Autocatalytic strategy for tuning drug release from peptide-drug supramolecular hydrogel

Peptide-drug conjugates (PDCs) composed of peptide, spacer and drug have gained extensive attention in the field of drug delivery owing to its precise control over the drug payload and architecture. However, the achievement of controllable and rapid drug release at targeted site by PDCs is still a great challenge for pharmaceutist. Herein, we introduced the histidine residue into PDCs to generate a supramolecular hydrogel via a pH-trigger strategy, which exhibited an autocatalytic effect to precisely tune drug release from PDCs hydrogel. Using indomethacin (Idm) as model drug, various PDCs (Y(Idm)EEH, Y(Idm)EEK and Y(Idm)EER) were synthesized and their self-assembling properties were investigated in terms of critical aggregation concentration (CAC), transmission electron microscopy (TEM) and rheometer. Introduction of histidine residue into PDCs presented a robust catalytic activity on the ester hydrolysis of p-nitrophenyl acetate in aqueous solution, as well conferred the autocatalytic capacity to hydrolyze the PDCs into active parent drug (Idm). Overall, we reported an autocatalytic activity of histidine residue to precisely tune drug release from PDCs hydrogels.     

Temperature and pH-Sensitive Polymers with Hydrophobic Spacers for the Controlled Delivery of Drugs

Summary: Acid methacrylates containing hydrophobic aliphatic and aromatic spacers were used to prepare pH-sensitive ampholytic hydrogels and bidimensional temperature- (T) and pH-sensitive hydrogels. Their swelling behaviour was studied by changing the pH and temperature of buffer solutions. Salicylamide, salicylic acid and green fluorescent protein (GFP) as model drugs were loaded into the gels and their release kinetics studied under simulated gastric and intestinal conditions. T- and pH-sensitive hydrogels containing aliphatic spacers show sustained release of analgesics depending on pH (e.g. 7.4); while longer aliphatic spacers resulted in drug release depending on pH and temperature (T < transition T). GFP was released from temperature- and pH-sensitive ampholytic hydrogels after different lag times depending on hydrogel composition.     

Urea derivatives as low-molecular-weight gelators

This paper reports an overview of low-molecular-weight gelators (LMWGs) that have a ureide moiety as a hydrogen-bonding site. Various mono-, bis-, tris-, and tetrakis-urea compounds can form supramolecular gels with organic solvents. The author developed a C ₃-symmetrical tris-urea molecule that can form a ubiquitous framework of LMWGs. The supramolecular organogel of the tris-urea molecule exhibited a chemical-stimuli-responsive reversible gel–sol phase transition. Supramolecular hydrogels are constructed from self-assemblies of amphiphilic urea derivatives. Sugar-connected amphiphilic tris-urea was found to form a gel with water, and the hydrogels showed chemical-stimuli-responsive gel–sol phase transitions. The potential of supramolecular hydrogels as matrices of electrophoresis has been demonstrated through the supramolecular gel electrophoresis (SUGE) of protein samples using our developed amphiphilic tris-urea LMWG.     

Bioinspired self-assembly supramolecular hydrogel for ocular drug delivery

Based on a recent report concerning endogenous agents (i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like protein (ASC) via the peptide epitope of KKFKLKL, we rationally designed and synthesized a nonapeptide (NapFFKKFKLKL), which can co-assemble with dexamethasone sodium phosphate (Dexp) to generate a NapFFKKFKLKL/Dexp supramolecular hydrogel for ocular drug delivery. The NapFFKKFKLKL/Dexp hydrogel formed instantly after the complexation of NapFFKKFKLKL with Dexp in aqueous solution. The formed supramolecular hydrogels were thoroughly characterized by transmission electron microscopy (TEM), fluorescent spectrum, circular dichroism (CD) spectra and rheology. The peptide concentration significantly affected the in vitro release behavior of Dexp from the supramolecular hydrogel, and the higher peptide concentration resulted in the slower drug release. Following a single intravitreal injection, the proposed NapFFKKFKLKL/Dexp hydrogel displayed good intraocular biocompatibility without having an adverse impact on the retinal architecture and eyesight functions during one month of follow-up. Using an experimental autoimmune uveitis (EAU) rat model, we demonstrated that the resulting NapFFKKFKLKL/Dexp hydrogel had potent capacity to alleviate the intraocular inflammation and retain the morphology of retinal architecture. Overall, the resulting NapFFKKFKLKL/Dexp hydrogel may be a promising drug carrier system to treat various posterior disorders (i.e., uveitis).     

Self‐Immolative Spacers: Kinetic Aspects,Structure–Property Relationships,and Applications

Self‐immolative spacers are covalent assemblies tailored to correlate the cleavage of two chemical bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller molecules. Originally introduced to overcome limitations for drug delivery, self‐immolative spacers have gained wide interest in medicinal chemistry, analytical chemistry, and material science. For most applications, the kinetics of the disassembly of the activated self‐immolative spacer governs functional properties. This Review addresses kinetic aspects of self‐immolation. It provides information for selecting a particular self‐immolative motif for a specific demand. Moreover, it should help researchers design kinetic experiments and fully exploit the rich perspectives of self‐immolative spacers.     

The Power of Confocal Laser Scanning Microscopy in Supramolecular Chemistry: In situ Real-time Imaging of Stimuli-Responsive Multicomponent Supramolecular Hydrogels

Multicomponent supramolecular hydrogels are promising scaffolds for applications in biosensors and controlled drug release due to their designer stimulus responsiveness. To achieve rational construction of multicomponent supramolecular hydrogel systems, their in-depth structural analysis is essential but still challenging. Confocal laser scanning microscopy (CLSM) has emerged as a powerful tool for structural analysis of multicomponent supramolecular hydrogels. CLSM imaging enables real-time observation of the hydrogels without the need of drying and/or freezing to elucidate their static and dynamic properties. Through multiple, selective fluorescent staining of materials of interest, multiple domains formed in supramolecular hydrogels (e. g. inorganic materials and self-sorting nanofibers) can also be visualized. CLSM and the related microscopic techniques will be indispensable to investigate complex life-inspired supramolecular chemical systems.     

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.     

Cargo Encapsulation in Photochromic Supramolecular Hydrogels Depends on Specific Guest-Gelator Supramolecular Interactions

Photochromic supramolecular hydrogels are prospective materials for light-triggered drug release and bionanotechnology. Here we present a structural analysis of peptide-derived photochromic supramolecular hydrogels, which were physically loaded with a selection of biologically related compounds, using advanced techniques of nuclear magnetic resonance. The results enable detailed and correct understanding of the loading process and will allow for correct design of pharmacologically relevant systems for phototriggered drug delivery.     

Synthesis of diverse N,O-bridged calix[1]arene[4]pyridine-C(60) dyads and triads and formation of intramolecular self-inclusion complexes

Starting from both the bridging nitrogen atom-functionalized and the upper rim-functionalized N,O-bridged calix[1]arene[4]pyridine reactants, different types of heteracalixaromatics-C(60) dyads and triads of varied spacers were expediently synthesized using mainly the click reaction as the key step. By means of various spectroscopic methods, the heteracalixaromatics-C(60) dyads and triads obtained have been shown to form intramolecular self-inclusion complexes rather than oligomers or polymers in solution because of a flexible spacer in between the heteracalixaromatic ring and C(60) moiety. The current study, coupled with previous investigations, would provide the guideline for the construction of supramolecular fullerene motifs based on molecular design of the dyads and triads.     

Design, synthesis, and cyclization of 4-aminobutyric acid derivatives: potential candidates as self-immolative spacers

Self-immolative spacers have gained significant interest in recent years due to their utility in numerous prodrug, sensor and drug delivery systems. However, there are a very limited number of spacers that are capable of undergoing spontaneous and rapid reactions under mild conditions. To address this need, 4-aminobutyric acid derivatives were explored as a potential class of self-immolative spacers. Using a modular approach, eleven N- and α-substituted derivatives of 4-aminobutyric acid were synthesized, and their intramolecular cyclizations to γ-lactams were studied. Kinetics experiments were carried out at physiological pH and temperature, and the observed half-lives for the spacers ranged from 2 to 39 s, depending on the molecular structure. In addition, the pH dependence of the cyclization rate was also explored and it was found that cyclization still occurred rapidly at mildly acidic pH. Therefore, this class of compounds exhibits promise for incorporation into a variety of self-immolative systems where rapid cyclization reactions are desired.     

"Self-immolative" spacer for uncaging with fluorescence reporting

Dual photoliberation: A caged, branched, self-immolative spacer (see scheme, gray box) was designed to rapidly and simultaneously release a desired compound (green) and a fluorophore?(red) upon photoactivation. Careful kinetic analysis of the disassembly of the spacer shows that it occurs on the shortest time scale reported to date.     

Polysaccharide-based supramolecular drug delivery systems mediated via host-guest interactions of cucurbiturils

With excellent biocompatibility and biodegradability,natural polysaccharides and their derivative s have exhibited great potential in constructing drug delivery ve hicles for tissue engineering and therapeutics.Cucurbit[n]uril(CB [n])-mediated reversible crosslinking of polysaccharides possess intrinsic stimuliresponsiveness towards competitive guests and have been extensively investigated to fabricate various particles and hydrogels for multiple stimuli-re sponsive drug release by incorpo ration with other stimuli including photo,redox,and enzyme.Through host-guest interactions between CB[6] and aliphatic diamines,functional tags covalently connected with CB[6] can be readily anchored into polysaccharidebased hydrogels,realizing multiple functionalization.The rheological prope rty and drug release profile of polysaccharide-based supramolecular hydrogels can be facilely tuned through CB [8]-mediated dyna mic homo or hetero crosslinking of polysaccharides and/or other polymers.In this review,we introduce and summarize recent progress regarding polysaccharide-based supramolecular drug delivery systems mediated via host-guest interactions of CB[6] and CB[8],covering both bulk hydrogels and particular systems.At the end,possible utilization of CB[7]-based host-guest interactions in constructing polysaccharide-based drug delivery systems and future perspectives of this research direction are also discussed.     

Supramolecular hydrogel formed by glucoheptonamide of l-lysine: simple preparation and excellent hydrogelation ability

We describe the simple preparation of new l-lysine derivatives with a gluconic or glucoheptonic group, their hydrogelation properties, and the thermal and mechanical properties of the supramolecular hydrogels. The l-lysine derivatives with a gluconic group have no hydrogelation ability, while the l-lysine-glucoheptonamide derivatives functioned as hydrogelators. Their hydrogelation abilities increased with the decreasing length of the spacer between the l-lysine segment and the glucoheptonic group. The compound, which has no spacer, formed a supramolecular hydrogel at 0.05 wt % in pure water. The thermal stability and high mechanical strength of the supramolecular hydrogels based on this compound significantly depended on the aqueous solutions. Electron microscopy and FTIR studies demonstrated that the hydrogelators created a three-dimensional network through hydrogen bonding and hydrophobic interactions in the supramolecular hydrogel. In addition, it was found that hydrophobic interactions played an important role in the thermal stability of the supramolecular hydrogel.     

Radiation formation of psyllium cross-linked poly(hydroxyethylmethacrylate)-<Emphasis Type="Italic">co</Emphasis>-poly(acrylamide) based sterile hydrogels for drug delivery applications

Both, gel forming dietary fiber psyllium and antibiotic drug ciprofloxacin, have pharmacological importance in case of gastrointestinal tract problems. Hence, in the present work, an attempt has been made to design the ciprofloxacin loaded psyllium cross-linked poly(hydroxyethylmethacrylate-co-acrylamide) based sterile hydrogels for drug delivery application in gastrointestinal tract problems diverticulitis which occur due to constipation and microbial infestation. These polymers have been characterized by SEM, cryo-SEM, EDAX, FTIR, TGA/DTA/DTG, XRD. The swelling of the hydrogels and release dynamics of drug from the hydrogels have been studied for the evaluation of the swelling and drug release mechanism respectively. The release of the drug from the hydrogels occurred through non-Fickian diffusion mechanism in slow manner. Overall, the ciprofloxacin loaded psyllium based drug delivery system may act with enhanced potential to cure the diverticulitis.     

Design of sterculia gum based double potential antidiarrheal drug delivery system

In view of the antidiarrheal properties of sterculia gum and ornidazole, an attempt has been made to synthesize novel hydrogels by functionalization of sterculia gum with poly(vinylpyrrolidone) (PVP) for release of the model antidiarrheal drug ornidazole. These hydrogels were characterized with FTIR, SEM, TGA and swelling behavior. Swelling kinetics of the hydrogels and in vitro release dynamics of ornidazole from the drug loaded hydrogels have been studied to determine the mechanism of swelling and drug release from the drug loaded hydrogels. A Fickian diffusion mechanism has been observed for the release of drug from the hydrogels. These hydrogels may have dual actions for the treatment of diarrhea.     

Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.     

Fast Cyclization of a Proline‐Derived Self‐Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Self‐immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)‐2‐(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease‐sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.     

Orthogonal Enzymatic Reactions to Control Supramolecular Hydrogelations

Enzyme‐responsive hydrogels have great potential in applications of controlled drug release, tissue engineering, etc. In this study, we reported on a supramolecular hydrogel that showed responses to two enzymes, phosphatase which was used to form the hydrogels and esterase which could trigger gel‐sol phase transitions. The gelation process and visco‐elasticity property of the resulting gel, morphology of the nanostructures in hydrogel, and peptide conformation in the self‐assembled nanostructure were characterized by rheology, transmission electron microscope (TEM), and circular dichroism (CD), respectively. Potential application of the enzyme‐responsive hydrogel in drug release was also demonstrated in this study. Though only one potential application of drug release was proved in this study, the responsive hydrogel system in this study might have potentials for the applications in fields of cell culture, controlled‐drug release, etc.     

Development of Antibacterial,Degradable and pH-Responsive Chitosan/Guar Gum/Polyvinyl Alcohol Blended Hydrogels for Wound Dressing

The present research is based on the fabrication preparation of CS/PVA/GG blended hydrogel with nontoxic tetra orthosilicate (TEOS) for sustained paracetamol release. Different TEOS percentages were used because of their nontoxic behavior to study newly designed hydrogels’ crosslinking and physicochemical properties. These hydrogels were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and wetting to determine the functional, surface morphology, hydrophilic, or hydrophobic properties. The swelling analysis in different media, degradation in PBS, and drug release kinetics were conducted to observe their response against corresponding media. The FTIR analysis confirmed the components added and crosslinking between them, and surface morphology confirmed different surface and wetting behavior due to different crosslinking. In various solvents, including water, buffer, and electrolyte solutions, the swelling behaviour of hydrogel was investigated and observed that TEOS amount caused less hydrogel swelling. In acidic pH, hydrogels swell the most, while they swell the least at pH 7 or higher. These hydrogels are pH-sensitive and appropriate for controlled drug release. These hydrogels demonstrated that, as the ionic concentration was increased, swelling decreased due to decreased osmotic pressure in various electrolyte solutions. The antimicrobial analysis revealed that these hydrogels are highly antibacterial against Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacterial strains. The drug release mechanism was 98% in phosphate buffer saline (PBS) media at pH 7.4 in 140 min. To analyze drug release behaviour, the drug release kinetics was assessed against different mathematical models (such as zero and first order, Higuchi, Baker–Lonsdale, Hixson, and Peppas). It was found that hydrogel (CPG2) follows the Peppas model with the highest value of regression (R² = 0.98509). Hence, from the results, these hydrogels could be a potential biomaterial for wound dressing in biomedical applications.     

Anticancer drug release from poly(N-isopropylacrylamide/itaconic acid) copolymeric hydrogels

The drug uptake and release of anticancer drug from N-isopropylacrylamide/itaconic acid copolymeric hydrogels containing 0–3 mol% of itaconic acid irradiated at 48 kGy have been investigated. 5-Fluorouracil (5-FU) is used as a model anticancer drug. The effect of 5-FU solution on swelling characteristics of PNIPAAm and P(NIPAAm/IA) copolymeric hydrogels have also been studied. The percent swelling, equilibrium swelling, equilibrium water/5-FU content and diffusion constant values are evaluated for poly(N-isopropylacrylamide) (PNIPAAm) and poly(N-isopropylacrylamide/itaconic) (P(NIPAAm/IA)) hydrogels at 130 ppm of 5-FU solution at room temperature. Diffusion of 5-FU solution into the hydrogels has been found to be the non-Fickian type. Finally, the kinetics of drug release from the hydrogels are examined.