeptide folate receptor ligands (1 and 2) recently identified from a screen of a DNA-encoded compound library, were synthesised and investigated for their hydrogelation ability and cytotoxicity. Compound 1, containing a naproxen capping group, rapidly forms hydrogels at concentrations as low as 0.03 wt%-one of the lowest critical gelation concentrations (CGCs) known for a supramolecular hydrogelator. In contrast, compound 2, which contains a 3-indolepropionic acid capping group, was unable to form hydrogels under a range of conditions and concentrations, instead forming nanospheres with diameters of 0.5 µm. Hydrogels of 1 were characterised by STEM microscopy, rheology, fluorescence spectroscopy and circular dichroism. Both compounds 1 and 2 had no impact on the proliferation of kerotinocytes (HaCaT cells) at concentrations up to 100 µM. Compound 1, containing the NSAID, was tested for anti-inflammatory activity in a human cyclooxygenase-1/2 model. The rate of the release of model drug compounds from within hydrogels of 1 was also investigated.

Plasmonic lipogels: driving co-assembly of composites with peptide-based gels for controlled drug release.

Supramolecular short peptide-based gels are promising materials for the controlled release of drugs (e.g. chemotherapeutic drugs) owing to the biocompatibility and similarity to cell matrix. However, the drug encapsulation and control over its release, mainly the hydrophilic drugs, can be a cumbersome task. This can be overcome through encapsulation/compartmentalization of drugs in liposomes, which can also enable spatiotemporal control and enhanced drug release through a trigger, such as photothermia. Having this in mind, we explored the assembly of silica-coated gold nanoparticles and liposomes (storage units) with dehydropeptide-based hydrogels as a proof-of-concept to afford peptide-based NIR light-responsive lipogels. Several liposomes compositions were assessed that displayed influence on the final assembly properties by combining with silica-coated gold nanorods (∼106 nm). Gold nanospheres (∼11 nm) were used to study the preparation method, which revealed the importance of initially combine liposomes with nanoparticles and then the gelator solution to achieve a closer proximity of the nanoparticles to the liposomes. The control over a hydrophilic model drug, 5(6)-carboxyfluorescein, was only achieved by its encapsulation in liposomes, in which the presence of silica-coated nanorods further enabled the use of photothermia to induce the liposomes phase transition and stimulate the drug release. Further, both composites, the liposomes and silica-coated gold nanorods, induced a lower elastic modulus, but also provided an enhanced gelation kinetics. Hereby, this work advances fabrication strategies for the development of short peptide-based hydrogels towards on-demand, sustained and controlled release of hydrophilic drugs through photothermia under NIR light irradiation.

Aryl-Capped Lysine-Dehydroamino Acid Dipeptide Supergelators as Potential Drug Release Systems.

Employing amino acids and peptides as molecular building blocks provides unique opportunities for generating supramolecular hydrogels, owing to their inherent biological origin, bioactivity, biocompatibility, and biodegradability. However, they can suffer from proteolytic degradation. Short peptides (<8 amino acids) attached to an aromatic capping group are particularly attractive alternatives for minimalistic low molecular weight hydrogelators. Peptides with low critical gelation concentrations (CGCs) are especially desirable, as the low weight percentage required for gelation makes them more cost-effective and reduces toxicity. In this work, three dehydrodipeptides were studied for their self-assembly properties. The results showed that all three dehydrodipeptides can form self-standing hydrogels with very low critical gelation concentrations (0.05−0.20 wt%) using a pH trigger. Hydrogels of all three dehydrodipeptides were characterised by scanning tunnelling emission microscopy (STEM), rheology, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy. Molecular modelling was performed to probe the structural patterns and interactions. The cytotoxicity of the new compounds was tested using human keratinocytes (HaCaT cell line). In general, the results suggest that all three compounds are non-cytotoxic, although one of the peptides shows a small impact on cell viability. In sustained release assays, the effect of the charge of the model drug compounds on the rate of cargo release from the hydrogel network was evaluated. The hydrogels provide a sustained release of methyl orange (anionic) and ciprofloxacin (neutral), while methylene blue (cationic) was retained by the network.

Nonlinear Behavior of Gelatin Networks Reveals a Hierarchical Structure.

We investigate the strain hardening behavior of various gelatin networks-namely physical gelatin gel, chemically cross-linked gelatin gel, and a hybrid gel made of a combination of the former two-under large shear deformations using the pre-stress, strain ramp, and large amplitude oscillations shear protocols. Further, the internal structures of physical gelatin gels and chemically cross-linked gelatin gels were characterized by small angle neutron scattering (SANS) to enable their internal structures to be correlated with their nonlinear rheology. The Kratky plots of SANS data demonstrate the presence of small cross-linked aggregates within the chemically cross-linked network whereas, in the physical gelatin gels, a relatively homogeneous structure is observed. Through model fitting to the scattering data, we were able to obtain structural parameters, such as the correlation length (ξ), the cross-sectional polymer chain radius (R(c)) and the fractal dimension (d(f)) of the gel networks. The fractal dimension d(f) obtained from the SANS data of the physical and chemically cross-linked gels is 1.31 and 1.53, respectively. These values are in excellent agreement with the ones obtained from a generalized nonlinear elastic theory that has been used to fit the stress-strain curves. The chemical cross-linking that generates coils and aggregates hinders the free stretching of the triple helix bundles in the physical gels.

Dehydrodipeptide Hydrogelators Containing Naproxen N-Capped Tryptophan: Self-Assembly, Hydrogel Characterization, and Evaluation as Potential Drug Nanocarriers.

In this work, we introduce dipeptides containing tryptophan N-capped with the nonsteroidal anti-inflammatory drug naproxen and C-terminal dehydroamino acids, dehydrophenylalanine (ΔPhe), dehydroaminobutyric acid (ΔAbu), and dehydroalanine (ΔAla) as efficacious protease resistant hydrogelators. Optimized conditions for gel formation are reported. Transmission electron microscopy experiments revealed that the hydrogels consist of networks of micro/nanosized fibers formed by peptide self-assembly. Fluorescence and circular dichroism spectroscopy indicate that the self-assembly process is driven by stacking interactions of the aromatic groups. The naphthalene groups of the naproxen moieties are highly organized in the fibers through chiral stacking. Rheological experiments demonstrated that the most hydrophobic peptide (containing C-terminal ΔPhe) formed more elastic gels at lower critical gelation concentrations. This gel revealed irreversible breakup, while the C-terminal ΔAbu and ΔAla gels, although less elastic, exhibited structural recovery and partial healing of the elastic properties. A potential antitumor thieno[3,2-b]pyridine derivative was incorporated (noncovalently) into the gel formed by the hydrogelator containing C-terminal ΔPhe residue. Fluorescence and Förster resonance energy transfer measurements indicate that the drug is located in a hydrophobic environment, near/associated with the peptide fibers, establishing this type of hydrogel as a good drug-nanocarrier candidate.

Antimicrobial lubricant formulations containing poly(hydroxybenzene)-trimethoprim conjugates synthesized by tyrosinase.

Poly(hydroxybenzene)-trimethoprim conjugates were prepared using methylparaben as substrate of the oxidative enzyme tyrosinase. MALDI-TOF MS analysis showed that the enzymatic oxidation of methylparaben alone leads to the poly(hydroxybenzene) formation. In the presence of trimethoprim, the methylparaben tyrosinase oxidation leads poly(hydroxybenzene)-trimethoprim conjugates. All of these compounds were incorporated into lubricant hydroxyethyl cellulose/glycerol mixtures. Poly(hydroxybenzene)-trimethoprim conjugates were the most effective phenolic structures against the bacterial growth reducing by 96 and 97% of Escherichia coli and Staphylococcus epidermidis suspensions, respectively (after 24 h). A novel enzymatic strategy to produce antimicrobial poly(hydroxybenzene)-antibiotic conjugates is proposed here for a wide range of applications on the biomedical field.

Viscoelastic Reversibility of Carrageenan Hydrogels under Large Amplitude Oscillatory Shear: Hybrid Carrageenans versus Blends.

The viscoelastic response of carrageenan hydrogels to large amplitude oscillatory shear (LAOS) has not received much attention in the literature in spite of its relevance in industrial application. A set of hybrid carrageenans with differing chemical compositions are gelled in the presence of KCl or NaCl, and their nonlinear viscoelastic responses are systematically compared with mixtures of kappa- and iota-carrageenans of equivalent kappa-carrageenan contents. Two categories of LAOS response are identified: strain softening and strain hardening gels. Strain softening gels show LAOS non-reversibility: when entering the nonlinear viscoelastic regime, the shear storage modulus G' decreases with increasing strain, and never recovers its linear value G0 after successive LAOS sweeps. In contrast to this, strain hardening carrageenan gels show a certain amount of LAOS reversibility: when entering the nonlinear regime, G' increases with strain and shows a maximum at strain γH. For strains applied below γH, G0 shows good reversibility and the strain hardening behavior is maintained. For strains larger than γH, G0 decreases significantly indicating an irreversible structural change in the elastic network. Strain hardening and elastic recovery after LAOS prevail for hybrid carrageenan and iota-carrageenan gels, but are only achieved when blends are gelled in NaCl, suggesting a phase separated structure with a certain degree of co-aggregated interface for mixed gels.

Multilayer Film Comprising Polybutylene Adipate Terephthalate and Cellulose Nanocrystals with High Barrier and Compostable Properties.

In the present study, a multilayer, high-barrier, thin blown film based on a polybutylene adipate terephthalate (PBAT) blend with polyhydroxyalkanoate (PHA), and composed of four layers including a cellulose nanocrystal (CNC) barrier layer and an electrospun poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) hot-tack layer, was characterized in terms of the surface roughness, surface tension, migration, mechanical and peel performance, barrier properties, and disintegration rate. The results showed that the film exhibited a smooth surface. The overall migration tests showed that the material is suitable to be used as a food contact layer. The addition of the CNC interlayer had a significant effect on the mechanical properties of the system, drastically reducing the elongation at break and, thus, the flexibility of the material. The film containing CNCs and electrospun PHBV hot-tack interlayers exhibited firm but not strong adhesion. However, the multilayer was a good barrier to water vapor (2.4 ± 0.1 × 10-12 kg·m-2·s-1·Pa-1), and especially to oxygen (0.5 ± 0.3 × 10-15 m3·m-2·s-1·Pa-1), the permeance of which was reduced by up to 90% when the CNC layer was added. The multilayer system disintegrated completely in 60 days. All in all, the multilayer system developed resulted in a fully compostable structure with significant potential for use in high-barrier food packaging applications.

Experimental Validation of a Micro-Extrusion Set-Up with In-Line Rheometry for the Production and Monitoring of Filaments for 3D-Printing.

The main objective of this work is to validate an in-line micro-slit rheometer and a micro-extrusion line, both designed for the in-line monitoring and production of filaments for 3D printing using small amounts of material. The micro-filament extrusion line is first presented and its operational window is assessed. The throughputs ranged between 0.045 kg/h and 0.15 kg/h with a maximum 3% error and with a melt temperature control within 1 °C under the processing conditions tested for an average residence time of about 3 min. The rheological micro slit is then presented and assessed using low-density polyethylene (LDPE) and cyclic olefin copolymer (COC). The excellent matching between the in-line micro-rheological data and the data measured with off-line rotational and capillary rheometers validate the in-line micro-slit rheometer. However, it is shown that the COC does not follow the Cox-Merz rule. The COC filaments produced with the micro-extrusion line were successfully used in the 3D printing of specimens for tensile testing. The quality of both filaments (less than 6% variation in diameter along the filament's length) and printed specimens validated the whole micro-set-up, which was eventually used to deliver a rheological mapping of COC printability.

From Seaweeds to Hydrogels: Recent Progress in Kappa-2 Carrageenans.

Hybrid carrageenans, also called kappa-2 (K2) or weak kappa, are a class of sulfated polysaccharides with thermo-reversible gelling properties in water and are extracted from a specific family of red seaweeds. K2 are known in the industry for their texturizing properties which are intermediate between those of kappa-carrageenans (K) and iota-carrageenans (I). As such, K2 are gaining industrial interest, as they can replace blends of K and I (K + I) in some niche applications. Over the last decade or so, some progress has been made in unravelling K2's chemical structure. The understanding of K2 gel's structure-rheological properties' relationships has also improved. Such recent progress is reported here, reviewing the literature on gelling K2 published since the last review on the topic. The focus is on the seaweeds used for extracting K2, their block copolymer chemical structures, and how these impact on the gel's formation and rheological properties. The outcome of this review is that additional rheological and structural studies of K2 hydrogels are needed, in particular to understand their viscoelastic behavior under large deformation and to unravel the differences between the texturizing properties of K2 and K + I.

Unveiling the Role of Capping Groups in Naphthalene N-Capped Dehydrodipeptide Hydrogels.

Self-assembled peptide-based hydrogels are archetypical nanostructured materials with a plethora of foreseeable applications in nanomedicine and as biomaterials. N-protected di- and tri-peptides are effective minimalist (molecular) hydrogelators. Independent variation of the capping group, peptide sequence and side chain modifications allows a wide chemical space to be explored and hydrogel properties to be tuned. In this work, we report the synthesis of a focused library of dehydrodipeptides N-protected with 1-naphthoyl and 2-naphthylacetyl groups. The 2-naphthylacetyl group was extensively reported for preparation of peptide-based self-assembled hydrogels, whereas the 1-naphthaloyl group was largely overlooked, owing presumably to the lack of a methylene linker between the naphthalene aromatic ring and the peptide backbone. Interestingly, dehydrodipeptides N-capped with the 1-naphthyl moiety afford stronger gels, at lower concentrations, than the 2-naphthylacetyl-capped dehydrodipeptides. Fluorescence and circular dichroism spectroscopy showed that the self-assembly of the dehydrodipeptides is driven by intermolecular aromatic π-π stacking interactions. Molecular dynamics simulations revealed that the 1-naphthoyl group allows higher order aromatic π-π stacking of the peptide molecules than the 2-naphthylacetyl group, together with hydrogen bonding of the peptide scaffold. The nanostructure of the gel networks was studied by TEM and STEM microscopy and was found to correlate well with the elasticity of the gels. This study contributes to understanding the interplay between peptide and capping group structure on the formation of self-assembled low-molecular-weight peptide hydrogels. Moreover, the results presented here add the 1-naphthoyl group to the palette of capping groups available for the preparation of efficacious low-molecular-weight peptide-based hydrogels.

Tuning the drug multimodal release through a co-assembly strategy based on magnetic gels.

Self-assembled short peptide-based gels are highly promising drug delivery systems. However, implementing a stimulus often requires screening different structures to obtain gels with suitable properties, and drugs might not be well encapsulated and/or cause undesirable effects on the gel's properties. To overcome this challenge, a new design approach is presented to modulate the release of doxorubicin as a model chemotherapeutic drug through the interplay of (di)phenylalanine-coated magnetic nanoparticles, PEGylated liposomes and doxorubicin co-assembly in dehydropeptide-based gels. The composites enable an enhancement of the gelation kinetics in a concentration-dependent manner, mainly through the use of PEGylated liposomes. The effect of the co-assembly of phenylalanine-coated nanoparticles with the hydrogel displays a concentration and size dependence. Finally, the integration of liposomes as doxorubicin storage units and of nanoparticles as composites that co-assemble with the gel matrix enables the tuneability of both passive and active doxorubicin release through a thermal, and a low-frequency alternating magnetic field-based trigger. In addition to the modulation of the gel properties, the functionalization with (di)phenylalanine improves the cytocompatibility of the nanoparticles. Hereby, this work paves a way for the development of peptide-based supramolecular systems for on-demand and controlled release of drugs.

Structure-Elastic Properties Relationships in Gelling Carrageenans.

Gelling carrageenans are polysaccharides extracted from the Gigartinales order of red algae. These are additives used essentially in the food industry for texturizing, stabilizing or gelling various formulations. Although a consensual gel mechanism has been reached which encompasses a coil-to-helix transition followed by the self-assembling of helices in a network, the structure-elastic relationships in the network are still to be clearly established. This paper reviews the reports in which carrageenan gel structures have been systematically compared with gel elastic properties. The focus is on the sizes documented for structural units, such as strands, aggregates, voids or network meshes, as well as on the reported linear and nonlinear elastic characteristics. The insufficient rationalization of carrageenan gel elasticity by models which take on board mechanically relevant structural features is underlined. After introducing selected linear and nonlinear elastic models, preliminary results comparing such models to structural and rheological data are presented. In particular, the concentration scaling of the strain hardening exhibited by two types of carrageenan gels is discussed.

In-Line Rheo-Optical Investigation of the Dispersion of Organoclay in a Polymer Matrix during Twin-Screw Compounding.

The dispersion mechanisms in a clay-based polymer nanocomposite (CPNC) during twin-screw extrusion are studied by in-situ rheo-optical techniques, which relate the CPNC morphology with its viscosity. This methodology avoids the problems associated with post extrusion structural rearrangement. The polydimethylsiloxane (PDMS) matrix, which can be processed at ambient and low temperatures, is used to bypass any issues associated with thermal degradation. Local heating in the first part of the extruder allows testing of the usefulness of low matrix viscosity to enhance polymer intercalation before applying larger stresses for clay dispersion. The comparison of clay particle sizes measured in line with models for the kinetics of particle dispersion indicates that larger screw speeds promote the break-up of clay particles, whereas smaller screw speeds favor the erosion of the clay tactoids. Thus, different levels of clay dispersion are generated, which do not simply relate to a progressively better PDMS intercalation and higher clay exfoliation as screw speed is increased. Reducing the PDMS viscosity in the first mixing zone of the screw facilitates dispersion at lower screw speeds, but a complex interplay between stresses and residence times at larger screw speeds is observed. More importantly, the results underline that the use of larger stresses is inefficient per se in dispersing clay if sufficient time is not given for PDMS to intercalate the clay galleries and thus facilitate tactoid disruption or erosion.

Rheologically Assisted Design of Conductive Adhesives for Stencil Printing on PCB.

Driven by the need to deliver new, lead-free, eco-friendly solder pastes for soldering electronic components to Printed Circuit Boards (PCB), electrically conductive adhesives (ECAs) based on epoxy, carbon nanotubes (CNT), and exfoliated graphite (EG) were designed. The rheology of the adhesives prepared is paramount for the success of the deposition process, which is based on stencil printing. Thus, a rheological analysis of the process was first performed. Then, an experimental protocol was defined to assess the relevant viscoelastic characteristics of the adhesives for stencil printing application. Different composite formulations of epoxy/CNT/EG were produced. Their rheological characteristics were established following the designed protocol and benchmarked with a commercial solder paste. The thermal and electrical properties of the composite formulations were also characterized. As a result, a new, electrically conductive adhesive was delivered with potential to be an eco-friendly alternative to the solder paste currently used in stencil printing of PCB.

Evaluation of a Model Photo-Caged Dehydropeptide as a Stimuli-Responsive Supramolecular Hydrogel.

Short peptides capped on the N-terminus with aromatic groups are often able to form supramolecular hydrogels, via self-assembly, in aqueous media. The rheological properties of these readily tunable hydrogels resemble those of the extracellular matrix (ECM) and therefore have potential for various biological applications, such as tissue engineering, biosensors, 3D bioprinting, drug delivery systems and wound dressings. We herein report a new photo-responsive supramolecular hydrogel based on a "caged" dehydropeptide (CNB-Phe-ΔPhe-OH 2), containing a photo-cleavable carboxy-2-nitrobenzyl (CNB) group. We have characterized this hydrogel using a range of techniques. Irradiation with UV light cleaves the pendant aromatic capping group, to liberate the corresponding uncaged model dehydropeptide (H-Phe-ΔPhe-OH 3), a process which was investigated by 1H NMR and HPLC studies. Crucially, this cleavage of the capping group is accompanied by dissolution of the hydrogel (studied visually and by fluorescence spectroscopy), as the delicate balance of intramolecular interactions within the hydrogel structure is disrupted. Hydrogels which can be disassembled non-invasively with temporal and spatial control have great potential for specialized on-demand drug release systems, wound dressing materials and various topical treatments. Both 2 and 3 were found to be non-cytotoxic to the human keratinocyte cell line, HaCaT. The UV-responsive hydrogel system reported here is complementary to previously reported related UV-responsive systems, which are generally composed of peptides formed from canonical amino acids, which are susceptible to enzymatic proteolysis in vivo. This system is based on a dehydrodipeptide structure which is known to confer proteolytic resistance. We have investigated the ability of the photo-activated system to accelerate the release of the antibiotic, ciprofloxacin, as well as some other small model drug compounds. We have also conducted some initial studies towards skin-related applications. Moreover, this model system could potentially be adapted for on-demand "self-delivery", through the uncaging of known biologically active dehydrodipeptides.

Bolaamphiphilic Bis-Dehydropeptide Hydrogels as Potential Drug Release Systems.

The self-assembly of nanometric structures from molecular building blocks is an effective way to make new functional materials for biological and technological applications. In this work, four symmetrical bolaamphiphiles based on dehydrodipeptides (phenylalanyldehydrophenylalanine and tyrosyldehydrophenylalanine) linked through phenyl or naphthyl linkers (terephthalic acid and 2,6-naphthalenedicarboxylic acid) were prepared, and their self-assembly properties were studied. The results showed that all compounds, with the exception of the bolaamphiphile of tyrosyldehydrophenylalanine and 2,6-naphthalene dicarboxylic acid, gave self-standing hydrogels with critical gelation concentrations of 0.3 wt % and 0.4 wt %, using a pH trigger. The self-assembly of these hydrogelators was investigated using STEM microscopy, which revealed a network of entangled fibers. According to rheology, the dehydrodipeptide bolaamphiphilic hydrogelators are viscoelastic materials with an elastic modulus G' that falls in the range of native tissue (0.37 kPa brain-4.5 kPa cartilage). In viability and proliferation studies, it was found that these compounds were non-toxic toward the human keratinocyte cell line, HaCaT. In sustained release assays, we studied the effects of the charge present on model drug compounds on the rate of cargo release from the hydrogel networks. Methylene blue (MB), methyl orange (MO), and ciprofloxacin were chosen as cationic, anionic, and overall neutral cargo, respectively. These studies have shown that the hydrogels provide a sustained release of methyl orange and ciprofloxacin, while methylene blue is retained by the hydrogel network.

Supramolecular ultra-short carboxybenzyl-protected dehydropeptide-based hydrogels for drug delivery.

Self-assembled peptide-based hydrogels are promising materials for biomedical research owing to biocompatibility and similarity to the extracellular matrix, amenable synthesis and functionalization and structural tailoring of the rheological properties. Wider developments of self-assembled peptide-based hydrogels in biomedical research and clinical translation are hampered by limited commercial availability allied to prohibitive costs. In this work a focused library of Cbz-protected dehydrodipeptides Cbz-L-Xaa-Z-ΔPhe-OH (Xaa= Met, Phe, Tyr, Ala, Gly) was synthesised and evaluated as minimalist hydrogels. The Cbz-L-Met-Z-ΔPhe-OH and Cbz-L-Phe-Z-ΔPhe-OH hydrogelators were comprehensively evaluated regarding molecular aggregation and self-assembly, gelation, biocompatibility and as drug carriers for delivery of the natural compound curcumin and the clinically important antitumor drug doxorubicin. Drug release profiles and FRET studies of drug transport into small unilamellar vesicles (as biomembrane models) demonstrated that the Cbz-protected dehydropeptide hydrogels are effective nanocarriers for drug delivery. The expedite and scalable synthesis (in 3 steps), using commercially available reagents and amenable reaction conditions, makes Cbz-protected dehydrodipeptide hydrogels, widely available at affordable cost to the research community.