Novel thermosensitive hydrogel composites based on poly(d,l‐lactide‐co‐glycolide) nanoparticles embedded in poly(n‐isopropyl acrylamide) with sustained drug‐release behavior

To reach sustained drug release, a new composite drug‐delivery system consisting of poly(d,l ‐lactide‐co‐glycolide) (PLGA) nanoparticles (NPs) embedded in thermosensitive poly(N‐isopropyl acrylamide) (PNIPAAm) hydrogels was developed. The PNIPAAm hydrogels were synthesized by free‐radical polymerization and were crosslinked with poly(ethylene glycol) diacrylate, and the PLGA NPs were prepared by a water‐in‐oil‐in‐water double‐emulsion solvent‐evaporation method. The release behavior of the composite hydrogels loaded with albumin–fluorescein isothiocyanate conjugate was studied and compared with that of the drug‐loaded neat hydrogel and PLGA NPs. The results indicate that we could best control the release rate of the drug by loading it to the PLGA NPs and then embedding the whole system in the PNIPAAm hydrogels. The developed composite hydrogel systems showed near zero‐order drug‐release kinetics along with a reduction or omission of initial burst release. The differential scanning calorimetry results reveal that the lower critical solution temperature of the developed composite systems remained almost unchanged (<1°C increase only). Such a characteristic indicated that the thermosensitivity of the PNIPAAm hydrogel was not distinctively affected by the addition of PLGA NPs. In conclusion, an approach was demonstrated for the successful preparation of a new hybrid hydrogel system having improved drug‐release behavior with retained thermosensitivity. The developed systems have enormous potential for many biotechnological applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40625.     

Development and characterization of thermosensitive hydrogels based on poly(N‐isopropylacrylamide) and calcium alginate

This work refers to the synthesis and characterization of thermosensitive hydrogels based on interpenetrating polymer networks (IPNs) of poly(N‐isopropylacrylamide) (PNIPAAm) and calcium alginate in the form of films. The influence of the crosslinking degree of PNIPAAm and alginate content on thermal, swelling, mechanical, and morphological properties of hydrogels is investigated in detail. Characterization of pure PNIPAAm hydrogels and IPN hydrogels was performed by FTIR, DSC, DMA, and SEM. In addition, the studies of equilibrium swelling behavior as well as swelling, deswelling, and reswelling kinetics are performed. The results obtained imply the benefits of synthesizing IPNs based on PNIPAAm and calcium alginate over pure PNIPAAm hydrogels. The presence of calcium alginate contributes to the improvement of mechanical properties, the deswelling rate of hydrogels, and the network porosity, without altering the thermosensitivity of PNIPAAm significantly. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Dual‐responsive semi‐interpenetrating network beads based on calcium alginate/poly(N‐isopropylacrylamide)/poly(sodium acrylate) for sustained drug release

To improve the mechanical strength of natural hydrogels and to obtain a sustained drug‐delivery device, temperature‐/pH‐sensitive hydrogel beads composed of calcium alginate (Ca‐alginate) and poly(N‐isopropylacrylamide) (PNIPAAm) were prepared in the presence of poly(sodium acrylate) (PAANa) with ultrahigh molecular weight (M_η ≥ 1.0 × 10⁷) as a strengthening agent. The influence of PAANa content on the properties, including the beads stability, swelling, and drug‐release behaviors, of the hydrogels was evaluated. Scanning electron microscopy and oscillation experiments were used to analyze the structure and mechanical stability of the hydrogel beads, respectively. The results show that stability of the obtained Ca‐alginate/PNIPAAm hydrogel beads strengthened by PAANa the alginate/poly(N‐isopropyl acrylamide) hydrogel bead (SANBs) was significantly improved compared to that of the beads without PAANa (NANBs) at pH 7.4. The swelling behavior and drug‐release capability of the SANBs were markedly dependent on the PAANa content and on the environmental temperature and pH. The bead sample with a higher percentage of PAANa exhibited a lower swelling rate and slower drug release. The drug release profiles from SANBs were further studied in simulated intestinal fluid, and the results demonstrated here suggest that SANBs could serve as a potential candidate for controlled drug delivery in vivo. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Dual pH‐ and thermal‐responsive nanocomposite hydrogels for controllable delivery of hydrophobic drug baicalein

Hydrogels have been widely used as mild biomaterials due to their bio‐affinity, high drug loading capability and controllable release profiles. However, hydrogel‐based carriers are greatly limited for the delivery of hydrophobic payloads due to the lack of hydrophobic binding sites. Herein, nano‐liposome micelles were embedded in semi‐interpenetrating poly[(N‐isopropylacrylamide)‐co‐chitosan] (PNIPAAm‐co‐CS) and poly[(N‐isopropylacrylamide)‐co‐(sodium alginate)] (PNIPAAm‐co‐SA) hydrogels which were responsive to both temperature and pH, thereby establishing tunable nanocomposite hydrogel delivery systems. Nano‐micelles formed via the self‐assembly of phospholipid could serve as the link between hydrophobic drug and hydrophilic hydrogel due to their special amphiphilic structure. The results of transmission and scanning electron microscopies and infrared spectroscopy showed that the porous hydrogels were successfully fabricated and the liposomes encapsulated with baicalein could be well contained in the network. In addition, the experimental results of response release in vitro revealed that the smart hydrogels showed different degree of sensitiveness under different pH and temperature stimuli. The results of the study demonstrate that combining PNIPAAm‐co‐SA and PNIPAAm‐co‐CS hydrogels with liposomes encapsulated with hydrophobic drugs is a feasible method for hydrophobic drug delivery and have potential application prospects in the medical field. © 2018 Society of Chemical Industry     

Covalently cross‐linked and hydrophobically modified alginic acid hydrogels and their application as drug carriers

Covalently crosslinked and hydrophobically modified alginate hydrogels were prepared through esterification of alginic acid (ALG‐H) with 1,10‐decanediol that functioned as a crosslinking agent and hydrophobic component. The preparation was accomplished with one step and was carried out in N,N‐dimethylformamide solution at a reduced pressure for removing the water produced. The characterization results confirmed the esterification of the products. The modified alginate hydrogels could be used as drug delivery vehicles for controlled release. The drug release study revealed that compared with a calcium alginate hydrogel the modified hydrogels possessed improved loading rate and encapsulation efficiency for the hydrophobic drug(ibuprofen), and a remarkable sustained release behavior was observed. The release kinetics was close to zero order, a desirable drug release pattern. The modified alginate hydrogels were nontoxic and were potentially applicable as a promising biomaterial. POLYM. ENG. SCI., 2013. © 2012 Society of Plastics Engineers     

Synthesis and characterization of a drug‐delivery system based on melamine‐modified poly(vinyl acetate‐co‐maleic anhydride) hydrogel

Three‐dimensional polymeric networks, which quickly swell by imbibing a large amount of water or deswell in response to changes in their external environment, are called hydrogels. These types of polymeric materials are good potential candidates for drug‐delivery systems. In this study, we first synthesized poly(vinyl acetate‐co‐maleic anhydride) by free‐radical copolymerization. Then, they were modified with different molar ratios of melamine to prepare hydrogels that could be used in drug‐delivery systems. The hydrogels were characterized by Fourier transform infrared spectroscopy, ¹H‐NMR, differential scanning calorimetry, and scanning electron microscopy. In the second step, Ceftazidime antibiotic was loaded on selected hydrogels. The in vitro drug release was investigated and compared in three different media (HCl solution at pH = 3 and buffer solutions at pH 6.1and pH 8). © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40389.     

pH/temperature‐responsive semi‐IPN hydrogels composed of alginate and poly(N‐isopropylacrylamide)

Amino semitelechelic poly(N‐isopropylacrylamide) (PNIPAAm) was prepared by radical polymerization with aminoethanethiol hydrochloride as a chain‐transfer agent. Semi‐interpenetrating polymer network (semi‐IPN) hydrogels, composed of alginate and amine‐terminated PNIPAAm, were prepared by crosslinking with calcium chloride. From the swelling behaviors of semi‐IPNs at various pH's and Fourier transform infrared spectra at high temperatures, the formation of a polyelectrolyte complex was confirmed from the reaction between carboxyl groups in alginate and amino groups in modified PNIPAAm. Semi‐IPN hydrogels reached an equilibrium swelling state within 24 h. The water state in hydrogels, investigated by differential scanning calorimetry, showed that sample CAN55 [alginate/PNIPAAm (w/w) = 50/50] exhibited the lowest equilibrium water content and free water content among the hydrogels tested, which was attributed to its more compact structure compared to other samples and the high content of interchain bonding within the hydrogels. Alginate/PNIPAAm semi‐IPN hydrogels exhibited a reasonable sensitivity to the temperature, pH, and ionic strength of swelling medium. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 1128–1139, 2002     

Bupivacaine‐loaded chitosan hydrogels for topical anesthesia in dentistry

The paper describes the preparation of polymeric hydrogels, loaded with bupivacaine, which could represent a good alternative in clinical dentistry as local anesthetics. The hydrogels were prepared by condensation using an amidation reaction between a natural polymer (chitosan) and a synthetic one, poly[(maleic anhydride)‐alt‐(vinyl acetate)]. Infrared spectroscopy studies confirmed crosslinking through the presence of amide bonds, formed between the two types of polymer chains. Scanning electron microscopy results demonstrated that the hydrogels have a porous structure, the pore dimensions being non‐uniform with diameters between 200 and 600 μm. Hydrogels presented good bupivacaine inclusion and release capacity whereas theoretical analysis confirmed the validity of the generalized fractal model, reinforcing a csavi‐universal pattern of drug release. Cytotoxicity tests on human dermal fibroblasts revealed that the obtained hydrogels are not cytotoxic. In vivo, the bupivacaine‐loaded hydrogels presented anesthetic effects after 15 min and no side effects were observed. This system has the advantage of alleviating or eliminating pain associated with invasive procedures and avoiding direct contact of the drug with tissues, leading thus to the prevention of side effects. © 2020 Society of Chemical Industry     

Preparation and properties of core–shell alginate–carboxymethylchitosan hydrogels

BACKGROUND: Hydrogels of alginate (ALG) with partially carboxymethylated chitosan (CMCHI) have been produced for drug delivery, based on the interactions between the negative groups and an ionic crosslinker. In the present work, CMCHI was used to evaluate the influence of amino groups that are positively charged at pH = 4 and 6 on the ALG–CMCHI core–shell hydrogel preparation. An ANOVA statistics tool was used to evaluate the effect of composition, pH and chitosan chemical nature on the morphology and swelling properties of the hydrogels in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). RESULTS: The ALG–CMCHI core–shell hydrogels presented smaller (ca 2.3 µm) and more homogeneous microparticles than those with unmodified chitosan (ca 5.5 µm). The ALG–CMCHI hydrogels showed higher thermal stability and lower degree of swelling in SGF (314%) compared to those with chitosan (708%), since in the former hydrogels the protective layers that surround the particles are negatively charged. CONCLUSION: CMCHI can replace chitosan in the production of core–shell hydrogels with improved properties since the negative charge surrounding the ALG–CMCHI particles favours a lower degree of swelling. The results point out a possible prevention of burst release in SGF, sustaining the swelling ability of the ALG–CMCHI core–shell hydrogels in SIF, promising appropriate drug release. Copyright © 2009 Society of Chemical Industry     

Preparation and characterization of PVA films with magnetic nanoparticles: The effect of particle loading on drug release behavior

This article deals with the drug release behavior of theophylline (Th) from poly(vinyl alcohol) (PVA) hydrogels, prepared with magnetic nanoparticles at different particle loadings. These biocompatible matrices were obtained by incorporating different amounts of an aqueous ferrofluid into PVA hydrogels, loaded with Th as a marker for drug‐delivery studies. PVA films with magnetic particles proved to be magnetic field‐responsive materials as the drug release decreased through the application of a relative low and uniform magnetic field for particle concentrations of 0.9% w/w or higher. Moreover, the percentage of restriction of drug release is found to be correlated with particle loading. The in vitro release profiles were analyzed by applying a semiempirical power law to obtain the kinetic parameters. The value of the release exponent was found to be in the range 0.54–0.56 in all experiments, which thus indicates a predominant diffusional mechanism for drug release from these smart magnetic hydrogels. This effect suggests the possibility of modulating the release behavior by controlling the particle content in the preparation of the composites. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Poly(HEMA)/cyclodextrin‐based hydrogels for subconjunctival delivery of cyclosporin A

To enhance the solubility and ocular permeability of immunosuppressive agent, cyclosporine A (CsA), three types of delivery systems were prepared using (2‐hydroxypropyl)‐β‐cyclodextrin (HPβCD), and 2‐hydroxyethyl methacrylate (HEMA). Those systems are (i) hydrogels of HPβCD with crosslinking agent ethylene glycol diglycidylether, (ii) poly(HEMA) hydrogels, and (iii) different amounts of HPβCD‐containing poly(HEMA) hydrogels indicated as poly(HEMA‐co‐HPβCD). In the presence of HEMA, hydrogels have desired mechanical integrity with lower equilibrium content than that of hydrogels without HEMA. CsA was loaded into the HPβCD‐based hydrogels by embedding from its aqueous suspensions in higher amounts than that of the poly(HEMA) hydrogels that were loaded by CsA–HPβCD complex solution. Although the poly(HEMA) hydrogels are releasing total CsA in 3 days, long‐term release was realized from HPβCD‐based hydrogels. For subconjunctival administration, regarding to the amounts of loaded CsA, release profiles, and mechanical integrity, the most suitable system is poly(HEMA‐co‐HPβCD) hydrogels in high HPβCD content. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40397.     

Gelatin‐carbohydrate phase‐separated hydrogels as bioactive carriers in vaginal delivery: Preparation and physical characterizations

The current study focuses on the alteration of properties of the gelatin hydrogels using polysaccharides (e.g., maltodextrin, dextran, and sodium carboxymethyl cellulose) for probable use in vaginal delivery of antimicrobials. The hydrogels were prepared by varying the proportions of gelatin and polysaccharides and were characterized by microscopy, mechanical testing, and impedance spectroscopy. Metronidazole (MZ), drug of choice for the treatment of bacterial vaginosis, was incorporated within the hydrogels. In vitro release studies of MZ from the hydrogels was studied in‐depth using modified Franz's diffusion cell. Antimicrobial efficiency of the MZ‐loaded hydrogels was tested against E. coli and B. subtilis. The results suggested that the incorporation of polysaccharides resulted in the phase‐separated hydrogels. The properties of the hydrogels was found be suitable for vaginal delivery. The drug release and antimicrobial efficiency from the hydrogels suggested that the developed hydrogels may be used for the delivery of antimicrobials in the vaginal lumen. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40445.     

New biomaterial based on cotton with incorporated Biomolecules

The aim of this study was to investigate a method of embedding l ‐cysteine (l ‐cys), an antimicrobial agent, between layers of chitosan (CH) and sodium alginate (ALG) onto cotton samples obtained via a layer‐by‐layer electrostatic deposition technique via several embedding methods. The results show that the best way to incorporate l ‐cys into the layers was the one that used the property of gelling ALG. To monitor the l ‐cys embedding into the CH/ALG multilayer film, different methods were used: energy‐dispersive X‐ray spectrometry analysis to assess the presence of sulfur on the sample, Ellman's reagent method to analyze l ‐cys release from the sample, and attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FTIR) to compare the ATR–FTIR spectra of the pure l ‐cys and l ‐cys embedded in the CH/ALG multilayer film to study the interaction between the l ‐cys and the CH/ALG multilayer films. Functionalized CH/ALG cotton samples were also investigated for their antibacterial properties toward Staphylococcus aureus and Klebsiella pneumonia with the Japanese Industrial Standard method JIS L 1902:2002, and the results show an enhancement of the antibacterial effect due to the presence of l ‐cys. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40519.     

Dual-responsive release behavior of pH-sensitive PVA/PAAc hydrogels containing temperature-sensitive PVA/PNIPAAm microcapsules

Both temperature and pH responsive drug delivery system was prepared by combining temperature-sensitive poly(vinyl alcohol) (PVA)/poly(N-isopropylacrylamide) (PNIPAAm) microcapsules and pH-sensitive PVA/poly(acrylic acid) (PAAc) hydrogels. The release of drug from the composite hydrogels increased as the pH increased due to the repulsion among the carboxylate anions in the PVA/PAAc hydrogels. The release of drug from the composite hydrogels also increased as the temperature decreased due to the higher hydrophilicity generated below the lower critical solution temperature of PNIPAAm. The compression moduli of composite hydrogels increased with increasing the content of PVA/PNIPAAm microcapsules. The biocompatibility of composite hydrogels was confirmed by the cytotoxicity test.     

Development of silver nanoparticles‐loaded calcium alginate beads embedded in gelatin scaffolds for use as wound dressings

Silver nanoparticles (AgNPs)‐loaded calcium alginate beads embedded in gelatin scaffolds were developed to sustain and maintain the release of silver (Ag⁺) ions over an extended time period. The UV irradiation technique was used to reduce Ag⁺ ions in alginate solution to AgNPs. The average sizes of AgNPs ranged between ca 20 and ca 22 nm. The AgNPs‐loaded calcium alginate beads were prepared by electrospraying of a sodium alginate solution containing AgNPs into calcium chloride (CaCl₂) solution. The AgNPs‐loaded calcium alginate beads were then embedded into gelatin scaffolds. The release characteristics of Ag⁺ ions from both the AgNPs‐loaded calcium alginate beads and the AgNPs‐loaded calcium alginate beads embedded in gelatin scaffolds were determined in either deionized water or phosphate buffer solution at 37 °C for 7 days. Moreover, the AgNPs‐loaded calcium alginate beads embedded in gelatin scaffolds were tested for their antibacterial activity and cytotoxicity. © 2014 Society of Chemical Industry     

Preparation and characterization of pH‐ and temperature‐responsive semi–interpenetrating polymer network hydrogels based on linear sodium alginate and crosslinked poly(N‐isopropylacrylamide)

In this study, pH‐ and temperature‐responsive hydrogels based on linear sodium alginate (SA) and crosslinked poly(N‐isopropylacrylamide) (PNIPAAm) were prepared by semi‐interpenetrating network (semi‐IPN) technique. The dually responsive hydrogels were characterized by FTIR, DSC, and SEM, and their temperature‐ and pH‐responsive behaviors were investigated by measuring equilibrium swelling ratios and pulsatile swelling experiments. The results showed that these hydrogels underwent volume phase transition at around 33°C irrespective of the pH value of the medium, but their pH sensitivity was evident only below their volume phase transition temperature. Under basic conditions, the swelling ratios of SA/PNIPAAm semi‐IPN hydrogels were greater than that of pure PNIPAAm hydrogel and increased with increasing SA content incorporated into the hydrogels, but the case was inverse under acidic conditions. The pulsatile swelling experiments indicated that the higher the SA content in SA/PNIPAAm semi‐IPN hydrogels, the faster the response rate to both pH and temperature change. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 1931–1940, 2005     

Polyurethane‐incorporated chitosan/alginate core–shell nano‐particles for controlled oral insulin delivery

Chitosan (CS) and polyurethane‐chitosan (PU‐CS) nano‐particles (NPs) were prepared for the core formation by complex coacervation method whereas alginate (ALG) and PU‐ALG were crosslinked by ionic gelation method to form the protective shell‐layer over the core. Effects of PU incorporation either within the core or shell or both were investigated by different in vitro and in vivo parameters. Fourier transform infrared (FTIR) spectroscopy of different compositions of nano‐particles showed distinct characteristic peaks for CS, PU, and ALG, indicating their presence in variable ratios. Significance of polyurethane‐incorporated systems towards insulin encapsulation efficiency, swelling parameters, insulin release, and in vivo pharmacological effect were also studied. Particle sizes, zeta potential, morphological analysis, mucoadhesion study, and in vivo acute toxicity studies of these core–shell nano‐particles were also performed. Bioavailability of insulin ranged from 9.04% to 11.6% for polyurethane‐incorporated chitosan‐alginate core–shell nano‐particle formulations which was significantly higher than the insulin bioavailability of basic CS/ALG core–shell nano‐particle system. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46365.     

Composites of polymeric gels and magnetic nanoparticles: Preparation and drug release behavior

The article is concerned with the preparation of polymer–iron oxide nanocomposites and the study as drug‐delivery matrices under the influence of applied magnetic field. Biocompatible materials were prepared by incorporating an aqueous ferrofluid in poly(vinyl alcohol) and scleroglucan (SCL) hydrogels, loaded with theophylline as model drug for release studies. The in vitro release profile was obtained using a flat Franz cell and the kinetic parameters were derived applying a semiempirical power law. A magnetic characterization of nanoparticles contained in the ferrofluid was performed by obtaining the magnetization curve. For both systems, the observed drug release profiles decreased when a uniform external magnetic field is applied suggesting they can be used as environmental responsive matrices for biomedical applications. Dynamic rheological measurements show that a higher storage modulus and a more compact structure are obtained by incorporating the ferrofluid into the hydrogels. These rheological results and environmental electron scanning microscopy micrographs point to an understanding of release behavior once the magnetic field is applied. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Thermally and magnetically dual‐responsive mesoporous silica nanospheres: preparation,characterization, and properties for the controlled release of sophoridine

Novel thermally and magnetically dual‐responsive mesoporous silica nanoparticles [magnetic mesoporous silica nanospheres (M‐MSNs)–poly(N‐isopropyl acrylamide) (PNIPAAm)] were developed with magnetic iron oxide (Fe₃O₄) nanoparticles as the core, mesoporous silica nanoparticles as the sandwiched layer, and thermally responsive polymers (PNIPAAm) as the outer shell. M‐MSN–PNIPAAm was initially used to control the release of sophoridine. The characteristics of M‐MSN–PNIPAAm were investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, X‐ray diffraction, thermogravimetry, N₂ adsorption–desorption isotherms, and vibrating specimen magnetometry analyses. The results indicate that the Fe₃O₄ nanoparticles were incorporated into the M‐MSNs, and PNIPAAm was grafted onto the surface of the M‐MSNs via precipitation polymerization. The obtained M‐MSN–PNIPAAm possessed superparamagnetic characteristics with a high surface area (292.44 m²/g), large pore volume (0.246 mL/g), and large mesoporous pore size (2.18 nm). Sophoridine was used as a drug model to investigate the loading and release properties at different temperatures. The results demonstrate that the PNIPAAm layers on the surface of M‐MSN–PNIPAAm effectively regulated the uptake and release of sophoridine. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40477.     

Intracellular pH‐sensitive dextran‐based micelles as efficient drug delivery platforms

As drug delivery systems, stimuli‐responsive polymer micelles hold great potential in cancer chemotherapeutics to improve therapeutic efficiency and eliminate organism adverse effects. Here, pH‐sensitive polymeric micelles based on dextran‐g‐benzimidazole were designed and used for intracellular anticancer drug delivery. The anticancer drug doxorubicin (DOX) was effectively loaded into the micelles via hydrophobic interactions. In vitro release studies demonstrated that the release of loaded DOX was greater and faster under acid conditions such as in carcinomatous areas (pH < 6.8) than in physiological conditions (pH 7.4). MTT assays and flow cytometric analyses showed that DOX‐loaded micelles had higher cellular proliferation inhibition towards HeLa and HepG2 cells than pH‐insensitive controls. These pH‐sensitive micelles with significant efficiency for intracellular drug release will be beneficial to the future of in vivo biomedical applications. © 2014 Society of Chemical Industry