Supramolecular hydrogels for enzymatically triggered self-immolative drug delivery

For the first time the combination of self-immolative spacers and supramolecular hydrogels has been tested in enzyme triggered drug release. Low-molecular weight drug-gelator conjugates have been prepared, which contain a gel forming lysine moiety linked to model drugs (benzylamine and phenethylamine) through a self-immolating spacer (p-aminobenzyloxycarbonyl). In the presence of trypsin the amide linkage between the gelator moiety and the spacer is hydrolyzed leading to the release of the model drug. This approach provides with distinct advantages, such as sustained release or versatility associated to the use of supramolecular hydrogels and self-immolative spacers, respectively.     

Fabrication of supramolecular hydrogels for drug delivery and stem cell encapsulation

Supramolecular hydrogels self-assembled by alpha-cyclodextrin and methoxypolyethylene glycol-poly(caprolactone)-(dodecanedioic acid)-poly(caprolactone)-methoxypolyethylene glycol (MPEG-PCL-MPEG) triblock polymers were prepared and characterized in vitro and in vivo. The sustained release of dextran-fluorescein isothiocyanate (FITC) from the hydrogels lasted for more than 1 month, which indicated that the hydrogels were promising for controlled drug delivery. ECV304 cells and marrow mesenchymal stem cells (MSC) were encapsulated and cultured in the hydrogels, during which the morphologies of the cells could be kept. The in vitro cell viability studies and the in vivo histological studies demonstrated that the hydrogels were non-cytotoxic and biocompatible, which indicated that the hydrogels prepared were promising candidates as injectable scaffolds for tissue engineering applications.     

Novel mucoadhesive carriers based on alginate-acrylamide hydrogels for drug delivery

New mucoadhesive two-component carriers for drug delivery based on synthetic acrylamide/diethylacrylamide and natural alginate hydrogels have been synthesized. The introduction of sodium alginate into polyacrylamide/ poly(diethylacrylamide) gels, followed by their crosslinking with metal ions, significantly changed structure and properties of hydrogels, such as swelling degree, drug capacity and drug release rate in physiological solution. The structure of the gels was characterized by FTIR spectroscopy and scanning electron microscopy.     

Recent advances of injectable hydrogels for drug delivery and tissue engineering applications

Injectable hydrogel is a kind of in situ gelling system but has its specificity on the process procedure, which requires a better control of gelation kinetics. Hydrogels with injectability under mild condition are preferred in the field of biomedicine, especially for drug delivery and tissue engineering, because of the favorable carrier property in three-dimension, biocompatibility, low invasive and adaptable shape for administration. Despite the advantages, the development of injectable hydrogels may also face some challenges to meet the various clinical requirements. In this review, we provide a brief summary on the recent progresses on the design, synthesis and evaluation of injectable hydrogels towards biomedical applications.     

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel showing a low swelling and an increased chemical stability in acidic medium. Ibuprofen, as a model drug, was loaded by soaking into INU-MA1 and INU-MA1-SA hydrogels and its release from these matrices was evaluated in simulated gastrointestinal fluids. INU-MA1 hydrogel showed the ability to quickly release the entrapped drug thus indicating its potential as a matrix for an oral formulation. INU-MA1-SA hydrogel showed a pH-responsive drug delivery. Therefore it is a promising candidate for controlled drug release in the intestinal tract.     

Synthesis, characterisation and evaluation of poly[lactose acrylate-N-vinyl-2-pyrrolidinone] hydrogels for drug delivery

New biodegradable polymeric hydrogels based on biocompatible materials, lactose acrylate (LA) and N-vinyl-2-pyrrolidinone were designed and synthesized. LA was synthesized and characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Hydrogel synthesis was carried out by free-radical polymerization of the co-monomers using azobisisobutyronitrile as initiator and N,N^′-methylenebisacrylamide as crosslinker. These hydrogels were also characterized. Equilibrium swelling of the hydrogels was studied in phosphate buffer of physiological pH, 7.4 and at 37 °C. Propranolol hydrochloride was entrapped into these hydrogels and the in vitro release profile of this drug was established in phosphate buffer. The drug release followed a near zero-order fashion in the first 6 h and thereafter slowed down releasing more than 90% of the entrapped drug at the end of 48 h.     

Methyl methacrylate-co-itaconic acid (MMA-co-IA) hydrogels for controlled drug delivery

In the present work methyl methacrylate-co-itaconic acid (MMA-co-IA) hydrogels were synthesized by free radical copolymerization of methyl methacrylate (MMA) and itaconic acid (IA) using ethylene glycol dimethacrylate (EGDMA) and methylene bisacrylamide (MBAAm) as crosslinkers and benzoyl peroxide as initiator. Selected samples were loaded with model drug lactulose. For the lactulose release, the effect of pH, monomeric compositions, degree of crosslinking were investigated. The release of lactulose was studied for 8 h period in USP phosphate buffer solutions of varying pH 1.2, 5.5, 6.5 and 7.0. The drug release data were fitted into various kinetics models like the zero order, first order, Higuchi and Peppas. The release kinetics of lactulose from MMA/IA hydrogels was found to be best described by the Peppas model. Results showed that drug release increased by increasing IA content in the hydrogels but the effect of changing of crosslinking ratio on drug release was not significant. The surface morphology of MMA/IA drug loaded hydrogel was studied by SEM which revealed uniform distribution of the drug in the hydrogels. In conclusion, it can be said that lactulose can be successfully incorporated into crosslinked MMA/IA hydrogels and its release can be modulated by changing the mole fraction of the acid component in the gels.     

A novel magnetic triple-responsive composite semi-IPN hydrogels for targeted and controlled drug delivery

In this work, Fe₃O₄/poly(3-acrylamidephenylboronic acid-co-(2-dimethylamino) ethyl methacrylate) (Fe₃O₄/P(AAPBA-co-DMAEMA)) hydrogels possessing magnetic and triple-responsive properties and semi-interpenetrated by β-cyclodextrin-epichlorohydrin (β-CD-EPI) were prepared via radical polymerization. The characteristics of the materials have been investigated by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM). The swelling measurements and the application of Fe₃O₄/P(AAPBA-co-DMAEMA)/(β-CD-EPI) hydrogels in controlled release of drug were also investigated. It was found that the magnetic hydrogels exhibit swelling behaviors affected by pH, temperature, glucose concentration and magnetic field, and have porous morphologies, superparamagnetism. Moreover, the hydrogels possess targeting and could control the release of quercetin by adjusting pH value, temperature, glucose concentration and magnetic field.     

Injectable biodegradable hydrogels composed of hyaluronic acid-tyramine conjugates for drug delivery and tissue engineering

The sequential injection of hyaluronic acid-tyramine conjugates and enzymes forms biodegradable hydrogels in vivo by enzyme-induced oxidative coupling, offering high potential as a promising biomaterial for drug delivery and tissue engineering.     

Synthesis and characterization of novel carboxymethyl chitosan grafted polylactide hydrogels for controlled drug delivery

Novel carboxymethyl chitosan‐polylactide (CMCS‐g‐PLA) hydrogels were prepared by using 1‐(3‐dimethylaminopropyl)‐3‐ethylcarbodiimide hydrochloride/N‐hydroxysuccinimide (EDC/NHS) as crosslinking agent and catalyst at room temperature. Solid‐state ¹³C‐NMR, SEM, and FT‐IR measurements showed that PLA blocks are successfully grafted onto the CMCS main chains. DSC measurements confirmed the effective crosslinking of carboxymethyl chitosan. With increasing the amount of EDC/NHS, the crosslink destiny of CMCS‐g‐PLA copolymers is improved. The swelling ratio of CMCS‐g‐PLA hydrogels is pH dependent, showing a minimum in the pH range of 3 to 5. Rheological studies confirmed the formation of hydrogels. The higher the crosslinking density, the higher the storage modulus of hydrogels. CMCS‐g‐PLA hydrogels only slightly degrade in PBS for 10 days. In the presence of lysozyme, however, hydrogels with low crosslink density are totally degraded in 10 days. Drug release studies show that after 96 h, 95% of thymopentin is released under in vitro conditions. Copyright © 2015 John Wiley & Sons, Ltd.     

Recombinant amphiphilic protein micelles for drug delivery

Amphiphilic block polypeptides can self-assemble into a range of nanostructures in solution, including micelles and vesicles. Our group has recently described the capacity of recombinant amphiphilic diblock copolypeptides to form highly stable micelles. In this report, we demonstrate the utility of protein nanoparticles to serve as a vehicle for controlled drug delivery. Drug-loaded micelles were produced by encapsulating dipyridamole as a model hydrophobic drug with anti-inflammatory activity. Murine studies confirmed the capacity of drug-loaded protein micelles to limit the in vivo recruitment of neutrophils in response to an inflammatory stimulus.     

Biodegradable thermo‐ and pH‐responsive hydrogels for oral drug delivery

In this article, novel smart hydrogels based on biodegradable pH sensitive poly(L ‐glutamic acid‐g‐2‐hydroxylethyl methacrylate) (PGH) chains and temperature‐sensitive hydroxypropylcellulose‐g‐acrylic acid (HPC‐g‐AA) segments were designed and synthesized. The influence of pH and temperature on the equilibrium swelling ratios of the hydrogels was discussed. The optical transmittance of the hydrogels was also changed as a function of temperature, which reflecting that the HPC‐g‐AA part of the hydrogels became hydrophobic at the temperature above the lower critical solution temperature (LCST). At the same time, the LCST of the hydrogels had a visible pH‐dependent behavior. Scanning electron microscopic analysis revealed the morphology of the hydrogels before and after enzymatic degradation. The biodegradation rate of the hydrogels was directly related to the PGH content and the pH value. The in vitro release of bovine serum albumin from the hydrogels were investigated. The release profiles indicated that both the HPC‐g‐AA and PGH contents played important roles in the drug release behaviors. These results show that the smart hydrogels seem to be of great promise in pH–temperature oral drug delivery systems. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of biocompatible nanocomposite hydrogels as a local drug delivery system

Nanocomposite biocompatible hydrogels (NCHG) were synthesised as model systems for in situ cured potentially local drug delivery devices for curing periodontal infections. The composite consists of the following components: nanoparticles (NPs), matrix gel, and chlorhexidine (CHX) as antibacterial drug. The NPs were obtained by free radical initiated copolymerization of the monomers, 2-hydroxyethyl methacrylate (HEMA) and polyethyleneglycol dimethacrylate (PEGDMA), in aqueous solution. The same monomers were used to prepare crosslinked matrices by photopolymerization. NCHGs were obtained by mixing NPs, monomers, and drug in an aqueous solution then crosslinked by photopolymerization. Mechanical properties, swelling behavior, and the kinetics of drug release have been investigated. It was found that compression strength values increased with increasing ratio of the crosslinker PEGDMA. Incorporation of NPs into the matrix resulted similar compression strength as the matrix hydrogel. The hydrated NCHGs swelled more slowly but admitted more water. The drug was incorporated in NPs by swelling in CHX aqueous solution or added to the solution of monomer mixture followed by photopolymerization. Studies of release kinetics revealed that on average 60% of the loaded drug was released. The most rapid release was observed over a 24 h period for matrix gels with low crosslinking density. For NCHGs, the release period exceeded 48 h. An unexpected result was observed for NCHGs without drug in the NPs. In this case, increasing release was observed for the first 24 h. Thereafter, however, the apparent quantity of detectable drug decreased dramatically.     

Biologically triggered exploding protein based microcapsules for drug delivery

Biologically triggered exploding microcapsules were synthesized by layer-by-layer assembly of biopolymers. The microcapsules showed controlled rupturing behaviour upon exposure to a pathologically relevant biomolecule, trypsin. These microcapsules offer significant potential for clinical applications.     

Preparation and properties of novel hydrogels from oxidized konjac glucomannan cross-linked chitosan for in vitro drug delivery

In this paper, a novel composite hydrogel was prepared by the use of dialdehyde konjac glucomannan (DAK) as macromolecular cross-linking agent for chitosan (CS). This biocompatible material cross-links and gels in minutes. The structure and morphology were characterized by various analyses. The results indicate that the hydrogels formed through the Schiff-base reaction between the amino groups of CS chains and the aldehyde groups of DAK. The cross-link density (rho(x)) increases with the enhancement of DAK content in hydrogels, while equilibrium swelling ratio (SR) and the average molecular weight between cross-links (Mc) value decrease. Drug release was evaluated by varying the pH of the release medium, reversed dependence of release rate on the equilibrium SR of hydrogel indicated that drug release may be impeded by the association of drug with the polymer. Importantly, this process offers an entirely new window of materials preparation when compared with the traditional preparation of CS-based hydrogels with small molecules cross-linking agent.     

Development and evaluation of a monolithic floating drug delivery system for acyclovir

Acyclovir (ACV), a model drug for this study, is one of the most effective drugs against viruses of the herpes group. Absorption of orally administered ACV is variable and incomplete, with a bioavailability of ca. 15-30%. The drug is absorbed in the duodenum after oral administration and hence, preparation of a floating drug delivery system (FDDS) for ACV may increase oral absorption of the drug. ACV matrix tablets (200?mg) containing an effervescent base (sodium bicarbonate and citric acid) and a binary combination of hydroxypropyl methylcellulose (HPMC) K4M with carbopol or sodium carboxymethyl cellulose (Na CMC) or polyvinylpyrrolidone (PVP) and/or sodium alginate were prepared by the direct compression method. The tablets were evaluated for physicochemical properties and in vitro floating ability (floating lag-time and duration), bioadhesiveness and drug release. The drug release studies were carried out in 0.1?N HCl (pH 1.2) at 37±0.5°C. At appropriate time intervals, samples were withdrawn and assayed spectrophotometrically at λ(max)=259?nm. The floating test showed tablets containing 15% effervescent base had a floating lag time of 10-30?s and a duration of floating time of 24?h. The formulations containing HPMC-PVP, HPMC-Na CMC, HPMC-carbopol, and HPMC-sodium alginate released about 60-90% of their drug content during a 12-h period. Increasing carbopol caused slower drug release. We concluded that the proposed tablets with 15% effervescent base, 20-30% HPMC, 30% Na CMC (and/or 20% PVP or 20% sodium alginate) showed good floating and drug release properties in vitro, and should be considered as FDDS for ACV.     

Synthesis of pH‐responsive photocrosslinked hyaluronic acid‐based hydrogels for drug delivery

Photocrosslinked hyaluronic acid/poly(vinyl alcohol)‐styrylpyridinium (HA/PVA‐SbQ) hydrogels were synthesized for controlled antitumor drug delivery. The photocrosslinking reaction was rapid, and the time required for completely converting into the insoluble hydrogels was less than 500 s on exposure to 5 mW/cm² UV light irradiation. The resulting hydrogels exhibited sensitivity to the pH value of the surrounding environment. Scanning electron microscopic analysis revealed that the morphology and the pore size of the hydrogels could be controlled by changing the ratio of HA and PVA‐SbQ in the formulations. Paclitaxel (PTX)‐loaded hydrogel could also be formed rapidly by UV irradiation of a mixed solution of HA/PVA‐SbQ and PTX. Release profiles of PTX from the hydrogels showed pH‐dependent and sustained manner. Moreover, our data revealed that PTX released from the HA hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of HA hydrogels without PTX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using HA‐based hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Chitosan based hybrid hydrogels for drug delivery: Preparation,biodegradation, thermal,and mechanical properties

In the present paper, biodegradable hybrid hydrogels were prepared by using chitosan as a natural polymer and polyurethane containing azomethine as a synthetic polymer for the drug delivery application for 5-fluorouracil. The fabricated hydrogels were characterized via FT-IR and SEM analysis. Besides, the thermal, mechanical, and wettability properties, water uptake, biodegradation, protein absorption, drug loading, and release behaviors of the hybrid hydrogels were studied. The obtained results indicated that the fabricated hybrid hydrogels have exhibited good mechanical, hydrophilic, water uptake, and biodegradation behaviors. The hybrid hydrogels also showed 50% drug release amounts and they could be a good candidate for the controlled delivery of 5-FU due to these properties.     

Design and preparation of pH-responsive curdlan hydrogels as a novel protein delivery vector

New pH-responsive saccharide hydrogels were designed and prepared using curdlan derivatives(curdlan-Bochistidine, CUR-HIS). The CUR-HIS hydrogels possessed highly porous structures. The swelling ratios of CUR-HIS hydrogels increased with the degree of substitution of Boc-histidine groups. And the addition of 0.5 mol/L Na Cl provoked a sharp reduction of swelling ratio of CUR-HIS hydrogels. Bovine serum albumin(BSA) can be efficiently encapsulated into CUR-HIS hydrogels. Moreover, the release profiles of BSA at different p H values from CUR-HIS hydrogels were significantly different. These hydrogels showed good biocompatibility in the cytotoxicity assays. The CUR-HIS hydrogels are of great potential in biomedical applications such as protein delivery systems.