Facile synthesis and fractal feature of pH-responsive poly(acrylic acid) hollow microspheres for ibuprofen delivery

The pH-responsive hollow poly(acrylic acid) (HPAA) microspheres with regulated cavity structure and various shell thicknesses were synthesized. Their structural parameters and textural properties were characterized by various techniques. The ibuprofen loading results indicate the good drug loading capabilities of HPAA microspheres from 13.81 to 17.18%. Their ibuprofen release properties demonstrated their good pH sensitivity and distance-controlled drug diffusion process. Specially, the small-angle X-ray scattering technique was used to suggest the surface roughness and structural irregularities of HPAA before and after drug loading and releasing. These findings clearly indicate the potential of HPAA microspheres to be used as promising candidates in drug delivery.     

Hollow MnO2/GNPs serving as a multiresponsive nanocarrier for controlled drug release

In this work, hollow manganese dioxide/gold nanoparticle (MnO₂/GNPs) hybrid drug nanocarriers were prepared by coupling the gold nanoparticles (GNPs) with hollow structure manganese dioxide (MnO₂). Among them, GNPs have been used as near-infrared (NIR)-responsive element for photothermal effect under NIR laser irradiation. The glutathione (GSH)-responsive and pH-responsive performances of drug release were derived from hollow MnO₂. Particularly, Doxorubicin hydrochloride (DOX) can be loaded into hollow MnO₂/GNPs with the drug loading efficiency up to 82.0%. Moreover, the photothermal effect and GSH-/pH-responsive properties of hollow MnO₂/GNPs were investigated. The hollow MnO₂/GNPs possessed satisfactory drug release efficiency (ca. 87.4% of loaded drug released in 12 h) and have high photothermal conversion efficiency, multiresponsive properties, and degradability. Finally, the kinetics of drug release was discussed in detail. Thus, our finding highlights that the multiresponsive nanocarriers are of great potential in the field of drug controlled release.     

Effect of graphene oxide on the pH-responsive drug release from supramolecular hydrogels

Polypseudorotaxane (PPR) hydrogels formed by inclusion complexes between poly(ethylene glycol) (PEG) and α-cyclodextrin (α-CD) are highlighted as promising biomaterial for drug delivery. Here, we report a novel injectable PPR hydrogel containing graphene oxide (GO) for pH-responsive controlled release of doxorubicin hydrochloride (DOX). Our results showed that the gelation rates of the PEG/α-CD supramolecular structures could be tailored depending on the reagent concentrations. The formation of PEG/α-CD inclusion complexes was confirmed by TEM and XRD, the latter further confirming that GO restricts their formation. The supramolecular hydrogels were easily loaded with DOX by simple addition into the PEG solution before the complex formation with the α-CD solution. Noteworthy, disruption of ionic interactions between DOX and GO in the nanocomposite at pH = 5.5 resulted in higher DOX release than under physiological conditions (pH = 7.4). This pH dependence was barely observed in pure PPR hydrogel. These findings introduce DOX-loaded supramolecular hydrogels nanocomposites as promising carriers for pH-responsive and therefore localized, drug delivery systems.     

Thermo- and pH-responsive HPC-g-AA/AA hydrogels for controlled drug delivery applications

This paper describes smart hydrogels composed of pH-sensitive poly(acrylic acid) (PAA) and biodegradable temperature-sensitive hydroxypropylcellulose-g-acrylic acid (HPC-g-AA) for controlled drug delivery applications. In a pH-responsive manner, the hydrogels with the higher HPC-g-AA content resulted in the lower equilibrium swelling. Although temperature had little influence on the swelling of the hydrogels, optical transmittance of the hydrogels was changed as a function of temperature, which reflecting that the HPC parts of hydrogel became hydrophobic at temperature above the lower critical solution temperature (LCST). Scanning electron microscopic analysis revealed that the pore size and the morphology of the hydrogels could be controlled by changing the composition of AA and the crosslinking density. Using BSA as a model drug, in vitro drug release experiment was carried out in artificial gastric juice (pH = 1.2) for the first 2 h and then in artificial intestinal liquid (pH = 6.8) for the subsequent 6 h. The release profiles indicated that both HPC-g-AA and AA contents played important roles in the drug release behaviors. The temperature- and pH-responsive HPC-g-AA/AA hydrogels might be exploited for wide applications in controlled drug delivery.     

pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis,characterization, and application as anticancer drug carrier

Amphiphilic A₂(BC)₂ miktoarm star polymers [poly(ϵ-caprolactone)]₂-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]₂ [(PCL)₂(PDEA-b-PPEGMA)₂] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC₅₀ of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)₂(PDEA-b-PPEGMA)₂ micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.     

ABC block copolymer as “smart” pH-responsive carrier for intracellular delivery of hydrophobic drugs

Amphiphilic triblock copolymer of poly(ethylene glycol)-block-poly(dimethylaminoethyl methacrylate)-block-poly(ε-caprolatone) (PEG-PDMA-PCL) was synthesized using a one-pot sequential oxyanionic polymerization of DMA and ε-CL, associated with a PEG-O⁻K⁺ macroinitiator. The pH-responsive micellization behavior of the copolymer was studied using dynamic light scattering (DLS), steady-state fluorescence and TEM techniques. The anti-cancer drug of doxorubicin (DOX) was chosen as a model drug to investigate the potential application of this triblock copolymer in drug controlled release. The results indicated the important roles of the PCL block for drug loading, the PDMA block for pH-responsive release, and PEG block for good bio-affinity. Cell cytotoxicity tests showed that the DOX-loaded PEG-PDMA-PCL micelles were pharmaceutically active to suppress the growth of SKOV-3 cells. This novel stimuli-responsive block copolymer is an attractive candidate as the “smart” pH-responsive carrier for intracellular delivery of hydrophobic drugs.     

Synthesis and characterization of a novel pH-responsive nanocomposite hydrogel based on chitosan for targeted drug release

Over the last decade, nanocomposite hydrogels have been provided a new approach for the biomedical field. In this work, a novel pH-responsive nanocomposite hydrogel was fabricated using simultaneous in situ formation of magnetite iron oxide nanoparticles and hydrogel networks of poly(acrylic acid) grafted onto chitosan. The effects of various types of precursor molecules, pH, salt, and loading pressure were examined on the swelling properties of resulting nanocomposite hydrogels. The synthesized nanocomposite hydrogel was well characterized using different instruments. In vitro drug releasing behavior of doxorubicin was studied at pH 5.4 and 7.4. The drug release mechanism was investigated through different kinetic models. These experimental results open a new opportunity to make pH-responsive nanocomposite hydrogel devices for controlled delivery of drug.     

Photonic porous silicon as a pH sensor

Chronic wounds do not heal within 3 months, and during the lengthy healing process, the wound is invariably exposed to bacteria, which can colonize the wound bed and form biofilms. This alters the wound metabolism and brings about a change of pH. In this work, porous silicon photonic films were coated with the pH-responsive polymer poly(2-diethylaminoethyl acrylate). We demonstrated that the pH-responsive polymer deposited on the surface of the photonic film acts as a barrier to prevent water from penetrating inside the porous matrix at neutral pH. Moreover, the device demonstrated optical pH sensing capability visible by the unaided eye.     

Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate)

Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a ¹H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a ¹H-NMR study in D₂O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell-bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery.     

A facile approach to synthesize SiO2?·?Re2O3 (Re?=?Y,Eu, La,Sm, Tb,Pr) hollow sphere and its application in drug release

Multifunctional SiO₂ · Re₂O₃ (Re = Y, Eu, La, Sm, Tb, Pr) hollow spheres (HSs) have been fabricated using an acidic Re³⁺ ion solution. Under ultraviolet radiation, functional HSs emit different colors of light according to the different rare-earth ions embedded into the shell of SiO₂ hollow spheres. The as-prepared hollow capsules were characterized by X-ray diffraction, transmission electron microscopy, high-resolution transmission electron microscopy, Brunauer-Emmett-Teller method, scanning electron microscopy, and energy-dispersive spectrometry. Drug loading and release experiments have been carried out using SiO₂ · Eu₂O₃ HSs that acted as drug carriers. The results demonstrate that the multifunctional HSs exhibit a high storage capacity and the ability of retaining drug stability and activity, which indicates that the as-synthesized fluorescent hollow capsules are a potential candidate as drug delivery materials.     

Dual stimuli-responsive polymeric hollow nanocapsules as “smart” drug delivery system against cancer

ABSTRACT

Novel thermal- and pH-responsive hollow nanocapsules (HNCaps) were fabricated through the grafting of a thiol-end capped PNIPAAm-b-PAA by thiol-ene “click” reaction onto PMMA HNCaps. The lowest critical solution temperature (LCST) of the fabricated HNCaps was obtained as 38–40°C. The fabricated nanosystem was loaded with doxorubicin hydrochloride (Dox), and its drug loading and encapsulation efficiencies were obtained as 62 and 53%, respectively. The in vitro stimuli-responsive drug release behavior of the fabricated nanomedicine was investigated extensively. The anticancer activity of the drug-loaded HNCaps was evaluated using MTT assay against MCF7 cells. The results exhibited excellent potential of nanosystem as a drug delivery system (DDS) for cancer chemotherapy.     

PEG-Coated Large Mesoporous Silicas as Smart Platform for Protein Delivery and Their Use in a Collagen-Based Formulation for 3D Printing

Silica-based mesoporous systems have gained great interest in drug delivery applications due to their excellent biocompatibility and high loading capability. However, these materials face challenges in terms of pore-size limitations since they are characterized by nanopores ranging between 6–8 nm and thus unsuitable to host large molecular weight molecules such as proteins, enzymes and growth factors (GFs). In this work, for an application in the field of bone regeneration, large-pore mesoporous silicas (LPMSs) were developed to vehicle large biomolecules and release them under a pH stimulus. Considering bone remodeling, the proposed pH-triggered mechanism aims to mimic the release of GFs encased in the bone matrix due to bone resorption by osteoclasts (OCs) and the associated pH drop. To this aim, LPMSs were prepared by using 1,3,5-trimethyl benzene (TMB) as a swelling agent and the synthesis solution was hydrothermally treated and the influence of different process temperatures and durations on the resulting mesostructure was investigated. The synthesized particles exhibited a cage-like mesoporous structure with accessible pores of diameter up to 23 nm. LPMSs produced at 140 °C for 24 h showed the best compromise in terms of specific surface area, pores size and shape and hence, were selected for further experiments. Horseradish peroxidase (HRP) was used as model protein to evaluate the ability of the LPMSs to adsorb and release large biomolecules. After HRP-loading, LPMSs were coated with a pH-responsive polymer, poly(ethylene glycol) (PEG), allowing the release of the incorporated biomolecules in response to a pH decrease, in an attempt to mimic GFs release in bone under the acidic pH generated by the resorption activity of OCs. The reported results proved that PEG-coated carriers released HRP more quickly in an acidic environment, due to the protonation of PEG at low pH that catalyzes polymer hydrolysis reaction. Our findings indicate that LPMSs could be used as carriers to deliver large biomolecules and prove the effectiveness of PEG as pH-responsive coating. Finally, as proof of concept, a collagen-based suspension was obtained by incorporating PEG-coated LPMS carriers into a type I collagen matrix with the aim of designing a hybrid formulation for 3D-printing of bone scaffolds.     

Effect of drug loading and laser surface melting on drug release profile from biodegradable polymer

The biodegradable polymer such as poly(l ‐lactic acid) is promising in drug delivery applications because it allows for drug release in a controlled manner. In a polymer‐based drug delivery system, drug release is controlled by polymer degradation and drug loading concentration. In this study, effect of drug concentration on drug release profile is investigated through polymer crystallinity, chain mobility, and polymer degradation, as characterized by the wide‐angle X‐ray diffraction, differential scanning calorimetry, and gel permeation chromatography, respectively. The addition of drug has been shown to accelerate polymer degradation and drug release rate. With a low drug concentration, the slow polymer degradation kinetics results in an induction period of drug release, during which a limited amount of drug is released. The induction period is undesirable because it delays drug release and effectiveness. Since drug release is controlled by polymer degradation, which is a function of polymer crystallinity, laser surface melting is conducted to reduce polymer surface crystallinity and modify its degradation. The effect of laser crystallinity modification on drug release is investigated. A numerical model is also implemented based on hydrolysis and diffusion mechanisms to investigate the effects of drug loading and laser surface melting on polymer degradation and drug release process. It has been demonstrated that laser treatment shortens the induction period of drug release while keeps the release rate unmodified, as desired in drug delivery applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 4147–4156, 2013     

Controlled loading and release of methylene blue for hydrogen-bonded LbL poly(vinyl pyrrolidone)/poly (acrylic acid) film

The layer-by-layer (LbL) assembled multilayer films are widely used in controlled drug delivery. Here, hydrogen-bonded LbL multilayer films were assembled through alternating deposition of poly(vinylpyrrolidone) (PVPON) and poly(acrylic acid) (PAA) on glass slides. Methylene blue (MB) was used as a model drug to investigate the loading and release ability of the prepared multilayer film. The results showed that the loading rate of MB was greatly influenced by pH value of the dye solution, and the release rate was controlled both by ionic strength and pH value of immersing solution. The result also indicated that the loading and release of MB were reversible and can be repeated many times. It suggested that the PVPON/PAA multilayer film had potential applications in drug delivery and controlled release.     

pH Responsive Abelmoschus esculentus Mucilage and Administration of Methotrexate: In-Vitro Antitumor and In-Vivo Toxicity Evaluation

The rapid progression in biomaterial nanotechnology apprehends the potential of non-toxic and potent polysaccharide delivery modules to overcome oral chemotherapeutic challenges. The present study is aimed to design, fabricate and characterize polysaccharide nanoparticles for methotrexate (MTX) delivery. The nanoparticles (NPs) were prepared by Abelmoschus esculentus mucilage (AEM) and chitosan (CS) by the modified coacervation method, followed by ultra-sonification. The NPs showed much better pharmaceutical properties with a spherical shape and smooth surface of 213.4–254.2 nm with PDI ranging between 0.279–0.485 size with entrapment efficiency varying from 42.08 ± 1.2 to 72.23 ± 2.0. The results revealed NPs to possess positive zeta potential and a low polydispersity index (PDI). The in-vitro drug release showed a sustained release of the drug up to 32 h with pH-dependence. Blank AEM -CS NPs showed no in-vivo toxicity for a time duration of 14 days, accompanied by high cytotoxic effects of optimized MTX loaded NPs against MCF-7 and MD-MBA231 cells by MTT assay. In conclusion, the findings advocated the therapeutic potential of AEM/CS NPs as an efficacious tool, offering a new perspective for pH-responsive routing of anticancer drugs with tumor cells as a target.     

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.     

The Pharmacokinetics and Pharmacodynamics of Lidocaine-Loaded Biodegradable Poly(lactic-co-glycolic acid) Microspheres

The purpose of this study was to develop novel lidocaine microspheres. Microspheres were prepared by the oil-in-water (o/w) emulsion technique using poly(d,l-lactide-co-glycolide acid) (PLGA) for the controlled delivery of lidocaine. The average diameter of lidocaine PLGA microspheres was 2.34 ± 0.3 μm. The poly disperse index was 0.21 ± 0.03, and the zeta potential was +0.34 ± 0.02 mV. The encapsulation efficiency and drug loading of the prepared microspheres were 90.5% ± 4.3% and 11.2% ± 1.4%. In vitro release indicated that the lidocaine microspheres had a well-sustained release efficacy, and in vivo studies showed that the area under the curve of lidocaine in microspheres was 2.02–2.06-fold that of lidocaine injection (p < 0.05). The pharmacodynamics results showed that lidocaine microspheres showed a significant release effect in rats, that the process to achieve efficacy was calm and lasting and that the analgesic effect had a significant dose-dependency.     

In vitro and in vivo evaluation of poly(2-methoxyethyl methacrylate-co-acrylic acid)-based microhydrogels for pH-responsive targeted delivery of model drug

ABSTRACT

The study aimed to develop chemically crosslinked poly(2-methoxyethyl methacrylate-co-acrylic acid) (p(MEMA-co-AA)) microhydrogels as carriers for pH-responsive oral targeted delivery of therapeutics. p(MEMA-co-AA) microgels were successfully synthesized by simple free radical suspension polymerization technique confirmed through Fourier transform infrared spectroscopy, thermogravimetic analysis, powdered x-ray diffractrometry, and scanning electron microscopy. Chemically crosslinked spherical microhydrogels with an average size in the range of 4.1 µm ± 2.21 to 9.7 µm ± 3.21 exhibited pH-dependent controlled release of the model drug. Maximum swelling, drug loading, and release were observed at pH 7.4. The optimal formulation achieved good delayed and sustained release features with decreased C_max, prolonged T_max, and mean residence time in comparison to oral drug solution.     

Periodic mesoporous silica and organosilica with controlled morphologies as carriers for drug release

In this paper, we report the effects of morphology, wall composition of mesoporous materials and different buffer solutions on drug delivery profiles. Hollow spheres of periodic mesoporous organosilica (PMO) were prepared and used as drug carriers which exhibited higher loading capacity and slower release rate compared to the conventional periodic mesoporous silica (PMS) spheres and solid spheres of PMO. This hollow PMO showed promising properties as a reservoir to encapsulate and store larger quantities of guest molecules within its “empty” core. Moreover, its organic reactive sites allowed stronger interactions to the hydrophobic guest molecules, in contrast to inorganic wall possessed by PMS materials. Antibiotic tetracycline was used as a model drug to study the effect of framework difference between PMO and PMS materials on the loading and release processes. Two kinds of release medium, simulated body fluid (SBF) solution (pH 7.4) and phosphate buffer (PB) solution (pH 1.5) were used in this study, which revealed very different release profiles. A slower delivery rate was observed in SBF solution, attributed to the different ionic interactions between the guest molecule and the host material in the two different pH solutions. Overall, hollow PMO shows the lowest release rate and the highest loading amount compared to the other two materials studied herein. The kinetic study reveals that drug release from host material follows the second order kinetic model better than the first order mass transfer model.     

Synthesis of pH-Responsive Multilayer Micelles for Sustained Release of Folic Acid

Two novel triblock copolymers poly(hydroxypropyl acrylate)-b-poly (methyl methacrylate)-b-poly(N,N-dimethylaminoethyl methacrylate) and poly(hydroxypropyl acrylate)-b-poly(methyl methacrylate)-b-poly(acrylic acid) were successfully synthesized. In acetone media, using the electrostatic interactions between N,N-dimethylaminoethyl methacrylate and acrylic acid units, they could form spherically shaped multilayer micelles with pH-responsive, and have a mean diameter around 110 nm. The critical micelle concentration of it was determined to be 2.42 mg/L. In vitro release experiments, the folic acid-loaded micelles exhibited sustained release behavior and the drug release rate was affected by the pH value of release media. These results indicate that the multilayer micelles may serve as a novel intelligent drug delivery system.