Control releasing 5-aminosalicylic acid using pH-sensitive hydrogel with novel albumin cross-linker

Intelligent drug delivery systems are growing and changing too fast, these systems usually show a proper response at the proper time to one or several environmental factors. In the current research a biodegradable drug delivery system (pectin-g-PMA-co-PAAm) was designed and synthesized to release 5 aminosalicylic acid (5-ASA). The synthesized hydrogel is based on natural pectin and is in the form of simultaneous graft copolymerization of synthesized acryl-acid and acryl-amid. Using vinylized bovine serum albumin (VBSA) as cross linker agent is amongst important characteristics of this hydrogel. VBSA was synthesized through BSA modification with methylene-bis-acrylamide (MBA). In addition to having high water absorption, this hydrogel is pH-sensitive. In vitro tests under acid and base conditions of stomach show that this hydrogel is an appropriate option to release drugs through mouth. SEM analysis images show that synthesized hydrogel has a porous surface composed of nano and micro cavities.     

Comprehensive Examination of Mechanical and Diffusional Effects on Cell Behavior Using a Decoupled 3D Hydrogel System

Hydrogels possess several physical and chemical properties suitable for engineering cellular environments for biomedical applications. Despite recent advances in hydrogel systems for cell culture, it is still a significant challenge to independently control the mechanical and diffusional properties of hydrogels, both of which are well known to influence various cell behaviors when using hydrogels as 3D cell culture systems. Controlling the crosslinking density of a hydrogel system to tune the mechanical properties inevitably affects their diffusional properties, as the crosslinking density and diffusion are often inversely correlated. In this study, a polymeric crosslinker is demonstrated that allows for the adjustment of the degree of substitution of reactive functional groups. By using this polymeric crosslinker, the rigidity of the resulting hydrogel is controlled in a wide range without changing the polymer concentration. Furthermore, their diffusional properties, as characterized by their swelling ratios, pore diameters, and drug release rates, are not significantly affected by the changes in the degree of substitution. 3D cell studies using this hydrogel system successfully demonstrate the varying effects of mechanical properties on different cell types, whereas those in a conventional hydrogel system are more significantly influenced by changes in diffusional properties.     

天然糖类纳米药物传递系统的研究进展

纳米技术作为影响未来人类生活的世界三大新兴科技之一,其与药物传递系统的融合,既可以将药物的药理作用极大限度地发挥出来,又克服了药物本身的局限性.天然糖类的来源十分广泛,不仅价格低廉、无毒性,且具有良好的生物相容性和生物可降解性,被广泛用于纳米药物传递系统.本文对纳米药物传递系统的体系组成进行了归纳,重点阐述了常见糖类及...     

The Research on Intelligent Controlled DDS of Polymer Carrier

The intelligent controlled drug delivery systems (DDS) are a series of the preparations including microcapsules or nanocapsules composed of intelligent polymers and medication. The properties of preparations can change with the external stimuli, such as pH value, temperature,chemical substance, light, electricity and magnetism etc. According to this properties, the DDS can be intelligently controlled. This paper has reviemed research on syntheses and applications of intelligent controlled DDS of polymer carriers.Drug delivery system with pH stimuliThe volume of polymer hydrogel can change with the pH value of external environment. The sensitive polymer hydrogels to pH are often as carriers. The polymer hydrogel carrying medicine is especially suitable for taking orally. In order to protect medicine from losing activation, we enwrapped medicine into polymer hydrogel with acidic group. In the acidic environment of stomach,the volume of polymer hydrogel contracts because of the hydrogen bond. The medicine in the polymer hydrogel cannot disperse out. When it goes to the intestine of basic environment, the hydrogen bond will be broken, and the medicine can release.Drug delivery system with temperatureTemperature sensitive polymer hydrogel can change its volume with changing of environmental temperature. This kind of polymer hydrogel can be also used as a carrier of medicine. At a low temperature, the polymer chains form hydrogen bond with water to swell to let medicine disperse out from the hydrogel. On the other hand, the hydrogen bond will be broken and polymer chain will lose water to contract with temperature's increasing. And the medicine will not disperse out. For example,the poly(N-isopropylacrylamide)(PNIPAAm) is the hydrogel that is swelled at lower temperature and contracted at higher temperature. PNIPAAm has the lower critical solution temperature(LCST).We can adjust its LCST to control PNIPAAm hydrogel's swelling or contraction to let medicine release or not.Drug delivery system with other stimuliThe polymer carrier drug delivery system can be intelligently controlled with the stimuli of pH value and temperature. In addition, there are still some other stimuli for DDS. For example, DDS with light; DDS with electricity(or electric field); DDS with magnetism(magnetic field); DDS with chemical substance; etc. The characteristic of intelligent polymer carrier is based on P.J.Flory's gel-swelling theory. Intelligent polymer carrier DDS will be widely used in biological and medical fields.     

Design Strategies of Conductive Hydrogel for Biomedical Applications

Conductive hydrogel, with electroconductive properties and high water content in a three-dimensional structure is prepared by incorporating conductive polymers, conductive nanoparticles, or other conductive elements, into hydrogel systems through various strategies. Conductive hydrogel has recently attracted extensive attention in the biomedical field. Using different conductivity strategies, conductive hydrogel can have adjustable physical and biochemical properties that suit different biomedical needs. The conductive hydrogel can serve as a scaffold with high swelling and stimulus responsiveness to support cell growth in vitro and to facilitate wound healing, drug delivery and tissue regeneration in vivo. Conductive hydrogel can also be used to detect biomolecules in the form of biosensors. In this review, we summarize the current design strategies of conductive hydrogel developed for applications in the biomedical field as well as the perspective approach for integration with biofabrication technologies.     

Structured emulsion-based delivery systems: Controlling the digestion and release of lipophilic food components

There is a need for edible delivery systems to encapsulate, protect and release bioactive and functional lipophilic constituents within the food and pharmaceutical industries. These delivery systems could be used for a number of purposes: controlling lipid bioavailability; targeting the delivery of bioactive components within the gastrointestinal tract; and designing food matrices that delay lipid digestion and induce satiety. Emulsion technology is particularly suited for the design and fabrication of delivery systems for lipids. In this article we provide an overview of a number of emulsion-based technologies that can be used as edible delivery systems by the food and other industries, including conventional emulsions, nanoemulsions, multilayer emulsions, solid lipid particles, and filled hydrogel particles. Each of these delivery systems can be produced from food-grade (GRAS) ingredients (e.g., lipids, proteins, polysaccharides, surfactants, and minerals) using relatively simple processing operations (e.g., mixing, homogenizing, and thermal processing). The structure, preparation, and utilization of each type of delivery system for controlling lipid digestion are discussed. This knowledge can be used to select the most appropriate emulsion-based delivery system for specific applications, such as encapsulation, controlled digestion, and targeted release.     

Injectable hydrogels for targeted delivering of therapeutic molecules for tissue engineering and disease treatment

Hydrogels are cross‐linked three‐dimensional polymeric networks that play a vital role in solving the pharmacological and clinical limitations of the existing systems due to their unique physical properties such as affinity for biological fluids, tunable porous nature, high water content, ease of preparation, flexibility, and biocompatibility. Hydrogel also mimics the living natural tissue, which opens several opportunities for its use in biomedical areas. Injectable hydrogel allows temporal control and exceptional spatial arrangements and can offset hitches with established hydrogel‐based drug delivery systems. Here, we review the recent development of injectable hydrogels and their significance in the delivery of therapeutics such as cells, genes, and drug molecules and how these innovatory systems can complement the current delivery systems.     

Sustained release drug delivery using supramolecular hydrogels of the triblock copolymer PCL–PEG–PCL and α-cyclodextrin

Supramolecular hydrogels (SMGel) have attracted much attention as a drug and gene delivery system in recent years. In this study, SMGels based on the tri-block copolymer of poly-ε-caprolactone–polyethylene glycol–poly-ε-caprolactone (PCL–PEG–PCL) and α-cyclodextrin (α-CD) were prepared and evaluated for the delivery of two model drugs, naltrexone hydrochloride and vitamin B₁₂. Tri-block copolymers were synthesized easily in 15 min by ring-opening polymerization using the microwave irradiation technique, and their structures were determined by gel permeation chromatography and nuclear magnetic resonance methods. SMGels composed of various concentrations of the copolymer and α-CD were prepared and characterized for their rheological behaviour, their gel formation time and in vitro drug release profile. The results indicated that copolymers with a PCL to PEG ratio of 1:4 are suitable for SMGel preparation. The most viscose system with good syringeability was prepared by mixing 12 % wt α-CD and 10 % wt of copolymer. The gelation was found to occur within a minute after mixing. The viscosity of the hydrogel systems was determined as a function of shear rate. Finally, in vitro B₁₂ release through the hydrogel systems was studied. Up to 80 % of Vitamin B₁₂ was released through this system during a period of 20 days. Rheological evaluation revealed that the hydrogel has shear thinning properties, and the system regained its ground rheological state in a time dependent manner. Polymer concentration did not affect the drug release profiles. Finally, it was concluded that such systems are appropriate drug delivery systems due to their ability to provide a controlled drug release profile and their shear thinning thixotropic behaviour, which makes them syringeable and injectable.     

NOVEL pH-SENSITIVE DRUG DELIVERY SYSTEM BASED ON NATURAL POLYSACCHARIDE FOR DOXORUBICIN RELEASE

A novel pH-sensitive nanoparticle drug delivery system (DDS) derived fl'om natural polysaccharide pullulan for doxorubicin (DOX) release was prepared.Pullulan was functionalized by successive carboxymethylization and amidation to introduce hydrazide groups.DOX was then grafted onto pullulan backbone through the pH-sensitive hydrazone bond to form a pullulan/DOX conjugate.This conjugate self-assembled to form nano-sized particles in aqueous solution as a result of the hydrophobic interaction of the DOX.Tr...     

Magnetic Resonance Methods as a Prognostic Tool for the Biorelevant Behavior of Xanthan Tablets

Hydrophilic matrix tablets with controlled drug release have been used extensively as one of the most successful oral drug delivery systems for optimizing therapeutic efficacy. In this work, magnetic resonance imaging (MRI) is used to study the influence of various pHs and mechanical stresses caused by medium flow (at rest, 80, or 150 mL/min) on swelling and on pentoxifylline release from xanthan (Xan) tablets. Moreover, a bimodal MRI system with simultaneous release testing enables measurements of hydrogel thickness and drug release, both under the same experimental conditions and at the same time. The results show that in water, the hydrogel structure is weaker and less resistant to erosion than the Xan structure in the acid medium. Different hydrogel structures affect drug release with erosion controlled release in water and diffusion controlled release in the acid medium. Mechanical stress simulating gastrointestinal contraction has no effect on the hard hydrogel in the acid medium where the release is independent of the tested stress, while it affects the release from the weak hydrogel in water with faster release under high stress. Our findings suggest that simultaneous MR imaging and drug release from matrix tablets together provide a valuable prognostic tool for prolonged drug delivery design.     

Dual-Responsive Alginate Hydrogel Constructed by Sulfhdryl Dendrimer as an Intelligent System for Drug Delivery

Intelligent stimulus-triggered release and high drug-loading capacity are crucial requirements for drug delivery systems in cancer treatment. Based on the excessive intracellular GSH expression and pH conditions in tumor cells, a novel glutathione (GSH) and pH dual-responsive hydrogel was designed and synthesized by conjugates of glutamic acid-cysteine dendrimer with alginate (Glu-Cys-SA) through click reaction, and then cross-linked with polyethylene glycol (PEG) through hydrogen bonds to form a 3D-net structure. The hydrogel, self-assembled by the inner disulfide bonds of the dendrimer, is designed to respond to the GSH heterogeneity in tumors, with a remarkably high drug loading capacity. The Dox-loaded Glu-Cys-SA hydrogel showed controlled drug release behavior, significantly with a release rate of over 76% in response to GSH. The cytotoxicity investigation indicated that the prepared DOX-loaded hydrogel exhibited comparable anti-tumor activity against HepG-2 cells with positive control. These biocompatible hydrogels are expected to be well-designed GSH and pH dual-sensitive conjugates or polymers for efficient anticancer drug delivery.     

Nanostructured Lipid Carriers-Hydrogels System for Drug Delivery: Nanohybrid Technology Perspective

Advanced hybrid component development in nanotechnology provides superior functionality in the application of scientific knowledge for the drug delivery industry. The purpose of this paper is to review important nanohybrid perspectives in drug delivery between nanostructured lipid carriers (NLC) and hydrogel systems. The hybrid system may result in the enhancement of each component’s synergistic properties in the mechanical strength of the hydrogel and concomitantly decrease aggregation of the NLC. The significant progress in nanostructured lipid carriers–hydrogels is reviewed here, with an emphasis on their preparation, potential applications, advantages, and underlying issues associated with these exciting materials.     

Hydrogel-mediated drug delivery for treating stroke

Stroke is a common disease and is the major cause of death and disability. It occurs and generates devastating neurological deficits when cerebral blood vessel is blocked(ischemic stroke, IS) or ruptured(hemorrhagic stroke, HS). Hydrogel, being biodegradable and biocompatible, have shown attractive advantages in stroke therapy as a new biomaterial with desirable mechanical properties and tunability of structure,owing to special ability to load different cargoes for multiple treatment strategies,...     

Photo‐Modulated Therapeutic Protein Release from a Hydrogel Depot Using Visible Light

The use of biomacromolecular therapeutics has revolutionized disease treatment, but frequent injections are required owing to their short half‐life in vivo. Thus there is a need for a drug delivery system that acts as a reservoir and releases the drug remotely “on demand”. Here we demonstrate a simple light‐triggered local drug delivery system through photo‐thermal interactions of polymer‐coated gold nanoparticles (AuNPs) inside an agarose hydrogel as therapeutic depot. Localized temperature increase induced by the visible light exposure caused reversible softening of the hydrogel matrix to release the pre‐loaded therapeutics. The release profile can be adjusted by AuNPs and agarose concentrations, light intensity and exposure time. Importantly, the biological activity of the released bevacizumab was highly retained. In this study we demonstrate the potential application of this facile AuNPs/hydrogel system for ocular therapeutics delivery through its versatility to release multiple biologics, compatibility to ocular cells and spatiotemporal control using visible light.     

Construction of Organelle-Like Architecture by Dynamic DNA Assembly in Living Cells

The design of controllable dynamic systems is vital for the construction of organelle-like architectures in living cells, but has proven difficult due to the lack of control over defined topological transformation of self-assembled structures. Herein, we report a DNA based dynamic assembly system that achieves lysosomal acidic microenvironment specifically inducing topological transformation from nanoparticles to organelle-like hydrogel architecture in living cells. Designer DNA nanoparticles are constructed from double-stranded DNA with cytosine-rich stick ends (C-monomer) and are internalized into cells through lysosomal pathway. The lysosomal acidic microenvironment can activate the assembly of DNA monomers, inducing transformation from nanoparticles to micro-sized organelle-like hydrogel which could further escape into cytoplasm. We show how the hydrogel regulates cellular behaviors: cytoskeleton is deformed, cell tentacles are significantly shortened, and cell migration is promoted.     

On-Demand Hydrophobic Drug Release Based on Microwave-Responsive Graphene Hydrogel Scaffolds

Electromagnetically driven drug delivery systems stand out among stimulus-responsive materials due to their ability to release cargo on demand by remote stimulation, such as light, near infrared (NIR) or microwave (MW) radiation. MW-responsive soft materials, such as hydrogels, generally operate at 2.45 GHz frequencies, which usually involves rapid overheating of the scaffold and may affect tissue surrounding the target location. In contrast, 915 MHz MW penetrate deeper tissues and are less prone to induce rapid overheating. In order to circumvent these limitations, we present here for the first time a graphene-based hydrogel that is responsive to MW irradiation of ν=915 MHz. This system is a candidate soft scaffold to deliver a model hydrophobic drug. The graphene present in the hydrogel acts as a heat-sink and avoids overheating of the scaffold upon MW irradiation. In addition, the microwave trigger stimulates the in vitro delivery of the model drug, thus suggesting a remote and deep-penetrating means to deliver a drug from a delivery reservoir. Moreover, the MW-triggered release of drug was observed to be enhanced under acidic conditions, where the swelling state is maximum due to the swelling-induced pH-responsiveness of the hydrogel. The hybrid composite described here is a harmless means to deliver remotely a hydrophobic drug on demand with a MW source of 915 MHz. Potential use in biomedical applications were evaluated by cytotoxicity tests.     

A Synthetic Toolbox for the In Situ Formation of Functionalized Homo‐ and Heteropolysaccharide‐Based Hydrogel Libraries

A synthetic toolbox for the introduction of aldehydo and hydrazido groups into the polysaccharides hyaluronic acid, alginate, dextran, pullulan, glycogen, and carboxymethyl cellulose and their use for hydrogel formation is reported. Upon mixing differently functionalized polysaccharides derived from the same natural precursor, hydrazone cross‐linking takes place, which results in formation of a hydrogel composed of one type of polysaccharide backbone. Likewise, hydrogels based on two different polysaccharide strands can be formed after mixing the corresponding aldehydo‐ and hydrazido‐modified polysaccharides. A second line of these studies paves the way to introduce a biomedically relevant ligand, namely, the adhesion factor cyclic RGD pentapeptide, by using an orthogonal click reaction. This set of modified polysaccharides served to create a library of hydrogels that differ in the combination of polysaccharide strands and the degree of cross‐linking. The different hydrogels were evaluated with respect to their rheological properties, their ability to absorb water, and their cytotoxicity towards human fibroblast cell cultures. None of the hydrogels studied were cytotoxic, and, hence, they are in principal biocompatible for applications in tissue engineering.     

Regioselective synthesis of 6-amino- and 6-amido-6-deoxypullulans

Hydrophobically modified polysaccharides that contain amine and amide groups possess valuable features for drug delivery and other applications. These chemical groups are known to play a fundamental role in the biological activity of important polysaccharides. Pullulan is known for its non-toxicity and biocompatibility, therefore, we have applied the versatile Staudinger reaction for the synthesis of regioselectively substituted pullulan derivatives containing amine or amide groups with promise for biomedical applications. The synthesis began with the regioselective bromination of pullulan at C-6 with N-bromosuccinimide and triphenylphosphine, providing 6-bromo-6-deoxy-pullulan, which is soluble in a range of organic solvents and therefore is a dynamic intermediate for the synthesis of other pullulan derivatives. Azide displacement of bromide from 6-bromo-6-deoxy-pullulan esters yielded the corresponding 6-azido-6-deoxy-pullulan esters. Staudinger reduction of these azides efficiently and chemoselectively afforded the corresponding amino- or amidopullulans.     

Multipurpose smart hydrogel systems

This paper represents the review of the last investigations in the field of smart polymeric hydrogels and our contribution to this matter. New hydrogel systems and nanocomposites based on acrylic monomers (acrylamide, acrylonitrile, acrylic acid, N-isopropylacrylamide etc.) with incorporated nanosized colloidal silver, hydroxyapatite and carbon nanotubes with a new set of properties have been obtained and examined. These systems can sharply change their characteristics when minor external physical (electric and magnetic fields, temperature etc.) or chemical (pH, ionic strength) stimuli are applied. Such stimulus-responsive polymeric systems are very promising from the standpoint of different medical applications, especially for the development of intelligent drug delivery systems. On the base of designed hydrogel iontophoretic transdermal therapeutic systems, endoprosthesis for the replacement of bone tissue and hydrogel burns coatings with immobilized mesenchymal cells were obtained and tested.     

Interfacial tension in aqueous biopolymer-surfactant mixtures

The current study offers a first insight into the interfacial properties of pullulan-sodium dodecyl sulphate (SDS) aqueous two-phase systems (ATPS) in the presence of sodium chloride (NaCl). The effect of composition on the interfacial tension (sigma) in these ATPS was investigated over a wide range of pullulan, SDS and NaCl concentrations. An increase in the interfacial tension was observed with increasing pullulan and SDS concentrations and a small increase was also observed as the NaCl concentration was increased. In both cases the interfacial tension increases were closely related to the phase behaviour of these systems; as a consequence of increasing the pullulan, SDS and/or NaCl concentrations, the system moves further away from the critical point. In all systems interfacial tensions (of the order of muN/m) were comparable with those reported for polymer-polymer ATPS. Interfacial tensions sigma can be well correlated with the difference in pullulan and SDS concentrations between the phases (DeltaC pul and DeltaC SDS) and also the tie-line length (TLL); all yield straight lines on a log-log scale.