pH-sensitive hydrogel based on carboxymethyl chitosan/sodium alginate and its application for drug delivery

Carboxymethyl chitosan sodium salt (CMCS)/sodium alginate (SA), a pH-sensitive hydrogel composed of CMCS and SA crosslinked by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide, has been evaluated in vitro as a potential carrier for protein drug delivery of bovine serum albumin (BSA). The crosslinked structures, pore morphologies, and mechanical properties of the composite CMCS/SA hydrogel at different pH have been characterized by Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and dynamic mechanical analysis (DMA). The swelling behavior of the prepared hydrogel was assessed at different pH values, 1.2, 4.0, 6.86, 7.4, and 9.0. The in vitro slow release ability of the CMCS/SA hydrogel was assessed at 37°C and pH 1.2 or pH 7.4 to simulate gastrointestinal and mouth environments in vivo. The efficiency was found to be greater than 90% at pH 7.4. The composite CMCS/SA hydrogel showed no cytotoxic effect toward L-929 cells according to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. These findings demonstrate that the composite hydrogel has promising potential for drug delivery. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 46911.     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006     

Calcium‐carboxymethyl chitosan hydrogel beads for protein drug delivery system

In this study, carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca²⁺. The pH‐sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions. As a potential protein drug delivery system, the beads were loaded with a model protein (bovine serum albumin, BSA). To improve the entrapment efficiency of BSA, the beads were further coated with a chitosan/CMC polyelectrolyte complex (PEC) membrane by extruding a CMC/BSA solution into a CaCl₂/chitosan gelation medium. Finally, the release studies of BSA‐loaded beads were conducted. We found that, the maximum swelling ratios of the beads at pH 7.4 (17–21) were much higher than those at pH 1.2 (2–2.5). Higher entrapment efficiency (73.2%) was achieved in the chitosan‐coated calcium‐CMC beads, compared with that (44.4%) in the bare calcium‐CMC beads. The PEC membrane limited the BSA release, while the final disintegration of beads at pH 7.4 still leaded to a full BSA release. Therefore, the chitosan‐coated calcium‐CMC hydrogel beads with higher entrapment efficiency and proper protein release properties were a promising protein drug carrier for the site‐specific release in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3164–3168, 2007     

Complex aggregates formed with a hyperbranched polyglycerol derivative for drug delivery

An amphiphilic hyperbranched polyglycerol derivative (HPG‐C18) was synthesized by the anionic ring‐opening copolymerization with glycidol and 1,2‐epoxyloctadecane as the monomers. This hyperbranched polymer formed large complex aggregates as confirmed by dynamic light scattering and transmission electron microscopy tests. Because of its amphiphilic properties, HPG‐C18 was explored to load hydrophobic docetaxel, a clinical antitumor drug, and deliver it into breast cancer cell line (MCF‐7) cells. To investigate the application of the aggregates in drug delivery, blood compatibility was studied by hemolysis analysis, red blood cell observation, and thromboelastography assay. These results indicate that HPG‐C18 inhibited MCF‐7 proliferation effectively with good blood compatibility, and this suggested a potential application in tumor therapy. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42895.     

Controlled drug delivery studies of biological macromolecules: Sodium alginate and lignosulphonic acid films

The ciprofloxacin (CPX)‐loaded blends made of sodium alginate and lignosulfonic acid (LS) were prepared by solution casting method in the ratio of 80/20. The blends were crosslinked for different intervals of time to control the drug release. The drug release was investigated for 24 hours in different pH medium (1, 4, 7, and 9). It was confirmed that drug release is controlled by diffusion through the polymer matrix followed by the erosion of the polymer. The pH of the surrounding medium influences the drug solubility, swelling, and degradation rate of the polymer and therefore the overall drug release process. The blend shows minimal drug release at pH 1 and 9, whereas moderate release at pH 4, but rapid release at pH 7. Further FTIR, XRD, and SEM characterization are carried, to confirm the chemical‐interaction, crystallization effects, and compatibility between the blend matrixes. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40442.     

Design of intelligent chitosan/heparin hollow microcapsules for drug delivery

In this study, a novel strategy has been developed for the assembly of polyelectrolyte multilayer (PEM) on CaCO₃ templates in acidic pH solutions, where consecutive polyelectrolyte layers (heparin/poly(allylamine hydrochloride) or heparin/chitosan) were deposited on PEM hollow microcapsules established previously on CaCO₃ templates. The PEM build‐up, hollow capsule characterization and successful encapsulation of fluorescein 5(6)‐isothiocyanate (FITC)‐Dextran by coprecipitation with CaCO₃ are demonstrated. Improvement by the removal of CaCO₃ core was achieved while the depositions. In the course of the release profile, high retardation for encapsulated FITC‐Dextran was observed. The combined shell capsules system is a significant trait that has potential use in tailoring functional layer‐by‐layer capsules as intelligent drug delivery vehicles where the preliminary in vitro tests showed the responsiveness on the enzymes. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44425.     

A rechargeable drug delivery system based on pNIPAM hydrogel for the local release of curcumin

This study was designed to develop a drug delivery system based on poly(N-isopropylacrylamide) (pNIPAM) hydrogel and a suitable solvent to enhance solubility and local release of curcumin. pNIPAM hydrogel was synthesized by radical polymerization. The chemical, mechanical and physical properties and biocompatibility of pNIPAM hydrogel were investigated as an implantable and rechargeable drug reservoir. Curcumin was loaded within pNIPAM hydrogel during swelling by using two different solvents; methanol, an organic solvent, and low molecular weight polyethylene glycol (PEG200), a polymeric solvent. The results of drug solubility showed that using PEG200 can increase curcumin solubility more than commonly used organic solvents such as methanol. Also, the release profile of drug-loaded hydrogels demonstrated that PEG200 has a superior effect on the cumulative amount of released curcumin (33.163 ± 0.319 μg/ml) compared to methanol (8.765 ± 0.544 μg/ml) during 1 week. Based on our results, curcumin-loaded hydrogels did not show any cytotoxicity, and pNIPAM/PEG combination represented an antibacterial effect within 12 hours. Accordingly, it can be concluded that pNIPAM hydrogel in combination with low molecular weight PEG200 could be used as an efficient drug delivery system to preserve and provide sustained release of curcumin as a hydrophobic drug.     

5‐Fluorouracil encapsulated magnetic nanohydrogels for drug‐delivery applications

For the first time, green‐tea (GT)‐based magnetic nanohydrogels were developed for drug‐delivery purposes. The hydrogel matrices were fabricated via the in situ polymerization of acrylamide with GT molecules. Magnetic nanoparticles were synthesized by the reduction of the 1:2 molar ratio mixture of ferrous sulfate heptahydrate and ferric chloride hexahydrate with an ammonia solution. A chemotherapeutic drug, 5‐fluorouracil, was chosen as a model drug, and its releasing profiles in the presence and absence of the external magnetic field were evaluated at a pH of 7.4. We observed that in the presence of the applied magnetic field, these magnetic nanohydrogels released 2.86% more drug than in the absence of a magnetic field. The magnetic nanohydrogels were characterized by X‐ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, vibrating sample magnetometry, and transmission electron microscopy. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43921.     

Gold/chitosan/pluronic composite nanoparticles for drug delivery

Composite nanoparticles were prepared and characterized as a sustained delivery system for paclitaxel, an anticancer drug. Gold nanoparticles were used as building blocks for constructing the composite nanoparticles. An ionic interaction between the anionic gold nanoparticles and cationic chitosan was induced to form the composite nanoparticles. Particle size analysis, field emission scanning electron microscopy, transmittance electron microscopy, and ultraviolet–visible were used to observe the formation of the composite nanoparticles. For the application of the composite nanoparticles as a drug carrier, paclitaxel was loaded into the composite nanoparticles, and the drug-release pattern was observed. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Thermal,electrical, and mechanical properties of tween 80/span 80–based organogels and its application in iontophoretic drug delivery

The present study describes the preparation and characterization of the Tween 80/Span 80 and sunflower oil–based organogels. Organogels were characterized using microscopy, X‐ray diffraction, thermal, mechanical, and electrical techniques. The properties were found to be dependent on the proportion of the water : surfactant mixture. The in vitro drug release studies were performed under electrical potential. The drug release in the presence of electrical current was compared with the passive drug release. The drug release from the organogels followed the zero‐order kinetics suggesting diffusion mediated release. The preliminary results suggested that the organogels may be used as drug carriers in iontophoretic drug delivery. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41419.     

Polyhydroxyalkanoates,a family of natural polymers,and their applications in drug delivery

Polyhydroxyalkanoates (PHAs) are natural biopolymers produced by various microorganisms as a reserve of carbon and energy. PHA synthesis generally occurs during fermentation under nutrient limiting conditions with excess carbon. There are two main types of PHAs, short chain length PHAs (scl‐PHAs) and medium chain length PHAs (mcl‐PHAs). The mechanical and thermal properties of PHAs depend mainly on the number of carbons in the monomer unit and its molecular weight. PHAs are promising materials for biomedical applications because they are biodegradable, non‐toxic and biocompatible. The large range of PHAs, along with their varying physical properties and high biocompatibility, make them highly attractive biomaterials for use in drug delivery. They can be used to produce tablets, micro‐ and nanoparticles as well as drug eluting scaffolds. A large range of different PHAs have been explored and the results obtained suggest that PHAs are excellent candidates for controlled and targeted drug delivery systems. © 2015 Society of Chemical Industry     

亲水性聚氨酯压敏胶经皮给药应用性能研究

针对目前经皮给药制剂发展急需性能优良的亲水性新型压敏胶基质,制备了亲水性聚氨酯压敏胶。对一些影响压敏胶贴剂力学性能的因素进行了考察,并重点研究了载药压敏胶贴剂经皮释放规律。结果表明,该聚氨酯压敏胶贴剂具有良好的药物控释能力,适用于经皮给药系统。     

Exploring poly(vinyl alcohol) hydrogels containing drug–cyclodextrin complexes as controlled drug delivery systems

Poly(vinyl alcohol) (PVA) hydrogels containing drug–β‐cyclodextrin inclusion complexes (ICs) were synthesized with glutaraldehyde (GA) as a crosslinker. The role of cyclodextrin (CD), the effect of the nature of drug, and the degree of crosslinking on the drug‐release process were investigated. The probable mechanism of drug release was also explored. Controlled release of the drug was achieved from the hydrogels containing the ICs. The nature of the drug, in terms of its binding efficacy with CD, played an important role. The effect of the degree of crosslinking on the release pattern was strikingly different from that in the hydrogels containing free drug and those with ICs. The role of CD in the drug‐release process was not only due to its inclusion ability but also its effect on the polymer relaxation. GA, apart from crosslinking PVA, probably interacted with the cyclodextrins and, thereby, influenced the matrix structure and the drug‐release kinetics. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40318.     

The effects of graphene oxide on the properties and drug delivery of konjac glucomannan hydrogel

Konjac glucomannan (KGM) hydrogel has good potential application in food and medical science, although to achieve this, the physical and mechanical properties need further improvement. In this study, graphene oxide (GO) was used to improve the functionality of KGM hydrogel. KGM/GO hydrogels were prepared by freezing the alkaline KGM/GO sols. Rotational rheometer was used to study the rheological properties of different alkaline KGM/GO sols. Fourier transform infrared, Raman, differential scanning calorimetry, thermogravimetric analyses, and scanning electron microscopy were used to evaluate the structure and properties of the hydrogels. In addition, different pH solutions and an in vitro assay were used to study the swelling property and the release behavior of KGM/GO hydrogels, respectively. The result revealed strong hydrogen‐bond interaction between KGM and GO. The incorporation of GO highly improved the gel properties of KGM/GO sol, higher thermal stability, and more compact structure of KGM/GO hydrogels. KGM/GO hydrogels showed better swelling properties in deionized‐distilled water and pH 7.2 PBS. The release of 5‐aminosalicylic acid (5‐ASA) from KGM/GO (KG4) hydrogel was different in various pH media, but the initial burst release effect was very severe. Therefore, incorporation of GO have a good potential in enhancing the properties of KGM hydrogel, but KGM/GO hydrogel is not an ideal carrier for 5‐ASA release. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45327.     

Barium chloride crosslinked carboxymethyl guar gum beads for gastrointestinal drug delivery

A mild method for microencapsulation of sensitive drugs, such as proteins, employing a suitably derivatized carboxymethyl guar gum (CMGG) and multivalent metal ions like Ca⁺⁺ and Ba⁺⁺ is reported. Initially, guar gum is derivatized with carboxymethyl groups so that it forms durable, self‐standing microbeads when its solution is dropped into CaCl₂ or BaCl₂ solutions. The swelling data of Ca⁺⁺ and Ba⁺⁺ crosslinked beads suggest that Ba⁺⁺ crosslinks CMGG much more efficiently than Ca⁺⁺. The drug loading efficiency of these Ba⁺⁺/CMGG beads, as a function of concentration of both metal ion as well as drug, was then determined using Bovine Serum Albumin as a model drug. The ability of these beads to protect the drug from the acidic environment of the stomach was investigated. It was found that a very little amount of the drug is released from the beads when they are suspended in NaCl–HCl buffer of pH 1.2 for 6 h. The beads were also shown to release almost the entire encapsulated drug when exposed to TRIS–HCl buffer of pH 7.4. Thus, the results indicate that Ba⁺⁺ crosslinked carboxymethyl guar gum beads can be used for gastrointestinal drug delivery. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 3084–3090, 2001     

Comparative delivery of Diltiazem hydrochloride through synthesized polymer: Hydrogel and hydrogel microspheres

In this study, interpenetrating polymer network (IPN) hydrogel based on polyvinyl alcohol (PVA) networking with polyacrylic acid (PAA) were prepared by a non‐conventional emulsion method without any added crosslinker, using benzoyl peroxide as initiator and sodium chloride (NaCl) as additive. The IPN hydrogel was characterized by using Fourier transformed infrared (FTIR) spectrophotometry, Thermo gravimetric analysis (TGA), and Scanning electron microscopy (SEM). (PVA‐co‐PAA)/NaCl normal IPN hydrogel (H) were fabricated into hydrogel microspheres (HM) by modified emulsion crosslinking method using glutaraldehyde‐saturated toluene as crosslinker and were loaded with Diltiazem hydrochloride (DL). The IPN hydrogel showed more swelling in simulated intestinal fluid (SIF). (PVA‐co‐PAA)/NaCl HM formulation A1 showed comparatively higher DL entrapment (79%) and better control over DL release up to 24 h. By comparing antihypertensive activity of DL loaded two formulations in normotensive rats, HM formulation A1 found more effective in reducing blood pressure to 40.1%. The experimental results demonstrated that (PVA‐co‐PAA)/NaCl HM had the greater potential than normal hydrogel to be used as a drug carrier. A single use of the prepared hydrogel microsphere system of DL can effectively control hypertension in rats. The system holds promise for clinical studies. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Carbohydrate crosslinked biocompatible polyurethanes: Synthesis,characterization, and drug delivery studies

A series of novel polyurethanes (PUs) with carbohydrate crosslinkers was synthesized. The drug loading and release kinetics were studied by using lamotrigine as a model drug. The polymers were designed in such a way that the drug release was tailored by differences in the stoichiometry of polymers. All the PUs were characterized for thermal and morphological properties by using differential scanning calorimetry and thermogravimetric analysis and scanning electron microscope , respectively. The encapsulation of drug inside PU matrix was confirmed via Fourier transform ‐ infrared (FT‐IR) spectra and scanning electron microscope . The kinetics and release mechanisms were observed to be a function of stoichiometric parameters such as type of crosslinker, polyol/crosslinker ratio and polyol/chain extender ratio. All the PUs were observed to be non‐cytotoxic in normal lung cell line L132. The synthesized PUs exhibited good mechanical strength, tunable release rates and biocompatibility that can be utilized in biomedical applications like wound dressing, biomedical implants , and drug delivery carriers. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42223.     

Green fabrication of porous chitosan/graphene oxide composite xerogels for drug delivery

Porous chitosan (CS)/graphene oxide (GO) composite xerogels were prepared through a simple and “green” freeze‐drying method. Scanning electron microscopy, Fourier transform infrared spectrometry, powder X‐ray diffraction, and compressive strength measurements were performed to characterize the microstructures and mechanical properties of as‐prepared composite xerogels. The results show that the incorporation of GO resulted in an observable change in the porous structure and an obvious increase in the compressive strength. The abilities of the composite xerogels to absorb and slowly release an anticancer drug, doxorubicin hydrochloride (DOX), in particular, the influence of different GO contents, were investigated systematically. The porous CS/GO composite xerogels exhibited efficient DOX‐delivery ability, and both the adsorption and slow‐release abilities increased obviously with increasing GO content. Additionally, the best adsorption concentration of DOX was 0.2 mg/mL, and the cumulative release percentage of DOX from the xerogels at pH4 much higher than that at pH 7.4. Therefore, such porous CS/GO composite xerogels could be promising materials as postoperation implanting stents for the design of new anticancer drug‐release carriers. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014 , 131, 40006.     

Impacts of PEGylation on the gene and oligonucleotide delivery system

Poly(ethylene glycol) (PEG) is the most widely used polymer and also the gold standard in the field of drug delivery. Therapeutic oligonucleotides, for example, are modified with PEG at the terminus to increases nuclease resistance and the circulating half‐lives. The surface of nanoparticle such as micelle and liposome has been also modified with PEG. At present, one PEGylated therapeutic oligonucleotide has been approved for the market and several more PEGylated products including oligonucleotide and liposome are being tested in clinical settings. This review summarizes the methods and effects of PEGylation on gene delivery. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40293.