Hydroxybisphosphonate‐containing polymeric drug‐delivery systems designed for targeting into bone tissue

The preparation and characterization of a novel polymeric drug‐delivery system designed for bone targeting of antineoplastics is described. The system was based on biocompatible poly[N‐(2‐hydroxypropyl)methacrylamide] carrier containing hydroxybisphosphonate targeting moieties and the model radiotherapeutics ¹²⁵I or ¹¹¹In or the anticancer drug doxorubicin. The in vitro binding studies with hydroxyapatite as a bone model proved that the system was efficiently adsorbed on this mineral. The systems contained model drugs bound by stable (amide), hydrolytically cleavable (hydrazone) or enzymatically cleavable (Gly‐Phe‐Leu‐Gly tetrapeptide) spacers. It was proven in vitro that, in the case of cleavable spacers, the drug could be released from the polymer carrier at a rate depending on the pH or enzymatic stimulus. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci: 3192–3201, 2006     

PCL microsphere/PEG-based composite hydrogels for sustained release of methadone hydrochloride

Hydrogels have increasingly received considerable attention for local opioids delivery in order to sustained wound pain relief. However, burst release of drugs is a critical problem of hydrogels. To this aim, a local drug delivery system consisting of polycaprolactone (PCL) microspheres containing methadone hydrochloride/polyethylene glycol (PEG)-based hydrogels were developed to prolong drug release with potential utilization in pain treatment. Four different drug delivery systems, including methadone hydrochloride/PEG-(N₃)₄-based hydrogel, methadone hydrochloride/PEG-(N₃)₂-based hydrogel, methadone hydrochloride/PCL/PEG-(N₃)₄, and methadone hydrochloride/PCL/PEG-(N₃)₂ composite hydrogels, were fabricated to investigate drug release profiles of these systems. The results showed that drug released can be controlled by both the double-barrier matrix (hydrogel/microsphere), and the crosslinking density of hydrogels. Therefore, methadone hydrochloride/PCL/PEG-(N₃)₂ composite hydrogel with high crosslinking density has great potential application in sustained release systems for wound pain relief. © 2020 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48967.     

Imidazole modified acrylate-containing photocured hydrogels for the efficient removal of malachite green dye from aqueous solutions

In this work, we aimed to prepare a simple and an efficient adsorbent for the removal of toxic, cationic dye; malachite green (MG). We reviewed many previous studies and designed our adsorbent based on the rationale that (1) acidic groups containing monomers which are capable of making hydrogen bonds (or electrostatic interactions) with MG are very effective in adsorption and (2) π-π stacking enhances the adsorption capacity. We first synthesized an imidazole-acrylate adduct and used it for the preparation of photocured hydrogels. The imidazole-acrylate adduct was characterized by H NMR and FTIR spectroscopy. The effect of experimental conditions on the MG adsorption properties of the hydrogels such as the effect of pH, time and MG concentration were also investigated. Under the optimum conditions (pH = 6 and 220 min contact time) at room temperature, the maximum adsorption capacity was found as high as 714.28 mg/g. The results showed that the adsorption process of the optimum hydrogel, which can be used 4 times without a significant loss in its adsorption capacity, fits the Langmuir isotherm model. The hydrogel adsorbent displayed good selectivity and reusability.     

New binary thermoresponsive polymeric system for local chemoradiotherapy

Radiolabeled thermoresponsive polymers (TRPs) with cloud‐point temperatures between room temperature and body temperature may have an advantage for local radiotherapeutical applications because TRPs may be isotopically labeled in solution at room temperature and injected as a solution, and at the site of application, the polymers form a depo because of phase separation at body temperature. A new polymeric drug‐delivery system designed for combined local chemoradiotherapy with an injectable TRP bearing a radionuclide and the hydrophobic moiety doxorubicin (DOX) was synthesized and characterized. In the system, DOX served as an antiproliferative agent with known synergic effects with ionizing radiation and the hydrophobic moiety controlling bioerosion and elimination of the system at the same time. DOX was bound to the polymer carrier by a hydrolytically labile N‐glycosylamine bond. Hydrolysis of the N‐glycosylamine bond thus controlled the DOX release and dissolution of the system in the model aqueous milieu. DOX was slowly released during incubation in aqueous milieu at 37°C, which caused complete dissolution of the bioerodable polymer within about 2 weeks. The model radionuclide iodine 125, bound to a small amount of poly(N‐isopropylacrylamide‐co‐N‐methacryloyl tyrosinamide), was retained in the separated phase and also slowly dissolved during the incubation. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Development and characterization of gelatin‐based hydrogels,emulsion hydrogels,and bigels: A comparative study

This study was designed to examine the physicochemical and electrical properties of gelatin‐based hydrogels, emulgels, and bigels. The chemical studies suggested an increase in hydrogen bonding in the emulgel and bigel when sesame oil (SO; representative vegetable oil) and SO organogel (OG; representative OG) were incorporated within the gelatin matrix. The emulgel and bigel showed better mechanical properties and higher electrical impedances compared to the hydrogel. The hydrogel showed similar swelling at pH 1.2 and 7.2. The swelling of the emulgel and bigel was higher at pH 7.2. The formulations were found to be highly hemocompatible; this indicated their biocompatible nature. Ciprofloxacin, a model antimicrobial drug, was incorporated within the formulations. The release of the drug was found to be diffusion‐mediated. The antimicrobial efficiency of all of the drug‐loaded formulations was found to be equivalent. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41502.     

Functionalized polymeric silver nanoparticle hybrid network as a dual antimicrobe: Synthesis,characterization, and antibacterial application

The present work describes a novel method for the synthesis of silver polymer nanocomposite for the delivery of amoxicillin (AMO). Silver nanoparticles (AgNPs) were synthesized with chitosan and silver nitrate. The reaction parameters were optimized. Three‐dimensional polymeric networks were synthesized by simple free‐radical graft copolymerization. UV–visible spectroscopy, Fourier transform infrared spectroscopy, X‐ray diffraction, SEM, atomic force microscopy, dynamic light scattering, and zeta potential analysis were used for the complete characterization of the samples. Swelling studies and swelling factors were evaluated. In vitro release of AMO and AgNPs at physiological pHs was analyzed using the Peppas kinetic model to explain the drug delivery mechanism. Cytotoxicity, free‐radical scavenging, and antibacterial activities were analyzed. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43479.     

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.     

Thermo‐responsive albumin hydrogels with LCST near the physiological temperature

This paper deals with the synthesis of thermoresponsive microspheres with proteic structure exhibiting a transition temperature close to the body temperature. The hydrogels were synthesized by free radical polymerization of methacrylate Bovine Serum Albumin (BSA‐MA) as crosslinker, and 2‐hydroxyethyl methacrylate (HEMA) and/or N‐isopropylacrylamide (NIPAAm), as hydrophilic and thermoresponsive monomers, respectively. The modification of the hydrophilic/hydrophobic balance in the polymerization feed allows to modulate the volume phase transition temperature of the macromolecular network. The hydrogels were characterized by infrared spectroscopy and thermal analyses, which showed negative thermoresponsive behavior for all compositions and, by increasing the content of the hydrophilic moieties in the network, the transition temperature was ranged from 34.2 to 36.8°C. To test the preformed materials as drug carriers, diclofenac diethyl ammonium salt was chosen and drug entrapment percent was determined. Drug release profiles, in media at different temperature, depend on the crosslinking degree and on the composition of the hydrogels. By using semiempirical equations, the release mechanism was extensively studied and the diffusional contribute evaluated. The physic‐chemical characteristics of thermoresponsive materials confirm the applicability of the microspheres as drug delivery device. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

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.     

Controlled delivery of growth‐hormone‐releasing peptide 6 from the poly(lactic‐co‐glycolic acid)–poly(ethylene glycol)–poly(lactic‐co‐glycolic acid) copolymer and the effect of a growth‐hormone‐releasing peptide 6–copolymer hydrogel on the growth of rex rabbits

Growth‐hormone‐releasing peptide 6 (GHRP‐6) plays an important role in animal growth. However, there have been few studies focusing on the effect of GHRP‐6 on animal growth through controlled release systems. We synthesized the poly(lactic‐co‐glycolic acid) (PLGA)–poly(ethylene glycol) (PEG)–PLGA copolymer to investigate its controlled released effect on GHRP‐6 in vitro and to study the effect of a GHRP‐6–copolymer hydrogel on the growth of rex rabbits. The copolymer was synthesized with ring‐opening copolymerization and characterized by ¹H‐NMR. The interaction between GHRP‐6 and the copolymer was characterized by Fourier transform infrared spectroscopy and X‐ray diffraction. The body weight, serum level of insulin‐like growth factor 1 (IGF‐1), and hair coat quality were studied in rex rabbits. The results show that hydrogen bonds formed between the N? H group in GHRP‐6 and the C?O group in the copolymer. The release mechanism of GHRP‐6 was a combination of a diffusion‐controlled mechanism and an erosion‐controlled mechanism in the copolymer. The serum level of IGF‐1, hair coat quality, and body weight were all significantly higher in the GHRP‐6–copolymer hydrogel group than in the other groups. These results indicate that the copolymer effectively controlled the release of GHRP‐6. In addition, the GHRP‐6–copolymer hydrogel increased the synthesis of IGF‐1 for a prolonged period and, thereby, increased the rex rabbits' growth and hair coat quality. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40185.     

Smart carboxymethylchitosan hydrogels that have thermo‐ and pH‐responsive properties

Thermo‐responsive poly(N‐isopropylacrylamide) (poly(NIPAAm)) and pH‐responsive poly(N,N′‐diethylaminoethyl methacrylate) (poly(DEAEMA)) polymers were grafted to carboxymethylchitosan (CMC) via radical polymerization to form highly water swellable hydrogels with dual responsive properties. Ratios of CMC, NIPAAm to DEAEMA used in the reactions were finely adjusted such that the thermo and pH responsiveness of the hydrogels was retained. Scanning electron microscopy (SEM) indicated the formation of an internal porous structure for the swollen CMC hydrogels upon incorporation of poly(NIPAAm) and poly(DEAEMA). Effect of temperature and pH changes on water swelling properties of the hydrogels was investigated. It was found that the water swelling of the hydrogels was enhanced when the solution pH was under basic conditions (pH 11) or the temperature was below its lower critical solution temperature (LCST). These responsive properties can be used to regulate releasing rate of an entrapped drug from the hydrogels, a model drug, indomethacin was used to demonstrate the release. These smart and nontoxic CMC‐based hydrogels show great potential for use in controlled drug release applications with controllable on‐off switch properties. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41505.     

Ultraviolet‐crosslinked hydrogel sustained‐release hydrophobic antibiotics with long‐term antibacterial activity and limited cytotoxicity

To prolong erythromycin (EM) release and prevent the side effects of EM, a Pluronic F‐127 diacrylate macromer (PF127) was synthesized and then self‐assembled into micelles with their hydrophobic cores loaded with EM. The EM‐loaded micelles were mixed with a photoinitiator to form the EM/PF127 hydrogels rapidly under a low‐intensity UV light. Afterward, the hydrogel properties, antibacterial performance, and cytotoxicity of this novel hybrid hydrogel were investigated. The results show that the EM/PF127 hydrogel had a rapid gelation time. The sustained release of EM reduced its side effects. With controlled antibacterial activity, the use of EM would be safer and more efficient. What is more, the EM/PF127 hydrogel showed a slight cytotoxicity, and this suggests great potential application as antibacterial hydrogels in the prevention of postoperative infection. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40438.     

Synthesis and characterization of novel pH‐responsive poly(2‐hydroxylethyl methacrylate‐co‐N‐allylsuccinamic acid) hydrogels for drug delivery

In this study, N‐allylsuccinamic acid (NASA) was synthesized in a single step with a yield of 85%. Carboxylic acid containing NASA was characterized through Fourier transform infrared (FTIR) radiation and ¹H‐NMR and ¹³C‐NMR analysis, and then it was used for synthesis of poly(2‐hydroxylethyl methacrylate‐co‐N‐allylsuccinamic acid) [p(HEMA‐co‐NASA)] hydrogels. The structure of the obtained pH‐responsive p(HEMA‐co‐NASA) hydrogels were characterized with FTIR spectroscopy and scanning electron microscopy analysis, and their swelling characterization was carried out under different drug‐release conditions. In the application step of the study, the hydrogels were used for the in vitro release of vitamin B12 and Rhodamine 6G, which were selected as model drugs. We determined that the hydrogels used as a drug‐delivery matrix could release the drug they had absorbed under different release conditions (phosphate‐buffered saline, 0.9% NaCl, and pH 1.2) at high rates for time periods of up to 24 h. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39660.     

Remote‐controlled peristaltic locomotion in free‐floating pnipam hydrogels

Peristalsis‐driven locomotion, by nature of its flexibility and deformability, is a highly advantageous mechanism for mobility in soft materials and robots; however, utilization of this mechanism has been limited to restricted, frictional environments. (Seok et al., presented at 2010 IEEE International Conference on Robotics and Automation, Anchorage, AK May 3–8, 2010; Boxerbaum et al., Int J Robotics Res 2012, 31, 302; Boxerbaum et al., presented at 2011 IEEE/RSJ International Conference on Intelligent Robots and Systems, San Francisco, CA, 2011; Arora et al., J Polym Sci Part A: Polym Chem 2009, 47, 5027). We have removed this limitation and expanded the use of peristaltic locomotion to open aqueous environments by remotely inducing peristalsis via spatially controlled volume phase transitions in thermosensitive poly(N‐isopropylacrylamide) (PNIPAM) hydrogels. The resulting asymmetry causes steady, incremental linear displacement in the hydrogel's center of mass, thus producing directed, remote‐controlled locomotion. In our proof‐of‐principle system, we controlled the peristaltic locomotion of the hydrogels using a handheld laser to selectively induce volume phase transitions in the hydrogel. The PNIPAM hydrogels' energy absorbance capability was enhanced by incorporating the New Indocyanine Green laser dye (IR‐820) into the gel. The use of IR‐820 is likely to expand the application space for these hydrogels due to new opportunities for conjugation chemistry. (Prajapati et al., Molecular Imaging 2009, 8, 45; Fernandez‐Fernandez et al., Molecular Imaging 2011, 11, 1). Overall, such an approach increases the capability of both peristaltic locomotion as a mechanism for mobility in soft robots, and PNIPAM hydrogels as a biotechnological platform. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40927.     

Reversible addition–fragmentation chain transfer polymerization of styrene using a novel thiophene dithioester as the reversible addition–fragmentation chain transfer agent

Benzyl thiophene‐2‐carbodithioate and 2‐methyl‐2‐(4‐methylcyclohex‐3‐enyl)propyl thiophene‐2‐carbodithioatewere synthesized. The reversible addition–fragmentation chain transfer polymerizations of styrene with benzyl thiophene‐2‐carbodithioate and 2‐methyl‐2‐(4‐methylcyclohex‐3‐enyl)propyl thiophene‐2‐carbodithioate as chain‐transfer agents and with 2,2′‐azobisisobutyronitrile as an initiator were carried out. The polymerization kinetics were investigated. An ab initio calculation method was used to explore the differences between benzyl thiophene‐2‐carbodithioate and benzyl benzodithioate. The structure of the obtained polymers was characterized with ¹H‐NMR. Chain‐extension experiments of the obtained polymer with styrene were carried out. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

Thermosensitive polymeric micelles based on the triblock copolymer poly(d,l‐lactide)‐b‐poly(N‐isopropyl acrylamide)‐b‐poly(d,l‐lactide) for controllable drug delivery

A thermosensitive amphiphilic triblock copolymer, poly(d,l ‐lactide) (PLA)‐b‐poly(N‐isopropyl acrylamide) (PNIPAAM)‐b‐PLA, was synthesized by the ring‐opening polymerization of d,l ‐lactide; the reaction was initiated from a dihydroxy‐terminated poly(N‐isopropyl acrylamide) homopolymer (HO‐PNIPAAM‐OH) created by radical polymerization. The molecular structure, thermosensitive characteristics, and micellization behavior of the obtained triblock copolymer were characterized with Fourier transform infrared spectroscopy, ¹H‐NMR, gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. The obtained results indicate that the composition of PLA‐b‐PNIPAAM‐b‐PLA was in good agreement with what was preconceived. This copolymer could self‐assemble into spherical core–shell micelles (ca. 75–80 nm) in aqueous solution and exhibited a phase‐transition temperature around 26 °C. Furthermore, the drug‐delivery properties of the PLA‐b‐PNIPAAM‐b‐PLA micelles were investigated. The drug‐release test indicated that the synthesized PLA‐b‐PNIPAAM‐b‐PLA micelles could be used as nanocarriers of the anticancer drug adriamycin (ADR) to effectively control the release of the drug. The drug‐delivery properties of PLA‐b‐PNIPAAM‐b‐PLA showed obvious thermosensitive characteristics, and the release time of ADR could be extended to 50 h. This represents a significant improvement from previous PNIPAAM‐based drug‐delivery systems. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45304.     

Preparation of antimicrobial polycarboxybetaine‐based hydrogels for studies of drug loading and release

A series of cationic poly(N‐isopropyl acrylamide) (PNIPAM)‐g‐poly(carboxybetaine ester) (PCBMAE) hydrogels were prepared by reversible addition–fragmentation chain‐transfer polymerization with PCBMAE precursors reacting with N‐isopropyl acrylamide in the presence of N,N′‐methylene bisacrylamide. These hydrogels exhibited excellent antimicrobial activities against Staphylococcus aureus and could switch to nontoxic zwitterionic hydrogels after hydrolysis. Nonionic tetracycline hydrochloride (TCHC) and anionic sodium salicylate (SA) were selected to evaluate the loading capacities and release kinetics of the cationic hydrogels. We found that the loading efficiencies of TCHC in the PNIPAM‐g‐PCBMAE hydrogels were approximately twice as high as those of SA. However, the cumulative release amount of TCHC was lower than that of SA from the corresponding cationic hydrogel at 37°C. In addition, the PNIPAM‐g‐PCBMAE hydrogels exhibited accelerated release rates of both TCHC and SA with increasing content of (2‐carboxymethyl)?3‐acryloxyethyldimethylammonium chloride methyl ester. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39839.     

In vitro silver ion release kinetics from nanosilver/poly(vinyl alcohol) hydrogels synthesized by gamma irradiation

A nanosilver (nano‐Ag)/poly(vinyl alcohol) (PVA) hydrogel device was synthesized with γ irradiation because it is a highly suitable tool for enhanced nano‐Ag technologies and biocompatible controlled release formulations. The amount of the Ag⁺ ions released in vitro by the nano‐Ag/PVA hydrogel device was in the antimicrobial parts per million concentration range. The modeling of the Ag⁺ ion release kinetics with the elements of the drug‐delivery paradigm revealed the best fit solution (R² > 0.99) for the Kopcha and Makoid–Banakar's pharmacokinetic dissolution models. The term A/B, derived from the Kopcha model, indicated that the nano‐Ag/PVA hydrogel was mainly an Ag⁺‐ion diffusion‐controlled device. Makoid–Banakar's parameter and the short time approximated Ag⁺‐ion diffusion constant reflected the importance of the size of the Ag nanoparticles. However, it appeared that the cell oxidation potential of the Ag nanoparticles depended on the diffusion characteristics of the fluid penetrating into the Ag/PVA nanosystem. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40321.     

2‐Mercapto thioxanthone as a chain transfer agent in free‐radical polymerization: A versatile route to incorporate thioxanthone moieties into polymer chain‐ends

2‐Mercapto thioxanthone (TX‐SH) was used as a chain transfer agent in free‐radical polymerization of methyl methacrylate (MMA) and styrene (St), by using 2,2′‐azobisisobutyronitrile (AIBN) as an initiator at 70°C. Chain transfer constants were found to be 1.41 and 0.12 for St and MMA, respectively. The use of TX‐SH as a chain transfer agent leads to the formation of polymers with thioxanthone (TX) end groups. The incorporation TX moiety was confirmed by spectral measurements. Polymers obtained this way were used as triplet photosensitizer in free‐radical polymerization of MMA in the presence of a hydrogen donor such as N‐methyldiethanolamine (MDEA). © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3766–3770, 2007     

Functionalization of hybrid poly(n‐isopropylacrylamide) hydrogels for Escherichia coli cell capture via adsorbed intermediate dye molecule

Poly(n‐isopropylacrylamide) Laponite (PNIPAM‐Lap) hybrid hydrogels, which use the synthetic clay Laponite as a crosslinker, permanently adsorb cationic laser dyes out of solution. This proof‐of‐concept expounds on this capability by adsorbing an intermediate dye molecule and using it as the foundation for successfully conjugating microbial antibodies to the surface of a PNIPAM hydrogel. The study involves using acriflavinium chloride molecules, adsorbed by a PNIPAM‐Lap hydrogel from an acriflavine laser dye solution, as an intermediate molecule to attach antibodies raised against E. coli to the hydrogel and demonstrate cell capture. Furthermore, this system exemplifies a novel biotechnological platform for greatly expanding PNIPAM hydrogels' capabilities and applicability through conjugation chemistry to surface‐bound molecules. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41557.