Temperature stimuli-responsive nanoparticles from chitosan-graft-poly(N-vinylcaprolactam) as a drug delivery system

This work describes the preparation of thermosensitive chitosan-graft-poly(N-vinylcaprolactam) nanoparticles by ionic gelation and their potential use as a controlled drug delivery system, using doxorubicin as a model drug. A systematic study of the effect of the main processing parameters on both the size and thermoresponsive behavior of nanoparticles was investigated. The size of the particles is strongly dependent on the length of the poly(N-vinylcaprolactam) grafted chains and the concentration of the copolymer and crosslinking agent solutions. The molecular structure of the copolymer plays an essential role in the phase transition temperature of the particles, which decreases with the length of PVCL grafted chain. The system displayed proper drug-association parameters, and the drug-loaded nanoparticles exhibited dose-dependent cytotoxicity. A significant increase in the doxorubicin delivery rate was observed above the phase transition temperature (40 °C). These features indicate that these nanoparticles are suitable for the development of a new thermally controlled anti-cancer drug delivery system. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47831.     

GSH-responsive polyglutamic acid nanocarriers for dual targeted cancer therapy

In order to reduce the toxic side effects of chemotherapeutic drugs and improve the targeting and efficiency of cancer treatment, the development of drug delivery system has received great attention. In this study, second generation polyglutamic acid dendrimers (G₂) are used as basic materials to produce porous nanoparticles through cross link by crosslinkers containing disulfide bonds. The crosslinked products (G₂)_n have negative electricity and abundant voids, which enable them to adsorb the electronegative anticancer drug DOX. At the same time, in order to transport DOX to the tumor site, we modified FA on DOX and encapsulated it in magnetic mesoporous silica (FA-DOX-MSNs). Therefore, the final nanoparticles (FA-DOX-MSNs/(G₂)_n) not only have dual targeting ability to transport DOX to the tumor site, but also have reductive responsiveness that can release drugs responsively in the tumor cells. In addition, it has good biocompatibility and endocytosis ability.     

Design and characterization of PNVCL-based nanofibers and evaluation of their potential applications as scaffolds for surface drug delivery of hydrophobic drugs

In this work, nanofiber scaffolds for surface drug delivery applications were obtained by electrospinning poly(N-vinylcaprolactam) (PNVCL) and its blends with poly(ε-caprolactone) and poly(N-vinylcaprolactam)-b-poly(ε-caprolactone). The process parameters to obtain smooth and beadless PNVCL fibers were optimized. The average fibers diameter was less than 1 μm, and it was determined by scanning electron microscopy analyses. Their affinity toward water was evaluated by measuring the contact angle with water. The ketoprofen release behavior from the fibers was analyzed using independent and model-dependent approaches. The low values of the release exponent (n < 0.5) obtained for 20 and 42 °C, indicating a Fickian diffusion mechanism for all formulations. Dissolution efficiencies (DEs) revealed the effect of polymer composition, methodology used in the electrospinning process, and temperature on the release rate of ketoprofen. PNVCL/poly(N-vinylcaprolactam)-b-poly(ε-caprolactone)-based nanofibers showed greater ability to control the in vitro release of ketoprofen, in view of reduced kinetic constant and DE, making this material promising system for controlling release of hydrophobic drugs. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48472.     

Stimuli-responsive hybrid microgels for controlled drug delivery: Sorafenib as a model drug

Microgels (MGs) are synthetic colloidal hydrogel particles made of three dimensional polymer networks. Their chemical composition is crucial for their use as intelligent drug release systems operated by temperature control. Herein, several MGs using N-isopropylacrylamide (Nipam)/N-isopropylmethacrylamide (Nipmam), chitosan and acrylic/methacrylic acid have been synthesized by free radical polymerization reactions (NC MGs) and the effects of surfactants and different reaction times on size and swelling properties have been investigated. MGs have been identified and characterized by dynamic light scattering and atomic force microscopy, and finally used to optimize the encapsulation protocol of the hydrophobic drug sorafenib. The drug delivery system here described has encapsulation efficiency of 40% and releases 10% of the entrapped drug over about 16 h after the temperature is raised above the volume phase transition temperature. Data suggest that MGs with optimized composition may act as properly instructed entities able to trap and release biomolecules following external stimuli.     

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.     

Microemulsion of erythromycine for transdermal drug delivery

The aim of this work was to prepare an erythromycin (EM) microemulsion (EM‐ microemulsion) for transdermal EM delivery using isotropic mixtures of oil and aqueous phases. The prepared EM‐microemulsion is a white dispersion, with a suitable viscosity for transdermal delivery. In stability experiments, the EM‐microemulsion showed no marked change in appearance for up to 3 weeks at 25°C. In accelerated stability experiments at 37 and 60°C, however, precipitated crystalline EM particles were observed in the EM‐microemulsion. Diffusion of EM into the skin exhibited a first order release profile. Fluorescein (FL)‐microemulsion penetrated to the dermis layer of skin. In conclusion, we confirmed that EM‐microemulsion could serve as an excellent transdermal carrier of EM. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Dual crosslinked carboxymethyl sago pulp/pectin hydrogel beads as potential carrier for colon‐targeted drug delivery

Carboxymethyl sago pulp (CMSP)/pectin hydrogel beads were synthesized by calcium crosslinking and further crosslinked by electron beam irradiation to form drug carrier for colon‐targeted drug. Sphere‐shaped CMSP/pectin 15%/5% hydrogel beads is able to stay intact for 24 h in swelling medium at pH 7.4. It shows pH‐sensitive behavior as the swelling degree increases as pH increases. Fourier transform infrared spectroscopy analysis confirmed the absence of chemical interaction between hydrogel beads and diclofenac sodium. Differential scanning calorimetric and X‐ray diffraction studies indicate the amorphous nature of entrapped diclofenac sodium. The drug encapsulation efficiency is up to about 50%. Less than 9% of drug has been released at pH 1.2 and the hydrogel beads sustain the drug release at pH 7.4 over 30 h. This shows the potential of CMSP/pectin hydrogel beads as carrier for colon‐targeted drug. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43416.     

Zein‐based micro‐ and nano‐particles for drug and nutrient delivery: A review

Zein is the major storage protein from corn with strong hydrophobicity and unique solubility and has been considered as a versatile food biopolymer. Due to the special tertiary structures, zein can self‐assemble to form micro‐ and nano‐particles through liquid–liquid dispersion or solvent evaporation approaches. Zein‐based delivery systems have been particularly investigated for hydrophobic drugs and nutrients. Recently, increasing attention has been drawn to fabricate zein‐based advanced drug delivery systems for various applications. In this review, the molecular models of zein tertiary structure and possible mechanisms involved in zein self‐assembly micro‐ and nano‐particles are briefly introduced. Then, a state‐of‐the‐art introduction and discussion are given in terms of preparation, characterization, and application of zein‐based particles as delivery systems in the fields of food science, pharmaceutics, and biomedicine. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40696.     

Fabrication of galactosylated chitosan–5‐fluorouracil acetic acid based nanoparticles for controlled drug delivery

In this study, a novel type of macromolecular prodrug, N‐galactosylated chitosan (GC)?5‐fluorouracil acetic acid (FUA) conjugate based nanoparticles, was designed and synthesized as a carrier for hepatocellular carcinoma drug delivery. The GC–FUA nanoparticles were produced by an ionic crosslinking method based on the modified ionic gelation of tripolyphosphate with GC–FUA. The structure of the as‐prepared GC–FUA was characterized by Fourier transform infrared and ¹H‐NMR analyses. The average particle size of the GC–FUA nanoparticles was 160.1 nm, and their drug‐loading content was 21.22 ± 2.7% (n = 3). In comparison with that of the freshly prepared nanoparticles, this value became larger after 7 days because of the aggregation of the GC–FUA nanoparticles. An in vitro drug‐release study showed that the GC–FUA nanoparticles displayed a sustained‐release profile compared to 5‐fluorouracil‐loaded GC nanoparticles. All of the results suggest that the GC–FUA nanoparticles may have great potential for anti‐liver‐cancer applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42625.     

Theophylline‐loaded pectin‐based hydrogels. I. Effect of medium pH and preparation conditions on drug release profile

In this study, a series of theophylline‐loaded calcium pectin gel films were prepared in three different Ca⁺² concentrations with three different methods for wound dressing applications. Drug release performance of the films were investigated in four different medium pH in order to mimic wound healing pH conditions. Hydrogel films were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and atomic force microscopy. Their absorbency (fluid handling), swelling behavior, dehydration rate, dispersion characteristic, dressing pH determination, water vapor permeability, oxygen permeability, surface contact angle, flexibility, Shore A hardness, mean mass per unit area and thickness were determined. The effect of the hydrogels on wound healing was evaluated with an in vitro wound healing assay. After evaluating all data, we suggested that the hydrogel film prepared with swelling method using 7% or 10% crosslinker and dried at 26 °C is more suitable for controlled drug release process. We showed that between pH 3.25 and 7.12 the form of the hydrogel did not change, and drug release was continuous. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46731.     

Facile fabrication of double‐walled polymeric hollow spheres with independent temperature and pH dual‐responsiveness for synergetic drug delivery

A dual‐responsive double‐walled polymeric hollow sphere (PHS) serving as a candidate for synergetic drug delivery platform is prepared by a simple and green template polymerization in aqueous medium. The PHS, comprised of thermo‐responsive crosslinked poly(N‐isopropylacrylamide) (PNIPAM) as the inner shell and pH‐responsive crosslinked poly(methacrylic acid) (PMAAc) as the outer shell, is assembled through self‐removal of the thermo‐responsive template from a core‐triple shell structure by free radical polymerization with sequential addition of reactants. The discrete double‐shell structure renders the PHS independent temperature and pH‐controlled swelling/shrinking capability. Taking the advantage of two compartmentalized internal spaces (the core and the interlayer spaces) with independent temperature‐ and pH‐dependent behaviors, two model drugs representing the small molecule and the macromolecule are loaded in selective locations of the PHS. Two drugs show dramatically different release profiles according to environmental temperature and pH, due to the localization of drugs and the stimuli‐dependent property of its protective shells. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44335.     

Design and study of the potential of crosslinked cationic polymers as drug delivery systems for dermal application

Crosslinked carriers based on cationic monomer [2‐(acryloyloxy)ethyl]trimethylammonium chloride or 2‐(dimethylamino)ethyl methacrylate were developed and investigated as new platform for ibuprofen transdermal delivery. Series of networks of varied composition and structure were synthesized and characterized by FTIR spectroscopy and following swelling kinetics in different solvents. Dermal safety tests to examine the skin irritation and sensitization potential of the network films were performed in vivo. Chosen network compositions were loaded with ibuprofen by swelling in its ethanol solution. The structures of the drug carriers were investigated by scanning electron microscopy. Ibuprofen release from the developed drug delivery systems was followed in phosphate buffer solution at 37 °C. The investigation proved the feasibility of the developed cationic copolymer networks as effective platforms with modified ibuprofen release for potential dermal application. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46420.     

Thermosensitive PMMA core/oligo(ethylene glycol)-based shell microgels as drug carriers in detoxification treatment

The core-shell structured polymer microgels were synthesized by coating the hydrophobic poly(methyl methacrylate) (PMMA) sphere cores with hydrophilic nonlinear poly(ethylene glycol)-based gel shell layer. The uniqueness of these core-shell microgels lies in the integration of the PMMA core microsphere with strong hydrophobicity and the novel oligo(ethylene glycol)-based gel layer with well-defined thermosensitivity for improving loading/release efficacy of two detoxification drugs (chlorpromazine and diltiazem). The hydrophilic shell is composed of hydrophilic copolymer of 2-(2-methoxyethoxy)ethyl methacrylate (MEO₂MA) with oligo(ethylene glycol) methyl ether methacrylates (MEO₅MA). It was found that the molar ratio of two shell monomers n(MEO₂MA)/n(MEO₅MA) of 1:6 was an ideal matching value for production of the P(MEO₂MA)/P(MEO₂MA-co-MEO₅MA) core-shell microgels with tunable volume phase transition temperature and excellent colloidal stability across the physiologically important temperature range. Moreover, chlorpromazine- and diltiazem-loaded microgels can show an obvious thermosensitive release and in vitro sustained-release characteristic up to 80 h.     

Polydopamine-mediated polypyrrole/doxorubicin nanocomplex for chemotherapy-enhanced photothermal therapy in both NIR-I and NIR-II biowindows against tumor cells

Photothermal therapy (PTT) is featured by the desirable spatiotemporal controllability and excellent specificity, which has been identified as one of the important tumor treatment methods. Although promising, the efficacy of PTT is still limited and needs further improvement. In this work, a kind of PPy-PDA-PEG@DOX nanocomplex was designed and constructed for chemotherapy-enhanced PTT in both near-infrared (NIR)-I and NIR-II biowindows against tumor cells, which was integrated by the polypyrrole (PPy) core, polydopamine (PDA) shell, polyethylene glycol (PEG) linkage, and doxorubicin (DOX) payload. This constructed PPy-PDA-PEG@DOX nanocomplex was uniform in size around 56.3 nm, and with the optimized DOX loading content at 37.4%. The photothermal conversion efficiencies of this nanocomplex were calculated to be around 23.1 and 30.8% in NIR-I and NIR-II biowindows, respectively, showing good photothermal capacity and stability. The loaded DOX could be released in stimuli-responsive manners. The therapeutic efficacy was enhanced by PPy-PDA-PEG@DOX nanocomplex, indicating the high effectiveness of chemotherapy-enhanced phototherapy. This developed PPy-PDA-PEG@DOX nanocomplex shows promising applications in tumor treatment applications.     

Novel electrospun nanofibers incorporating polymeric prodrugs of ketoprofen: Preparation,characterization, and in vitro sustained release

A facile and efficient protocol for the preparation of nanofibers incorporating polymeric ketoprofen prodrugs and polyvinylpyrrolidone was developed. Polymeric ketoprofen prodrugs were constructed by a two‐step chemo‐enzymatic synthetic route, and nanofibers prepared by electrospinning from dimethylformamide/ethanol (1 : 1, v/v) solutions. The morphological characteristics of the fibers were influenced by the concentration of active agent in the spinning solution; average diameters varied from 196 to 370 nm. In vitro release studies indicated that the ketoprofen release rate from the electrospun fibers was significantly higher than that from the pure polymeric prodrugs. Cumulative drug release from the electrospun fibers reached 40–70% after 3 h and 75–100% after 12 h, while the pure polymeric prodrug released only 7–9% of the active agent over 12 h. Functional nanofibers incorporating polymeric prodrugs therefore comprise potentially effective drug delivery systems for sustained release. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 1570–1577, 2013     

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.     

Drug‐loaded polyurethane/clay nanocomposite nanofibers for topical drug‐delivery application

In this study, polyurethane/nanoclay nanocomposite nanofibrous webs were prepared by electrospinning. An antiseptic drug, chlorhexidine acetate (CA), was loaded onto montmorillonite clay and was then incorporated into polyurethane nanofibers. For comparison, the CA drug was loaded directly into the polyurethane solution dope used to electrospin the nanofibers. The emphasis was on investigating the effect of the drug loading into the nanoclay vis‐à‐vis direct drug loading on the drug‐release behavior of nanofibrous webs. The nanofibrous webs were also evaluated for other properties, such as moisture vapor transmission, porosity determination, contact angle measurement, and antibacterial activity, which are important for topical drug‐delivery application. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40230.     

Chitosan/nanocellulose-based bionanocomposite films for controlled betamethasone and silver sulfadiazine delivery

Bionanocomposite films based on chitosan and nanocellulose (nanocrystals or nanofibrils) have gained considerable attention for biomedical applications, especially for wound dressings. However, the development of these films as controlled drug release dressings is still under-exploited. Therefore, this work aimed to design chitosan/nanocellulose-based bionanocomposite films, loaded by betamethasone or silver sulfadiazine, as functional dressings. The films were obtained by solvent casting and characterized by physicochemical, mechanical, barrier properties, in vitro drug release, and antimicrobial activity. The nanocellulose type, physical state, and content caused influence on the film's properties providing different physical, barrier, and drug release profiles. They are semi-occlusive and mechanically resistant; the drug release is controlled, and possesses antimicrobial activity. In conclusion, the developed biodegradable bionanocomposite films are promising as active dressings for controlled drug delivery in the wound site and have specific applications according to their features to treat inflamed and purulent wounds, non-infectious dry wounds, and infectious wounds.     

Hydroxypropylmethyl cellulose‐based sponges loaded self‐microemulsifying curcumin: Preparation,characterization, and in vivo oral absorption studies

Novel hydroxypropylmethyl cellulose (HPMC)‐based sponges containing self‐microemulsifying curcumin (SME‐Cur) were prepared by a freeze drying method using different grades of HPMC (E5 LV, E15 LV, E50 LV, A15 LV, and A4C). The physical properties and drug release from these carriers were characterized and compared among the different formulations. The mean pore size values of the sponges from image analysis ranged from 43.36 ± 4.54 to 123.22 ± 8.19 nm. An increase in the concentration or viscosity of the HPMC, resulted in denser sponges and a slower drug release. The average microemulsion droplet size from the optimal sponge formulation was 34.80 ± 0.1 nm, and the curcumin was almost completely released within 120 min. The AUC after oral administration of the liquid and solid SME‐Cur were 7‐ and 5‐fold greater than that of the curcumin powder in the rabbit, respectively. The results demonstrated that the HPMC‐based sponges loaded with SME‐Cur could be efficiently used to enhance the oral bioavailability and might be useful as they could be administered at a lower dose compared to normal curcumin powder. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42966.