Novel alginate-poly(L-histidine) microcapsules as drug carriers: in vitro protein release and short term stability

Spherical, smooth-surfaced and mechanically stable alginate-poly(L-histidine) (PLHis) microcapsules with narrow particle size distributions were prepared by incubating calcium alginate beads in aqueous solutions of PLHis. The in vitro release characteristics, drug loading and encapsulation efficiency of the microcapsules were investigated using bovine erythrocytes hemoglobin (Hb) as a model drug. The results showed that the concentration of Ca(2+) ions had a considerable effect on the drug loading, encapsulation efficiency and in vitro release behavior of the microcapsules. When the concentration of CaCl(2) in the PLHis solution was increased from 0 to 3.0% (w/v), the drug loading and encapsulation efficiency decreased significantly from 38.0 to 4.3% and from 92.9 to 8.0%, respectively, while the total cumulative release of Hb from microcapsules in phosphate buffered saline solution (PBS, pH 6.8) decreased from 96.2 to 72.8% in 24 h. No significant protein release was observed during 70 h of incubation in hydrochloric acid solution (pH 1.2). However, under neutral conditions (PBS, pH 6.8), the Hb was completely and stably released within 24-70 h. An explosion test showed that the stability of alginate-PLHis microcapsules depended strongly on the concentration of PLHis and the calcium ions in solution. [Diagram: see text] Microscopy photo of Hb-loaded alginate-PLHis microcapsules.     

Fabrication of polyvinyl alcohol/chitosan oligosaccharide hydrogel: physicochemical characterizations and in vitro drug release study

Abstract

Hydrogel composites from polyvinyl alcohol and chitosan have been developed by various researchers as a function of their composition for various medical applications. Although, the solubility of chitosan in acidic solvents may limit its wide bioengineering applications. In this article, we demonstrate that polyvinyl alcohol-chitosan oligosaccharide (water soluble) to develop cross-linked hydrogel network using chemical cross linker. X ray diffraction, Fourier transform infrared spectroscopy, and wettability study of these hydrogels were also performed. Lomefloxacin drug was loaded into the hydrogels and its release profile was studied.     

Monodisperse gelatin microspheres as a drug delivery vehicle: release profile and effect of crosslinking density

Uniform gelatin microspheres (GMS) of a wet size of 100 microm in diameter were fabricated by the electric field assisted precision particle fabrication (E-PPF) method and crosslinked with different glutaraldehyde (GA) concentrations to study the effect of the crosslinking density on drug release. The drug release profiles of the crosslinked GMS were studied along with the intraparticle drug distribution and the particle degradation characteristics. Due to the concentration gradient of GA along the diffusion path into the GMS, the crosslinking density is higher on the GMS surface, making it less susceptible to degradation. As a result, the GMS with higher GA concentrations (0.375-0.875%) exhibited a highly resistant surface toward enzymatic degradation. On the other hand, the amount of drug complexation at the surface decreases as the GA concentration increases, which can be attributed to the lowered basicity of gelatin caused by the increased crosslinking density. These factors collectively affect the drug release kinetics and give rise to similar release profiles for GMS above a GA concentration of 0.375%.     

Effect of the Molecular Weights of Poly‐L‐Arginine on Membrane Strength and Permeability of Poly‐L‐Arginine Group Microcapsules

A novel poly‐L ‐arginine group microcapsule was produced to investigate its nutritional function and pharmacological efficacy. The molecular weight of poly‐L ‐arginine is an important parameter for its membrane strength, but does not obviously affect its release property. Thus, poly‐L ‐arginine can be used as a kind of new membrane material in microcapsules, and it is expected to be used as an therapeutic and biodegradable drug carrier.

Influence of the molecular weight of poly‐L ‐arginine on membrane thickness.     

Chemical synthesis of MnFe2O4/chitosan nanocomposites for controlled release of ofloxacin drug

In this study, we synthesized ofloxacin‐loaded MnFe₂O₄ nanoparticles (NPs) surface modified with chitosan (CS‐MnFe₂O₄) for prolonged antibiotic release in a controlled manner. It was found that the synthesized CS‐MnFe₂O₄ was spherical in shape with an average size of 30–50 nm, low aggregation, and good magnetic responsibility. An in vitro drug loading and release kinetics study reveals that the drug delivery system can take 86% of drug load and can release ofloxacin over a sustained period of 3 days. The release kinetics study reveals that the drug follows zero order kinetics and the mechanism of drug release is diffusion‐controlled type. These results indicated that CS‐MnFe₂O₄ NPs with pH‐sensitive properties can be used as candidates for intestinal targeted drug delivery through oral administration by avoiding the drug release in the highly acidic gastric fluid region of the stomach.     

A novel pH‐ and thermo‐sensitive PVP/CMC semi‐IPN hydrogel: Swelling,phase behavior,and drug release study

Poly(N‐vinyl‐pyrrolidone) (PVP) hydrogel has been considered as a very interesting and promising thermosensitive material. The most vital shortcoming of PVP hydrogel as thermosensitive material is that it does not exhibit thermosensitivity under usual conditions. In this work, semi‐interpenetrating polymer network (semi‐IPN) hydrogels based on PVP and carboxymethylcellulose (CMC) were prepared. The volume phase transition temperature (VPTT) of the hydrogels was determined by swelling behavior and differential scanning calorimetry (DSC). The results showed that the VPTT was significantly dependent on CMC content and the pH of the swelling medium. The amount of CMC in the semi‐IPN hydrogels was 0.050, 0.075, and 0.100 g, the VPTT in buffer solution of pH 1.2 was 29.9 °C, 27.5 °C and 24.5 °C, respectively. In addition, the VPTT occurred in buffer solution of pH 1.2, but did not appear in alkaline medium. Bovine serum albumin (BSA) as a model drug was loaded and the in vitro release studies were carried out in different buffer solutions and at different temperatures. The results of this study suggest that PVP/CMC semi‐IPN hydrogels could serve as potential candidates for protein drug delivery in the intestine. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 1749–1756, 2010     

Microgels for the encapsulation and stimulus-responsive release of molecules with distinct polarities

A microfluidic strategy for the encapsulation and stimulus-responsive release of molecules with distinct polarities from the interior of microgels is reported. The approach relies on (i) the generation of a primary O/W emulsion by the ultrasonication method, (ii) MF emulsification of the primary emulsion, and (iii) photopolymerization of the monomer present in the aqueous phase of the droplets, thereby transforming them into microgels. Non-polar molecules are dissolved in oil droplets embedded in the microgels. Polar molecules are physically associated with the hydrogel network. Upon heating, the microgels contract and release polar and non-polar cargo molecules. The approach paves the way for stimuli-responsive vehicles for multiple drug delivery.     

Confinement and controlled release of quinine on chitosan–montmorillonite bionanocomposites

To accomplish the controlled‐release systems based on layered clay minerals, one of the best ways is to intercalate organic molecules into the interlayer gallery of clay minerals. Into a series of chitosan (CS) intercalated montmorillonite (MMT) nanocomposites, prepared via ion‐exchange route, antimalarial drug [quinine (QUI)] was loaded to act as effective drug delivery systems. Among the CS–MMT nanocomposites, higher drug adsorption with decreasing CS concentration was observed. CS–MMT and CS–MMT/QUI intercalated compounds were characterized by powder X‐ray diffraction, Fourier transform infrared spectroscopy, and thermal analysis. The synthesized nanocomposites, filled in the gelatin capsules followed by coating of Eudragit® L 100, were tested for in vitro drug release performance in the sequential buffer environments at 37 ± 0.5 °C. As no drug release (0%) was observed in the gastric fluid, the coating of Eudragit® L 100 to the capsules is highly adequate. However, the drug release rate was comparatively faster from the CS intercalated clay with compare with pure clay. The drug release kinetic data revealed that the release of QUI from the nanocomposites can be explained by modified Freundlich model. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Hydroxypropyl chitosan bearing beta-cyclodextrin cavities: synthesis and slow release of its inclusion complex with a model hydrophobic drug

Hydroxypropyl chitosan-graft-carboxymethyl beta-cyclodextrin (HPCH-g-CM beta-CD) was synthesized by grafting CM beta-CD onto HPCH using water soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the condensing agent. Due to the presence of hydrophobic beta-CD rings onto the HPCH backbone, this polymer can be used as a matrix for controlled drug release. The adsorption of a hydrophobic model drug, ketoprofen, by HPCH-g-CM beta-CD microparticles (using tripolyphosphate as an ionic crosslinking agent) fitted well in the Langmuir isotherm equation. The drug dissolution profile showed that HPCH-g-CM beta-CD microparticles provided a slower release of the entrapped ketoprofen than chitosan, and the release behavior was influenced by the pH value of the medium. These results suggest that beta-CD grafted with chitosan derivatives may become a potential biodegradable delivery system to control the release of hydrophobic drugs with pH-responsive capability.     

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH-sensitive drug release property

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH sensitivity were developed for oral delivery of protein drugs, using bovine serum albumin (BSA) as a model drug. The composite drug-loaded microparticles with a mean particle size less than 200 μm were prepared by a convenient shredding method. Since the microparticles were formed by tripolyphosphate cross-linking, electrostatic complexation by alginate and/or pectin, as well as ionotropic gelation with calcium ions, the microparticles exhibited an improved pH-sensitive drug release property. The in vitro drug release behaviors of the microparticles were studied in simulated gastric (pH 1.2 and pH 5.0), intestinal (pH 7.4) and colonic (pH 6.0 and pH 6.8 with enzyme) media. For the composite microparticles with suitable compositions, the releases of BSA at pH 1.2 and pH 5.0 could be effectively sustained, while the releases at pH 7.4, pH 6.8 and pH 6.0 increased significantly, especially in the presence of pectinase. These results clearly suggested that the microparticles had potential for site-specific protein drug delivery through oral administration.     

Magnetic‐targeted pH‐responsive drug delivery system via layer‐by‐layer self‐assembly of polyelectrolytes onto drug‐containing emulsion droplets and its controlled release

Novel magnetic‐targeted pH‐responsive drug delivery system have been designed by the layer‐by‐layer self‐ assembly of the polyelectrolytes (oligochitosan as the polycation and sodium alginate as the polyanion) via the electrostatic interaction with the oil‐in‐water type hybrid emulsion droplets containing the superparamagnetic ferroferric oxide nanoparticles and drug molecules [dipyridamole (DIP)] as cores. Here the drug molecules were directly encapsulated into the interior of droplets without etching the templates and refilling with the desired guest molecules. The drug‐delivery system showed high encapsulation efficiency of drugs and drug‐loading capacity. The cumulative release ratio of dipyridamole from the oligochitosan/sodium alginate multilayer‐encapsulated magnetic hybrid emulsion droplets (DIP/Fe₃O₄‐OA/OA)@(OCS/SAL)₄ was up to almost 100% after 31 h at pH 1.8. However, the cumulative release ratio was only 3.3% at pH 7.4 even after 48 h. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Star‐shaped polypeptide/glycopolymer biohybrids: Synthesis,self‐assembly,biomolecular recognition,and controlled drug release behavior

Star‐shaped polypeptide/glycopolymer biohybrids composed of poly(γ‐ benzyl L ‐glutamate) and poly(D ‐gluconamidoethyl methacrylate), exhibiting controlled molecular weights and low polydispersities, were synthesized by the combination of ring‐opening polymerization of γ‐benzyl‐L ‐glutamate N‐carboxyanhydride and the direct atom transfer radical polymerization of unprotected D ‐gluconamidoethyl methacrylate glycomonomer. These biohybrids were characterized in detail by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, and wide angle X‐ray diffraction. Independent of weight fraction of hydrophilic glycopolymer segment, the biohybrids self‐assembled into large spherical micelles in aqueous solution, which had a helical polypeptide core surrounded by a multivalent glycopolymer shell. The deprotected poly(L ‐glutamate)/glycopolymer hybrid exhibited a pH‐sensitive self‐assembly behavior, and the average size of the nanoparticles decreased gradually over the aqueous pH value. Moreover, whatever these biohybrids existed in unimolecular level or glycopolymer‐surfaced nanoparticles, they had specific biomolecular recognition with Concanavalin A compared with bovine serum albumin. Furthermore, star‐shaped biohybrids showed a higher doxorubicin loading efficiency and longer drug‐release time than linear analogues. This potentially provides a platform for fabricating targeted anticancer drug delivery system and studying glycoprotein functions in vitro. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2009–2023, 2009     

Synthesis and properties of chitosan‐based thermo‐ and pH‐responsive nanoparticles and application in drug release

In this research, thermo‐ and pH‐responsive nanoparticles with an average diameter of about 50–200 nm were synthesized via the surfactant‐free emulsion polymerization. The thermal/pH dual responsive properties of these nanoparticles were designed by the addition of a pH sensitive monomer, acrylic acid (AA), to be copolymerized with N‐isopropylacrylamide (NIPAAm) in a chitosan (CS) solution. The molar ratio of CS/AA/NIPAAm in the feed was changed to investigate its effect on structure, morphology, thermal‐ and pH‐responsive properties of the nanoparticles. It was found that CS‐PAA‐PNIPAAm nanoparticles could be well dispersed in the aqueous solution and carried positive charges on the surface. The addition of thermal‐sensitive NIPAAm monomer affected the polymerization mechanism and interactions between CS and AA. The particle size of the nanoparticles was found to be varied with the composition of NIPAAm monomer in the feed. The synthesized nanoparticles exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in vitro release experiment. The environmentally responsive nanoparticles are expected to be used in many fields such as drug delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2798–2810, 2009     

Chemo-physical and biological evaluation of poly(L-lysine)-grafted chitosan copolymers used for highly efficient gene delivery

For the success of non-viral gene delivery, it is of great importance to develop gene vectors with high efficiency but low toxicity. We demonstrate that PLL-grafted chitosan copolymers combine the advantages of PLL with its good pDNA-binding ability and of chitosan with its good biocompatibility. The chemo-physical properties of the prepared Chi-g-PLL copolymers are thoroughly characterized. The in vitro transfection study shows that the copolymers have a much higher gene transfer ability than the starting materials chitosan and PLL. A positive correlation between PLL chain lengths and transfection efficiency of the copolymers is found. Our results suggest that these novel Chi-g-PLL copolymers are good candidates for gene delivery in vivo.     

Polynonanolactone synthesized from vegetable oil: Evaluation of physical properties,biodegradation, and drug release behavior

A systematic investigation of the synthesis, physical properties, biodegradation, and drug release behavior of an aliphatic polynonanolactone from vegetable oil was performed. The chemical structure of the lactone monomers and polylactones were confirmed by NMR spectrometry and molecular weights were determined by gel permeation chromatography (GPC). The thermal behavior of the polymers was assessed by modulated differential scanning calorimetry (MDSC) and thermogravimetric analysis (TGA). The polynonanolactones are crystalline with melting enthalpies (ΔH_m) ranging from 90 to 135 J/g. The crystalline nature of the polylactides was further evaluated by X‐ray diffraction (XRD) and peaks corresponding to planes (110), (200), and (210) were detected. The hydrolytic and enzymatic degradation properties of the polynonanolactones were studied and the degradation rate is comparable to that of widely used polycaprolactone. The enzyme proteinase K was used for the degradation of polynonanolactones. The extent of degradation was evaluated by scanning electron microscopy (SEM). Drug incorporation and release traits due to hydrolytic degradation of the polymer film was carried out with 5‐fluorouracil (5‐FU) as a model drug. This new class of polynonanolactones obtained from vegetable oil was demonstrated to be a potentially competent candidate to replace petroleum‐based polycaprolactone especially for drug delivery applications where slow release of drugs is a requisite. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6373–6387, 2009     

Investigation of drug release from thermo‐ and pH‐sensitive poly(N‐isopropylacrylamide/itaconic acid) copolymeric hydrogels

N‐Isopropylacrylamide/itaconic acid copolymeric hydrogels were prepared by irradiation of the ternary mixtures of N‐isopropylacrylamide/itaconic acid/water by γ‐rays at ambient temperature. The dependence of swelling properties and phase transitions on the comonomer concentration and temperature were investigated. The hydrogels showed both temperature and pH responses. The effect of comonomer concentration on the uptake and release behavior of the hydrogels was studied. Methylene blue (MB) was used as a model drug for the investigation of drug uptake and release behavior of the hydrogels. The release studies showed that the basic parameters affecting the drug release behavior of the hydrogels were pH and temperature of the solution. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and In-vitro drug release of insulin-loaded poly(n-butyl cyanoacrylate) nanoparticles

Nanoparticles have been prepared by dispersion polymerisation of n-butyl cyanoacrylate in acidified water, with and without the inclusion of insulin. The molecular weight of the polymerising material increases by a stepwise process, in which chains are initiated, terminated, and reinitiated, until an equilibrium molecular weight is reached. This equilibrium molecular weight is higher at lower dispersion pH. The reaction is complete within two hours. Insulin is capable of initiating polymerisation, but if introduced after all of the monomer has been incorporated into the growing nanoparticles it has no effect on polymer molecular weight. A drug loading of 72% was achieved in particles produced at 25 °C and pH 3.0, with insulin introduced one hour after monomer initiation. Particle degradation characteristics were assessed using solutions of esterase in phosphate buffered saline at pH 7.0, with butanol release monitored as a measure of polymer degradation. Insulin release was monitored under the same conditions. Both butanol production and insulin release showed a similar biphasic mechanism, indicating that the drug release rate is determined by polymer degradation characteristics. An initial burst release of both materials is associated with the degradation of surface species, and this is then followed by a steady-state release from sub-surface material.

Insulin release as a function of time at an esterase concentration of 2.0 mg · ml⁻¹.     

pH and ionic sensitive chitosan/carboxymethyl chitosan IPN complex films for the controlled release of coenzyme A

pH and ionic sensitive interpenetrating polymer network (IPN) complex films based on chitosan (CS) and carboxymethyl chitosan (CM-CS) were prepared by using glutaraldehyde as crosslinking agent. Its structure was characterized by FT-IR, which indicated that the IPN was formed. The films were studied by swelling, weight loss with time, and release of coenzyme A (CoA). It was found that the IPN films were sensitive to pH and ionic strength of the medium. The cumulative release rate of CoA decreased with CoA loading content, ionic strength or crosslinking agent increasing. The composition of the IPN films and pH of release medium also had significant effect on the release of CoA. The differences in the rates and amounts of released CoA may be attributed to the swelling behavior, the degradation of films, and interaction between drug molecule and polymer matrix. These results suggested CS/CM-CS IPN films could be used as drug delivery carrier.     

Design of a poly(L‐histidine)‐carbohydrate conjugate for a new pH‐sensitive drug carrier

A poly(L ‐histidine) (PLH)‐carbohydrate conjugate has been synthesized as a new macromolecule extracting pH‐dependent properties of PLH with imidazole groups. Because of poor water solubility at physiological pH, the application of PLH with a pK_a around 6.0 has been limited in spite of the native possession of the pH‐dependent property change at endosomal pH. Although the PLH modified with aliphatic primary amino groups suddenly precipitated out of the aqueous medium above pH 6.0 as a result of the deprotonation of the imidazole groups, the water solubility of PLH was improved at physiological pH by the conjugation of the aminated PLH with hydrophilic maltopentaose. The resulting PLH‐maltopentaose conjugates and metalloporphyrins formed the complexes which varied their assembling structure below pH 6.0. The PLH‐maltopentaose would be the fundamental compound for designing various drug carriers with the pH sensitivity at endosomal pH. Copyright © 2004 John Wiley & Sons, Ltd.     

Lipo‐Poly(L‐histidine) Hybrid Materials with pH‐Sensitivity,Intracellular Delivery Efficiency,and Intrinsic Targetability to Cancer Cells

Biocompatible lipo‐histidine hybrid materials conjugated with IR820 dye show pH‐sensitivity, efficient intracellular delivery of doxorubicin (Dox), and intrinsic targetability to cancer cells. These new materials form highly uniform Dox‐loaded nanosized vesicles via a self‐assembly process showing good stability under physiological conditions. The Dox‐loaded micelles are effective for suppressing MCF‐7 tumors, as demonstrated in vitro and in vivo. The combined mechanisms of the EPR effect, active internalization, endosomal‐triggered release, and drug escape from endosomes, and a long blood circulation time, clearly prove that the IR820 lipopeptide DDS is a safe theranostic agent for imaging‐guided cancer therapy.