Effect of drug-loading methods on drug load, encapsulation efficiency and release properties of alginate/poly-L-arginine/chitosan ternary complex microcapsules

The drug-loaded alginate/poly-L-arginine/chitosan ternary complex microcapsules were prepared by mixing method, absorption method and the combined method of mixing and absorption, respectively. The effect of drug-loading methods on drug load, the encapsulation efficiency and the release properties of the complex microcapsules were investigated. The results showed that the absorption process is a dominating factor to greatly increase the drug load of Hb into microcapsules. Upon loading Hb into microcapsules by combined method of mixing and absorption, the drug load (19.9%) is up to the maximum value, and the encapsulation efficiency is 93.8%. Moreover, the drug release is a zero-order kinetics process for the ternary complex microcapsules made by mixing. For the complex microcapsules made by absorption, the drug release is a first-order kinetics. However, for the complex microcapsules made by combining the mixing and the absorption, the drug release obeys a first-order kinetics during the first eighteen hours, changing afterwards to a zero-order kinetics process. Effect of drug-loading methods on drug load and encapsulation efficiency of alginate/poly-L-arginine/chitosan ternary complex microcapsules.     

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.     

Synthesis of degradable functional poly(ethylene glycol) analogs as versatile drug delivery carriers

Poly(ethylene glycol) (PEG) is widely used as a water soluble carrier for polymer-drug conjugates. Herein, we report degradable linear PEG analogs (DPEGs) carrying multifunctional groups. The DPEGs were synthesized by a Michael addition based condensation polymerization of dithiols and PEG diacrylates (PEGDA) or dimethacrylates (PEGDMA). They were stable at pH 7.4 but quickly degraded at pH 6.0 and 5.0. Thus, DPEGs could be used as drug carriers without concern for their retention in the body. DPEGs could be made to carry such functional groups as terminal thiol or (meth)acrylate and pendant hydroxyl groups. The functional groups were used for conjugation of drugs and targeting groups. This new type of PEG analog will be useful for drug delivery and the PEGylation of biomolecules and colloidal particles.     

Poly(L‐histidine) with several aminoethyl groups for a new pH‐sensitive DNA carrier

In this study, poly(L ‐histidine) with several aminoethyl groups, i.e. aminated poly(L ‐histidine), is reported to be able to make complexes with DNA and to transfect cells in vitro in the presence of serum. The present study was performed to determine whether the pH of the medium had an influence on the complex formation with DNA, on the cell membrane fusion activity and on the transfection efficiency. Agarose gel retardation assays proved that the polyion complex formation of the aminated poly(L ‐histidine) with DNA was affected by pH of the medium, owing to the basicity (protonation–deprotonation) of the imidazole groups with a pK_a value around 6.0. Hemolysis assay showed that the resulting DNA complex enhanced membrane disruptive ability at endosomal pH. The aminated poly(L ‐histidine) gene carrier demonstrated significant transfection efficacy which was decreased by the inclusion of chloroquine as an endosomolytic agent. These results suggest that the aminated poly(L ‐histidine) promises to be a new pH‐sensitive DNA carrier for endosomal escape. Copyright © 2005 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.

     

Water-soluble dendrimer–poly(ethylene glycol) starlike conjugates as potential drug carriers

The design and synthesis of a new dendrimer–poly(ethylene glycol) (PEG) conjugate that may be used as a model drug carrier are described. The starting material is a polyether dendrimer with two different types of chain end functionalities. The dendritic assembly is made water soluble through attachment of short PEG chains to the dendrimer via one type of functionality. The remaining chain end functionalities then were used to incorporate model drug molecules of varying polarity into the modified dendrimer. Cholesterol and two amino acid derivatives were selected as model drugs for attachment through their respective hydroxyl, carboxylic acid, and amino functional groups to the dendrimer via carbonate, ester, and carbamate linkages. The resulting water-soluble dendrimer-model drug conjugates were characterized by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3492–3503, 1999     

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%.     

Preparation of poly(butylene-co-ε-caprolactone carbonate) and their use as drug carriers for a controlled delivery system

Poly(butylene-co-ε-caprolactone carbonate) (PBCCL) was successfully synthesized via terpolymerization of carbon dioxide, 1,2-butylene oxide (BO), and ε-caprolactone (ε-CL). ε-CL was inserted into the backbone of BO-CO₂. The glass transition temperature (T_g) and the decomposition temperature (T_d) of PBCCL were much higher than those of poly(butylene carbonate) (PBC). The degradation rate of PBCCL was higher than that of PBC in a pH 7.4 phosphate-buffered solution. ε-CL offered an ester structural unit that gave the terpolymers remarkable degradability. PBC and PBCCL microcapsules containing a hydrophilic antibiotic drug pazufloxacin mesilate (PZFX) were elaborated by solvent evaporation method based on the formation of double W/O/W emulsion. Microcapsules were characterized in terms of the morphology, size, amount of encapsulated, and encapsulation efficiency. The results showed that the microcapsules had smooth and spherical surfaces, and the mean diameter of the microcapsules was in the range of 0.5–1 μm. Of all, 87.90% drug encapsulation efficiency has been achieved for microcapsules of 38.21% drug loading. In vitro drug release of these microcapsules was performed in a pH 7.4 phosphate-buffered solution. The release profiles were investigated from the measurement of PZFX presented in the release medium at various intervals. The release profiles of PZFX from PBC and PBCL microcapsules were found to be biphasic with a burst release followed by a gradual release phase. The release rate of PZFX from the microcapsules increased with increasing the content of ε-CL inserted into the copolymers. It showed that the release profiles of PZFX were highly polymer-dependent. © 2007 Wiley Periodicals, Inc. JPolym Sci Part A: Polym Chem 45: 2152–2160, 2007     

Novel mucoadhesive carriers based on alginate-acrylamide hydrogels for drug delivery

New mucoadhesive two-component carriers for drug delivery based on synthetic acrylamide/diethylacrylamide and natural alginate hydrogels have been synthesized. The introduction of sodium alginate into polyacrylamide/ poly(diethylacrylamide) gels, followed by their crosslinking with metal ions, significantly changed structure and properties of hydrogels, such as swelling degree, drug capacity and drug release rate in physiological solution. The structure of the gels was characterized by FTIR spectroscopy and scanning electron microscopy.     

Carboxymethyl poly(L‐histidine) as a new pH‐sensitive polypeptide at endosomal/lysosomal pH

A carboxymethyl poly(L ‐histidine) has been synthesized as a new pH‐sensitive polypeptide at endosomal/lysosomal pH. Because of its poor water solubility at physiological pH, an application of poly(L ‐histidine) 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 unmodified poly(L ‐histidine) suddenly precipitates out of the aqueous medium above pH 6.0 as the result of the deprotonation of the imidazole groups, the water solubility of the resulting carboxymethyl poly(L ‐histidine) has been improved at physiological pH. A solution turbidity measurement proved that no significant effect on a rapid aggregate formation or phase separation of serum proteins is induced by carboxymethyl poly(L ‐histidine). Hemolysis assay showed that the carboxymethyl poly(L ‐histidine) enhances membrane disruptive ability at endosomal/lysosomal pH. The cellular uptake of luciferase in the presence of the carboxymethyl poly(L ‐histidine) increases intracellular luciferase activity, which suggests that the carboxymethyl poly(L ‐histidine) makes the luciferase escape from lysosomal degradation. The carboxymethyl poly(L ‐histidine) would be the fundamental compound for designing various drug carriers with the pH sensitivity at endosomal/lysosomal pH. Copyright © 2007 John Wiley & Sons, Ltd.     

Temperature sensitive poly[N-isopropylacrylamide-co-(acryloyl beta-cyclodextrin)] for improved drug release

The model drugs ibuprofen (IBU) and tegafur (T-Fu) were loaded into poly[N-isopropylacrylamide-co-(acryloyl beta-cyclodextrin)] [P(NIPA-co-A-CD)] and PNIPA hydrogels by immersing dried gels in IBU or T-Fu alcohol solutions until they reached equilibrium. Drug release studies were carried out in water at 25 degrees C. In contrast to the release time of conventional PNIPA hydrogel, that of IBU from the beta-CD incorporated hydrogel was significantly prolonged and the drug loading was also greatly increased, which may be the result of the formation of inclusion complexes between CD and ibuprofen. However, another hydrophilic drug, tegafur, did not display these properties because it could not form a complex with the CD groups. [diagram in text].     

Morphology engineering of a novel poly(L‐lactide)/poly(1,5‐dioxepan‐2‐one) microsphere system for controlled drug delivery

Morphology is presented as a powerful tool to control the in vitro degradation and drug release characteristics of novel drug delivery microspheres prepared from homopolymer blends of 1,5‐dioxepan‐2‐one, DXO, and L ‐lactide, L‐LA. Their performance in this respect was compared to analogous P(L‐LA‐co‐DXO) microspheres. Blends formed denser and less porous microspheres with a higher degree of matrix crystallinity than copolymers of corresponding L‐LA:DXO composition. The morphology differences of blends and copolymers, further adjustable by means of component ratio, are shown to have a vital impact on the in vitro performance. Sustained drug delivery was obtained from both copolymers and blends. Molecular weight loss was retarded and diffusion‐mediated release was inhibited in the latter case, further delaying the release process. The effects of storage on the physicochemical properties of these systems were evaluated under desiccated and moist conditions for 5 months. Storage‐induced physicochemical changes, such as matrix crystallization and molecular weight decrease, were accelerated at higher relative humidities. P(L‐LA‐co‐DXO) demonstrated higher moisture sensitivity than a PLLA‐PDXO blend of corresponding composition. The more crystalline and dense morphology of blend microspheres may thus be considered an improvement of the storage stability. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 786–796, 2000     

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.     

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.     

Novel amphiphilic fluorescent graft copolymers: synthesis,characterization, and potential as gene carriers

Amphiphilic fluorescent graft copolymer (PVP‐PyATAm) was successfully synthesized by the free radical copolymerizations of hydrophobic monomer N‐acryloyl‐thioureylene‐4‐(1‐pyrene)‐butyryl amide (PyATAm) with hydrophilic precursor polymers of vinyl‐functionalized poly (N‐vinylpyrrolidone) (Acryloyl‐PVP) in DMF. FT‐IR, ¹H NMR, TEM, gel permeation chromatography‐multi‐angle laser light scattering, UV‐vis spectroscopy, viscometric measurement, and fluorescence spectroscopy were used to characterize this copolymer. The TEM observation showed that the copolymer PVP‐ PyATAm formed spherical micelles in an aqueous solution and the size of micelles was between 50 and 70 nm in diameter. The interaction of PVP‐PyATAm copolymer and plasmid DNA was examined by agarose gel electrophoresis and TEM. Results indicated that the copolymer–DNA complexes were self‐assembled and the size of complexes was between 90 and 120 nm in diameter. Cytotoxity studies using MTT colorimetric assays suggested good biocompatibility of PVP‐PyATAm in vitro. These results suggested the potential of this graft copolymer as gene delivery carrier. Copyright © 2007 John Wiley & Sons, Ltd.     

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     

Methoxypoly(ethylene glycol)‐block‐Poly(L‐glutamic acid)‐Loaded Cisplatin and a Combination With iRGD for the Treatment of Non‐Small‐Cell Lung Cancers

CDDP is loaded into methoxypoly(ethylene glycol)‐block‐poly(L ‐glutamic acid) (mPEG‐b‐PLG), and a combination with iRGD is applied for NSCLC chemotherapy. The CDDP‐loaded micelles show sustained cisplatin release in PBS, dose‐ and time‐dependent inhibition to HeLa and A549 cell proliferation, and no apparent hemolysis activities. In in vivo studies using subcutaneous NSCLC xenograft models (A549), both free CDDP and CDDP‐loaded micelles show an evident anti‐tumor effect. However, the toxicity of CDDP is significantly reduced in the cases of CDDP‐loaded micelles and co‐administration with iRGD, and the survival time is prolonged by over 30%. Therefore, mPEG‐b‐PLG‐loaded cisplatin and the combination with iRGD provides a promising new therapy for NSCLC.

     

Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis,properties, and in vitro release

Degradable hydrogels crosslinked with disulfide bonds were prepared by Michael addition between amine groups of branched polyethylenimine and carbon–carbon double bonds of N,N′‐bis(acryloyl)cystamine. The influences of the chemical composition of the resulted hydrogels on their properties were examined in terms of morphology, surface area, swelling kinetics, and degradation. The hydrogels were uniformly crosslinked and degraded into water‐soluble polymers in the presence of the reducing agent of dithiothreitol, which improved the control over the release of encapsulated drug. The degradation of hydrogels can trigger the release of encapsulated molecules, as well as facilitate the removal of empty vehicles. Results obtained from in vitro drug release suggested that the disulfide crosslinked hydrogels exhibited an accelerated release of encapsulated drug in dithiothreitol‐containing PBS buffer solution. Moreover, the drug release rate decreased gradually with increasing crosslinking density. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4074–4082, 2009     

Synthesis and characterization of poly(ethylene glycol)‐based thermo‐responsive polyurethane hydrogels for controlled drug release

The thermo‐responsiveness, swelling and mechanical properties of a series of novel poly(ester‐ether urethane) hydrogels have been investigated. These thermo‐sensitive hydrogels were obtained by combining hydrophobic biodegradable poly(ε‐caprolactone) diols and hydrophilic two‐, three‐ and four‐arm hydroxyl terminated poly(ethylene glycol) (PEG) of various molecular weights, using hexamethylene diisocyanate, dichloroethane as solvent and a tin‐based catalyst. The use of multifunctional PEGs leads to the formation of covalent crosslinking points allowing an additional control of the swelling capability. Thus, it was found that tuning the hydrophilic/hydrophobic balance and the crosslinking degree by changing the composition, the swelling and the thermo‐responsive behavior of these hydrogels could be modulated. The obtained hydrogels showed a volume transition at around room temperature. Therefore, and taking into account their biocompatibility, these hydrogels show promising properties for biomedical applications, such as drug delivery. Thus, the loading and release of diltiazem hydrochloride, an antihypertensive drug used as model, were investigated. These new PEG polyurethane hydrogels were able to incorporate a high amount of drug providing a sustained release after an initial burst effect. Copyright © 2013 John Wiley & Sons, Ltd.     

Preparation of 5‐Fluorouracil‐Poly(L‐lactide) Microparticles Using Solution‐Enhanced Dispersion by Supercritical CO2

Summary: 5‐Fluorouracil‐poly(L ‐lactide) (5‐Fu‐PLLA) microparticles have been prepared by an SEDS process. First, the 5‐Fu is successfully micronized and is then used to produce the 5‐Fu‐PLLA microparticles. The 5‐Fu‐PLLA microparticles synthesized by the SEDS process exhibit a rather spherical shape and a narrow particle size distribution, where it ranges from 615 to 1 990 nm, with a mean particle size of 980 nm. The dichloromethane residue in the 5‐Fu‐PLLA microparticles without any further treatment is 46 ppm. The average drug load and encapsulation efficiency of the 5‐Fu‐PLLA microparticles are 3.05 and 17.8%, respectively. The rate of drug release from the 5‐Fu‐PLLA microparticles shows mainly first‐order kinetics.

Scanning electron spectroscopy image of 5‐Fu‐PLLA microparticles.