A pH-sensitive charge-conversion system for doxorubicin delivery

A novel pH-sensitive charge-conversion shielding system was designed by the electrostatic binding of polyethylenimine (PEI)-poly(l-lysine)-poly(l-glutamic acid) (PELG), PEI, and cis-aconityl-doxorubicin (CAD). Doxorubicin (DOX) was modified by cis-aconityl linkage to form acid-sensitive CAD, which was then adsorbed by the positively charged PEI. The PEI/CAD complexes were subsequently shielded with the pH-responsive charge-conversion PELG. In normal tissues, the PELG/PEI/CAD complexes were negatively charged; in acidic tumor tissues, the shielding PELG was positively charged and detached from the PELG/PEI/CAD complexes. The resulting positively charged PEI/CAD complexes thus became exposed and were endocytosed. CAD was then cleaved in the acidic intracellular environment of endosomes and lysosomes, and converted back into DOX. The charge reversal of the PELG/PEI/CAD complexes was verified by zeta potential analysis at different pH values. Moreover, DOX release increased with decreasing pH. Cell uptake and confocal laser scanning microscopy analyses showed that, at pH 6.8, PELG/PEI/CAD had the highest endocytosis rate and more DOX entered cell nuclei. More importantly, the system showed remarkable cytotoxicity against cancer cells. These results revealed that the combination of pH-sensitive charge-conversion shielding with pH-sensitive drug release is a potential drug delivery system for tumor treatment.     

Biodegradation of chitosan-tripolyphosphate beads: in vitro and in vivo studies

In this study, chitosan [(1 --> 4) linked 2-amino-2-deoxy-beta-D-glucopyranose] beads were prepared by interacting this polycation (> 90% deacetylated) with the tripolyphosphate (TPP) polyanion. The resulting chitosan-TPP beads (C) were modified either by coating with sodium alginate (CA) or by cross-linking with glutaraldehyde (CGA). The in vitro degradation of C beads was found to be faster than its CA and CGA counterparts. C beads degraded faster at pH 6.5, compared to pH 7.4 conditions. At pH 7.4, about 41%, 37% and 10% of dry mass loss after 12 months was determined for C, CA and CGA, respectively. At pH 6.5, the dry mass loss of CA and CGA after the same period of time was found to be 73% and 37%, respectively. However, C beads completely degraded at pH 6.5 after 8 months of in vitro incubation. The in vivo biodegradation experiments were performed on Wistar rats (n = 24) for a duration of 6 months. No sign of fibrotic capsule formation was observed around any of the implanted beads at 2 and 6 months post-transplantation. At 2 months, the in vivo-degradation was slow-going and the beads in all groups were intact; CGA beads had more tissue reaction than C and CA beads at this time point. While the C beads had almost completely degraded after 6 months, the biodegradation process in CA and CGA beads was progressing. Histomorphometric analysis revealed that the in vivo biodegradation was in the order of C (approximately 85%) > CA (approximately 50%) > CGA (approximately 25%) after 6 months. Neovascularization was observed at the vicinity of the bead implants close to major blood vessels, both at 2 and 6 months time-points.     

Fluorination of electrospun hydrogel fibers for a controlled release drug delivery system

Electrospinning and fluorination were carried out in order to obtain a controlled release drug delivery system to solve the problem of both an initial burst of the drug and a limited release time. Poly(vinyl alcohol) was electrospun with Procion Blue as a model drug and heat treated in order to obtain cross-linked hydrogel fibers. Two different kinds of electrospun fibers of thin and thick diameters were obtained by controlling the electrospinning conditions. Thin fibers offer more available sites than thick fibers for surface modification during fluorination. Fluorination was conducted to control the release period by introducing hydrophobic functional groups on the surface of fibers. With an increase in the reaction pressure of the fluorine gas hydrophobic C–F and C–F₂ bonds were more effectively introduced. Over-fluorination of the fibers at higher reaction pressures of fluorine gas led to the introduction of C–F₂ bonds, which made the surface of the fibers hydrophobic and resulted in a decrease in their swelling potential. When C–F bonds were generated the initial drug burst decreased dramatically and total release time increased significantly, by a factor of approximately 6.7 times.     

Swelling characteristics and drug delivery properties of nifedipine-loaded pH sensitive alginate-chitosan hydrogel beads

The aim of the present work was to investigate the swelling behavior and in vitro release of nifedipine from alginate-chitosan hydrogel beads. Structure and surface morphology of the hydrogel were characterized by FTIR and SEM, respectively. Alginate-chitosan mixed beads and alginate-chitosan coated beads were prepared by ionic gelation method. The swelling ability of the beads and in vitro release of nifedipine in simulated gastric fluid (pH 1.5) and different phosphate buffer solutions (pH 2.5, 5.0, 6.8, 7.4, and 8.0) were found to be dependent on the presence of the polyelectrolyte complex between chitosan and alginate. The amount of nifedipine released from the mixed beads at pH 1.5 was relatively low (42%), whereas this value approached to 99% at pH 6.8. In comparison with the mixed beads, the released nifedipine from the coated beads was minimal at pH 1.5 (18%), whereas approximately 99% nifedipine was released at pH 6.8. The results suggested that the coated beads can hold drug better at low pH than the mixed beads and show excellent pH sensitivity. Therefore, the alginate-chitosan coated beads could be a suitable polymeric carrier for drug delivery in the intestinal tract.     

Novel pH-sensitive chitosan-based hydrogel for encapsulating poorly water-soluble drugs

Carboxymethyl–hexanoyl chitosan (CHC) is an amphiphilic chitosan derivative with excellent swelling ability and water solubility under natural conditions. In this work, the influence of the degree of carboxymethyl and hexanoyl substitution on the pH-sensitive swelling behavior, drug release behavior, and antiadhesion behavior of CHC hydrogels (cross-linked with genipin) were studied. It was found that the pH sensitivity was more pronounced in CHC than in N,O-carboxymethyl chitosan because the hexanoyl group altered the state of water in CHC by inhibiting intermolecular hydrogen bonding. In addition, greater pH sensitivity was observed in samples bearing longer hydrophobic chains (carboxymethyl–palmityl chitosan). Interestingly, when used with ibuprofen (a poorly water-soluble therapeutic agent used here as a model drug), the bursting release of the drug was less prominent in the CHC samples having a high degree of carboxymethyl substitution. The CHC hydrogel also demonstrated good cell compatibility and its antiadhesive ability after grafting was altered by changes in the degree of hexanoyl substitution.     

Ionically cross-linked carrageenan-alginate hydrogel beads

Hydrogel beads based on the carbohydrate biopolymers kappa-carrageenan and sodium alginate were newly prepared. Both classical and experimental design (Taguchi) methods were used to obtain the optimum conditions for the full-polysaccharide hydrogel preparation. The carrageenan-alginate (Caralgi) beads exhibited a surface morphology smoother than that of the one-polysaccharide network beads. Infrared spectroscopy and DSC/TGA thermal methods were used to study the chemical structure and thermal properties of the beads. The carrageenan parts appreciably enhanced thermostability of the networks. The fully carbohydrate-based hydrogel beads are expected to be biologically compatible and degradable. They are being considered as new carriers for drug loading and controlled delivery systems.     

Ionically cross-linked carrageenan-alginate hydrogel beads

Hydrogel beads based on the carbohydrate biopolymers kappa-carrageenan and sodium alginate were newly prepared. Both classical and experimental design (Taguchi) methods were used to obtain the optimum conditions for the full-polysaccharide hydrogel preparation. The carrageenan-alginate (Caralgi) beads exhibited a surface morphology smoother than that of the one-polysaccharide network beads. Infrared spectroscopy and DSC/TGA thermal methods were used to study the chemical structure and thermal properties of the beads. The carrageenan parts appreciably enhanced thermostability of the networks. The fully carbohydrate-based hydrogel beads are expected to be biologically compatible and degradable. They are being considered as new carriers for drug loading and controlled delivery systems.     

A conformal hydrogel nanocomposite for local delivery of paclitaxel

Conventional surgical methods can not completely remove the tumor cells, and an inevitable recurrence always results in death. In this study, we prepared a conformal hydrogel nanocomposite with potential to inhibit the recurrence of glioma. Based on the MRI of a patient’s brain tumor cavity (BTC), we 3D-printed a mould for preparing the customized implants that could match the resection cavity. The obtained macroporous hydrogel, containing Paclitaxel (PTX) nanoparticles, could sustained release PTX. From the confocal microscopy image, we could detect that the hydrogel nanocomposite combined with nanoparticles uniformly. The nanoparticles were fabricated through a self-assembled process with PTX. Moreover, the in vitro studies showed that nanoparticles could release PTX slowly and efficiently inhibited the proliferation of tumor cells. This work prepared a conformal hydrogel nanocomposite for local delivery of paclitaxel, which could inspire the development of future protocols for precision therapy of residual glioma after surgical resection.     

Polyethyleneimine-lipid conjugate-based pH-sensitive micellar carrier for gene delivery

A low molecular weight polyethyleneimine (PEI 1.8 kDa) was modified with dioleoylphosphatidylethanolamine (PE) to form the PEI-PE conjugate investigated as a transfection vector. The optimized PEI-PE/pDNA complexes at an N/P ratio of 16 had a particle size of 225 nm, a surface charge of +31 mV, and protected the pDNA from the action of DNase I. The PEI-PE conjugate had a critical micelle concentration (CMC) of about 34 μg/ml and exhibited no toxicity compared to a high molecular weight PEI (PEI 25 kDa) as tested with B16-F10 melanoma cells. The B16-F10 cells transfected with PEI-PE/pEGFP complexes showed protein expression levels higher than with PEI-1.8 or PEI-25 vectors. Complexes prepared with YOYO 1-labeled pEGFP confirmed the enhanced delivery of the plasmid with PEI-PE compared to PEI-1.8 and PEI-25. The PEI-PE/pDNA complexes were also mixed with various amounts of micelle-forming material, polyethylene glycol (PEG)-PE to improve biocompatibility. The resulting particles exhibited a neutral surface charge, resistance to salt-induced aggregation, and good transfection activity in the presence of serum in complete media. The use of the low-pH-degradable PEG-hydrazone-PE produced particles with transfection activity sensitive to changes in pH consistent with the relatively acidic tumor environment.     

A peptide-modified chitosan-collagen hydrogel for cardiac cell culture and delivery

Myocardial infarction (MI) results in the death of cardiomyocytes (CM) followed by scar formation and pathological remodeling of the heart. We propose that chitosan conjugated with the angiopoietin-1 derived peptide, QHREDGS, and mixed with collagen I forms a thermoresponsive hydrogel better suited for the survival and maturation of transplanted cardiomyocytes in vitro compared to collagen and chitosan-collagen hydrogels alone. Conjugation of QHREDGS peptide to chitosan does not interfere with the gelation, structure or mechanical properties of the hydrogel blends. The storage modulus of 2.5 mg ml(-1) 1:1 mass:mass (m:m) chitosan-collagen was measured to be 54.9 ± 9.1 Pa, and the loss modulus 6.1±0.9 Pa. The dose-response of the QHREDGS peptide was assessed and it was found that CMs encapsulated in High-peptide gel (651 ± 8 nmol peptide ml-gel(-1)) showed improved morphology, viability and metabolic activity in comparison to the Low-peptide (100 ± 30 nmol peptide ml-gel(-1)) and Control (No Peptide) groups. Construct (CMs in hydrogel) functional properties were not significantly different between the groups; however, the success rate of obtaining a beating construct was improved in the hydrogel with the High amount of QHREDGS peptide immobilized compared to the Low and Control groups. Subcutaneous injection of hydrogel (Control, Low and High) with CMs in the back of Lewis rats illustrated its ability to localize at the site of injection and retain cells, with CM contractile apparati identified after seven days. The hydrogel was also able to successfully localize at the site of injection in a mouse MI model.     

Facile synthesis of magnetic-/pH-responsive hydrogel beads based on Fe3O4 nanoparticles and chitosan hydrogel as MTX carriers for controlled drug release

In the present study, methotrexate (MTX)-encapsulated magnetic-/pH-responsive hydrogel beads based on Fe₃O₄ nanoparticles and chitosan were successfully prepared through a one-step gelation process, which is a very facile, economic and environmentally friendly route. The developed hydrogel beads exhibited homogeneous porous structure and super-paramagnetic responsibility. MTX can be successfully encapsulated into magnetic chitosan hydrogel beads, and the drug encapsulation efficiency (%) and encapsulation content (%) were 93.8 and 6.28%, respectively. In addition, the drug release studies in vitro indicated that the MTX-encapsulated magnetic chitosan hydrogel beads had excellent pH-sensitivity, 90.6% MTX was released from the magnetic chitosan hydrogel beads within 48 h at pH 4.0. WST-1 assays in human liver hepatocellular carcinoma cells (HepG2) demonstrated that the MTX-encapsulated magnetic chitosan hydrogel beads had good cytocompatibility and high anti-tumor activity. Therefore, our results revealed that the MTX-encapsulated magnetic chitosan hydrogel beads would be a competitive candidate for controlled drug release in the area of targeted cancer therapy in the near future.     

Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin

pH responsive cisplatin prodrug crosslinked polysaccharide-based nanoparticles were developed from succinic acid decorated dextran (Dex-SA) for active loading and triggered intracellular release of doxorubicin (DOX). Nanoparticles with uniform size were formed spontaneously in aqueous medium via electrostatic interaction between anionic Dex-SA and cationic DOX, and subsequently transformed into crosslinked nanoparticles (CL-Nanoparticles) in situ by readily crosslinking the micelles via chelate interactions between the ionic polymeric carrier and the platinum (II) antitumor drug. This strategy eliminated the need of organic solvents and sophisticated processes in the drug loading procedure. The in vitro release studies showed that DOX was released from the CL-Nanoparticles in a controlled and pH-dependent manner. Furthermore, the pharmacokinetics and biodistribution investigations indicated that, as compared to the non-crosslinked nanoparticles (NCL-Nanoparticles) and free DOX, the CL-Nanoparticles significantly prolonged the blood circulation time of drug, decreased accumulation in the normal tissues and enriched drug into the tumors. As a consequence, the DOX-loaded CL-Nanoparticles exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with the NCL-Nanoparticles and free DOX, which were further confirmed by the histological and immunohistochemical analyses. These cisplatin prodrug crosslinked polysaccharide nanoparticles proved to be a promising nanomedicine drug delivery system for tumor-targeted delivery of DOX.     

Novel etherified locust bean gum-alginate hydrogels for controlled release of glipizide

On many occasions, homopolysaccharide hydrogel networks alone are not suitable for controlled drug delivery. In this study, interpenetrating networks (IPNs) of sodium alginate (ALG) and etherified locust bean gum (ELBG) were developed through ionotropic gelation with Al³⁺ ions, tested for glipizide release, and were compared with homopolymer hydrogel networks. The degree of reticulation in IPNs was explained by the neutralization equivalent, tensile strength measurement, and drying kinetics of drug-free hydrogels. IPNs afforded a maximum of 94.40?±?0.35% drug entrapment efficiency and exhibited slower drug release profiles up to 8?h. Al³⁺-ALG network almost completed the release of embedded drug in 3.5?h; however, the homopolymer Al³⁺-ELBG network discharged their content at a slow, uniform rate up to 8?h like the IPNs. All the networks appeared spherical under scanning electron microscope. In all cases, a faster drug release rate was assumed in phosphate buffer (pH 7.4) than in KCl/HCl buffer (pH 1.2) solution. The pH-responsive swelling of the beads was responsible for the variable drug release rate in different media. NonFickian diffusion mechanism was operative for the transport of drug from the IPNs. Moreover, IPNs gained appreciation for their better mechanical strength (63.79?±?1.59?MPa) than Al³⁺-ELBG network. Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry, and X-ray diffraction analyses indicated a compatible environment for drug encapsualtion and release from the IPNs. The drug release curves of Al³⁺-ELBG and IPNs were found similar to a reference product. Hence, Al³⁺-ELBG and IPNs could be useful in controlling diabetes over longer periods.     

Silica-coated calcium pectinate beads for colonic drug delivery

The aim of this work is to develop novel organic–inorganic hybrid beads for colonic drug delivery. For this purpose, calcium pectinate beads with theophylline are prepared by a cross-linking reaction between amidated low-methoxyl pectin and calcium ions. The beads are then covered with silica, starting from tetraethyoxysilane (TEOS), by a sol–gel process. The influence of TEOS concentration (0.25, 0.50, 0.75 and 1.00 M) during the process is studied in order to modulate the thickness of the silica layer around the pectinate beads and thus to control the drug release. The interactions between the silica coating and the organic beads are weak according to the physicochemical characterizations. A good correlation between physicochemical and in-vitro dissolution tests is observed. At concentrations of TEOS beyond 0.25 M, the silica layer is thick enough to act as a barrier to water uptake and to reduce the swelling ratio of the beads. The drug release is also delayed. Silica-coated pectinate beads are promising candidates for sustained drug delivery systems.     

Synthesis and characterization of pH-sensitive glycopolymers for oral drug delivery systems

pH-sensitive hydrogels are suitable candidates for oral delivery of therapeutic peptides and proteins, due to their ability to respond to environmental pH changes. New pH-sensitive glycopolymers have been developed by free-radical photopolymerization of methacrylic acid and 2-methacryloxyethyl glucoside, using tetra(ethylene glycol) dimethacrylate as a cross-linking agent. To determine the suitability of these hydrogels as carriers for oral drug delivery devices, their swelling behavior was investigated as a function of the pH and copolymer compositions, and various structural parameters such as the number-average molecular weight between cross-links, Mc, the mesh size, xi, and the cross-linking density, rho(x), were calculated. The transition between the swollen and the collapsed states of these hydrogels was at a pH of 5. The swelling ratios of the hydrogels increased at pH values above 5. The mesh sizes of the hydrogels were between 18 and 35 A in the collapsed state (at pH 2.2) and between 70 and 111 A in the swollen state (at pH 7.0). Finally, as the cross-linking ratio of the copolymer increased, the swelling ratio of the hydrogels decreased at both pH 2.2 and 7.0.     

Synthesis and characterization of pH-sensitive glycopolymers for oral drug delivery systems

pH-sensitive hydrogels are suitable candidates for oral delivery of therapeutic peptides and proteins, due to their ability to respond to environmental pH changes. New pH-sensitive glycopolymers have been developed by free-radical photopolymerization of methacrylic acid and 2- methacryloxyethyl glucoside, using tetra(ethylene glycol) dimethacrylate as a cross-linking agent. To determine the suitability of these hydrogels as carriers for oral drug delivery devices, their swelling behavior was investigated as a function of the pH and copolymer compositions, and various structural parameters such as the number-average molecular weight between cross-links, M _c, the mesh size, ξ, and the cross-linking density, ρ _x, were calculated. The transition between the swollen and the collapsed states of these hydrogels was at a pH of 5. The swelling ratios of the hydrogels increased at pH values above 5. The mesh sizes of the hydrogels were between 18 and 35 Å in the collapsed state (at pH 2.2) and between 70 and 111 Å in the swollen state (at pH 7.0). Finally, as the cross-linking ratio of the copolymer increased, the swelling ratio of the hydrogels decreased at both pH 2.2 and 7.0.     

Synthesis and characterization of a pH-sensitive hydrogel made of pyruvic-acid-modified chitosan

Pyruvic-acid-type chitosan (PA-CS) was prepared by the reaction of an amine group on chitosan with a carbonyl group on pyruvic acid. Then, a novel hydrogel film was obtained via cross-linking of poly(ethylene glycol) diglycidyl ether (PEGDE) with PA-CS. 1H-NMR and FT-IR spectrometry were applied for the verification of the CS and PA-CS structure. The degree of swelling was studied by changing the molar ratio of PEGDE and PA-CS. Moreover, the swelling ratio of cross-linked membrane in different pH buffer solutions was measured. The result showed that the swelling of hydrogel exhibited obvious pH-sensitivity. The swelling ratio was higher at pH 1-4 and pH 7-12, but lower at pH 5-6.     

A novel two-level microstructured poly(N-isopropylacrylamide) hydrogel for controlled release

The aim of this work was to demonstrate that conventional poly(N-isopropylacrylamide) (PNIPAAm) hydrogels can improve their shrinkage and release properties solely due to the introduction of a heterogeneous density fluctuation-based microstructure. To this end, a novel structurally engineered PNIPAAm hydrogel was designed and compared with a chemically similar, but homogeneous, PNIPAAm hydrogel reference. For the two-step preparation PNIPAAm microgels were firstly synthesized with surface amine groups and further functionalized with polymerizable acrylate groups. In the second step the microgels, themselves acting as crosslinkers, were crosslinked to form a bulk network by inter-connecting the microgels with linear PNIPAAm chains. Although the chemical composition of the newly prepared hydrogel was generally the same as conventional PNIPAAm hydrogels (a relative control), significantly improved shrinkage properties and a more efficient “on–off” switching induced by temperature modulations were observed for the novel gel as compared with the homogeneous reference. These improved shrinkage properties were ascribed to the novel structure, which is believed to enable rapid shrinking of the small microgel crosslinkers and, thereupon, the generation of a sufficient number of diffusion channels for quick water release. Rhodamine B and ibuprofen (IBU) as model compounds were completely released from this novel gel at 20 °C, whereas at temperatures above the lower critical solution temperature release stopped after initial 40% and 70% “bursts” for rhodamine B and IBU, respectively, due to shrinkage of the gel network. This approach may provide an avenue to design temperature-sensitive drug delivery systems with state of the art switching properties and fast release kinetics by combining the here presented innovative strategy with complementary enhancements, such as the introduction of porosity.     

A pH-sensitive nano drug delivery system derived from pullulan/doxorubicin conjugate

A novel pH-sensitive nanoparticle drug delivery system for doxorubicin (DOX) is prepared. Pullulan, a natural biocompatible polysaccharide, was partly carboxymethylized; hydrazine hydrate was condensed with the carboxyl groups forming hydrazide. The hydrazide was coupled with DOX through the formation of hydrazone bond. The chemical structure of the conjugate was determined by FTIR and (1)H NMR. The pullulan/DOX conjugate nanoparticles were formed through the aggregation of hydrophobic DOX. The size and morphology of prepared nanoparticles were characterized using dynamic light scattering and transmission electron microscope. The results showed that the nanoparticles were spherical and their size was less than 100 nm. The content of DOX in conjugate was 3.18 wt %. The investigation of the release behavior in vitro indicated that the DOX was released from nanoparticles faster at pH 5.0 (62% DOX released within 24 h) than at pH 7.4 (29% DOX released within 24 h). The in vitro cytotoxicity of pullulan/DOX conjugate nanoparticles was tested by the MTT assay.     

A squeeze-type osmotic tablet for controlled delivery of nifedipine

Osmotic delivery systems are based on osmotic driving force. Nifedipine tablets, available under the trade names Procardia XL (Pfizer) and Adalat (Bayer), are commercialized drug-delivery systems of an elemental osmotic pump that the push-pull osmotic tablet operates successfully in delivering water-insoluble drugs. For the improvement of the release pattern and the solubility of the drug, we developed a squeeze-type osmotic tablet (SQT) for nifedipine as a model drug. The SQT was composed of one or more ring type of squeeze-push layer (squeeze-disc) and a centered drug core. Squeeze-discs were stacked up with different physicochemical properties with gradient such as viscosity, swelling ratio and water absorption ratio using the osmotic agents from a disc of bottom to top. The present work investigated the effect of different preparation factors, such as hydrophilic polymers, the molecular weight of polymers, coating process, orifice size and types of excipient on release performance of nifedipine. With the purpose of delivering water-insoluble nifedipine at an approximate zero-order rate and step-function rate for 24 h, SQT has been successfully prepared, and significantly improved in the release rate and patterns in comparison with the Adalat push-pull system in vitro release features.