Preparation and characterization of metronidazole‐loaded chitosan nanoparticles for drug delivery application

This study describes the preparation of mucoadhesive chitosan nanoparticles containing metronidazole (MZ) intended for colon‐specific delivery. The chitosan nanoparticles were prepared by the ionic gelation method and their in vitro properties were studied. The release profiles of MZ from the nanoparticles were determined by UV–Vis absorption measurement at λ_max 278 nm. Scanning electron microscopy was used for morphology observation. The nanoparticles exhibited mucoadhesive properties, which diminished with increasing drug content. The nanoparticles with a particle size range between 200 and 300 nm exhibited excellent mucoadhesive properties. The results show that the formulated nanoparticles have succeeded in controlling the release of MZ over a 12‐hr period. In conclusion, the release of MZ was found to be dependent upon the composition of the nanoparticles, the ratio of the components and possible particle size, as well as bioadhesive ability. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of Polynucleotide Modified Gold Nanoparticles as a High Potent Anti‐Cancer Drug Carrier

Gold nanoparticles have been developed for the photoacoustic imaging, delivery of genes and laser induced photothermal therapy. In this study, we have developed oligonucleotide conjugated gold nanoparticles as the carrier for simultaneous DNA and anti‐cancer nucleoside delivery. The polynucleotidenanoparticle complex presented higher capacity in carrying 5‐FU anti‐cancer compounds than the original gold particles. The hydrodynamic size of the gold nanoparticles increased from 25 to 35 nm with an increase in the negative surface charge from ?9.58 to 21.66 mV after polynucleotide conjugation and drug loading. A positive association between environmental pH and drug release was observed in PBS, which implied their potential use in the controlled localized drug release in the lower GI tract. The MTT assay revealed dose dependent cytotoxicity to colon cancer cell line than free compounds. These results suggest the potential use of this new polynucleotide‐gold nanoparticles complex as the environmental controlled anti‐cancer nanocapsule, especially suitable for per oral colon cancer chemotherapy.     

Effect of decrease in both postprandial blood glucose (PBG) and fasting blood glucose (FBG) levels in normal beagle dogs with nateglinide enteric coated granules and immediate release tablets

Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic((R)) tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric coated granules having an dissolution pH of 6.5 were administered simultaneous to administration of nateglinide immediate release tablets to normal beagle dogs just before feeding followed by measurement of plasma nateglinide concentration, plasma insulin concentration and blood glucose level. In the case of administering enteric coated granules alone (nateglinide: 9 mg/kg), the absorption of nateglinide was confirmed to tend to be delayed as the dissolution pH increased. In the case of an dissolution pH of 5.5, decreases in both PBG and FBG were observed. In the case of dissolution pH values of 6.5 and 7.2, only decrease in FBG was observed. In case of nateglinide immediate release tablets (nateglinide: 9 mg/kg), only decrease in PBG was observed. Decreases in both PBG and FBG were observed in the case of simultaneous administration of dissolution pH 6.5 enteric coated granules and nateglinide immediate release tablets just before feeding (nateglinide: 90 mg/head+60 mg/head). A correlation was observed between plasma nateglinide concentrations and blood glucose levels. On the other hand, there were no correlations observed between changes in plasma insulin concentrations and blood glucose levels. In case of nateglinide immediate release tablets (nateglinide: 150 mg/head), Decreases in both PBG and FBG were observed. However, the nateglinide controlled release formulation is more useful than the nateglinide immediate release tablets from the view point of avoidance of side effect, or of easy control of both PBG and FBG. On the basis of these results, the design of a controlled release formulation that contains nateglinide was suggested to enable control of both PBG and FBG for moderate and severe diabetes patients.     

Preparation and characteristics of nanostructured lipid carriers for control-releasing progesterone by melt-emulsification

Nanostructured lipid carriers (NLC) made from mixtures of solid and spatially incompatible liquid lipids were prepared by melt-emulsification. Their drug loading capacity and releasing properties of progesterone were compared with those of solid lipid nanoparticles (SLN), and the NLC prepared by solvent diffusion method. Monostearin (MS) and stearic acid (SA) were used as solid lipid, whilst the oleic acid (OA) was used as liquid lipid. Properties of carriers such as the particle size and its distribution, drug loading, drug encapsulation efficiency and drug release behavior were investigated. As a result, the drug encapsulation efficiencies were improved by adding the liquid lipid into the solid lipid of nanoparticles. The drug release behavior could be adjusted by the addition of liquid lipid, and the NLC with higher OA content showed the faster rate of drug releasing. NLC had higher efficiency of encapsulation and slower rate of drug release than those of NLC prepared by solvent diffusion method. On the other hand, the NLC with higher drug loading was obtained, though the drug encapsulation efficiency was decreased slightly due to the increase of the amount of drug. The NLC modified with polyethylene glycol (PEG) was also prepared by using polyethylene glycol monostearate (PEG-SA). It was observed that the incorporation of PEG-SA reduced the drug encapsulation efficiency, but increased the rate of drug release. A sample with almost complete drug release in 24 h was obtained by modifying with 1.30 mol% PEG-SA. It indicated that the modified NLC was a potential drug delivery system for oral administration.     

Design and characterization of a new drug nanocarrier made from solid-liquid lipid mixtures

The classical lipid nanoparticles that have been proposed for drug delivery are composed of solid lipids. Due to their composition, these nanoparticles have a limited drug loading and controlled release capacity. The present work was aimed at modifying the inner structure of nanoparticles made of tripalmitin, lecithin, and poly(ethylene glycol) (PEG)-stearate with the incorporation of a liquid lipid (Miglyol 812 oil). The composition and structural organization of the components of the resulting nanoparticles were characterized by (1)H NMR spectroscopy. Any possible changes in the crystalline domains of individual components when in the form of the nanoparticles were investigated by differential scanning calorimetry (DSC) and X-ray diffraction spectroscopy. The results of the NMR analysis indicated a significant incorporation of the oil to the solid nanoparticle matrix. Furthermore, the relaxation time constants as well as the peak width of the (1)H NMR spectrum of the nanoparticles suggest the presence of the oil in the form of phase-separated liquid nanoreservoirs within the nanoparticles. This conclusion was supported by the observation of restricted diffusion dynamics for the oil molecules. Interestingly, the incorporation of the oil did not interfere with the crystallization of the solid lipids (tripalmitin and PEG-stearate). In conclusion, a new nanostructure consisting of solid lipids and oily nanodomains was developed. This structural modification of the solid lipid nanoparticles may have an effect on their encapsulation capacity and controlled release properties.     

Application of TPGS in polymeric nanoparticulate drug delivery system

d-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has great potential in pharmacology and nanotechnology. The present work investigated the molecular behaviour of TPGS at the air-water interface, its effect on a model bio-membrane composed of dipalmitoylphosphatidylcholine (DPPC) lipid monolayer, and the interaction between the TPGS coated nanoparticles with the lipid model membrane. Paclitaxel loaded polymeric nanoparticles with TPGS as surfactant stabiliser were fabricated and characterised in terms of their drug incorporation capability and release kinetics. The result showed that TPGS exhibited notable effect on the surface properties of air-water interface as well as the lipid monolayer. The inter-particle force and the interaction between nanoparticles and lipid monolayer varied with the surface substance. The penetration of various nanoparticles into the model membrane indicated that an optimal balance between hydrophilicity and hydrophobicity on nanoparticle surface is needed to achieve an effective cellular uptake of nanoparticles. The results also demonstrate that the drug incorporation capability and the release characteristics of drug-loaded nanoparticles can be influenced by surfactant stabiliser.     

Preparation and characteristics of nanostructured lipid carriers for control-releasing progesterone by melt-emulsification

Nanostructured lipid carriers (NLC) made from mixtures of solid and spatially incompatible liquid lipids were prepared by melt-emulsification. Their drug loading capacity and releasing properties of progesterone were compared with those of solid lipid nanoparticles (SLN), and the NLC prepared by solvent diffusion method. Monostearin (MS) and stearic acid (SA) were used as solid lipid, whilst the oleic acid (OA) was used as liquid lipid. Properties of carriers such as the particle size and its distribution, drug loading, drug encapsulation efficiency and drug release behavior were investigated. As a result, the drug encapsulation efficiencies were improved by adding the liquid lipid into the solid lipid of nanoparticles. The drug release behavior could be adjusted by the addition of liquid lipid, and the NLC with higher OA content showed the faster rate of drug releasing. NLC had higher efficiency of encapsulation and slower rate of drug release than those of NLC prepared by solvent diffusion method. On the other hand, the NLC with higher drug loading was obtained, though the drug encapsulation efficiency was decreased slightly due to the increase of the amount of drug. The NLC modified with polyethylene glycol (PEG) was also prepared by using polyethylene glycol monostearate (PEG-SA). It was observed that the incorporation of PEG-SA reduced the drug encapsulation efficiency, but increased the rate of drug release. A sample with almost complete drug release in 24 h was obtained by modifying with 1.30 mol% PEG-SA. It indicated that the modified NLC was a potential drug delivery system for oral administration.     

Poly(D,L-lactide-co-glycolide) nanoparticle agglomerates as carriers in dry powder aerosol formulation of proteins

A dry powder aerosol drug delivery system was designed with both nano- and microstructure to maximize the protein loading via surface adsorption and to facilitate delivery to the deep lung, respectively. Ovalbumin was employed as a model protein to adsorb to and controllably flocculate DOTAP-coated PLG nanoparticles into "nanoclusters" possessing low density microstructure. The mechanism of nanoparticle flocculation was probed by evaluating the effects of ionic strength, shear force, and protein concentration on the geometric and aerodynamic diameters of the nanoclusters as well as the protein adsorption efficiency. Salt ions were found to compete with ovalbumin adsorption to nanoparticles and facilitate flocculation; therefore, formulation of nanoclusters for inhaled drug delivery may require the lowest possible ionic strength to maximize protein adsorption. Additional factors, such as shear force and total protein-particle concentration can be altered to optimize nanocluster size, suggesting the possibility of regional lung delivery. Immediate release of ovalbumin was observed, and native protein structure upon release was confirmed by circular dichroism and fluorescence spectroscopy studies. Controlled flocculation of nanoparticles may provide a useful alternative to spray drying when formulating dry powders for pulmonary or nasal administration of protein therapeutics or antigens.     

Triclosan-loaded with high encapsulation efficiency into PLA nanoparticles coated with β-cyclodextrin polymer

The purpose was to prepare triclosan-loaded polylactic acid nanoparticles containing β-cyclodextrin polymer shell, evaluate triclosan release from the particles using Franz diffusion cells and to study the stability of the particles in presence of a model protein, bovine serum albumin. The nanoparticles were prepared by a solvent displacement process. The nanoparticles were characterized by their size, encapsulation efficiency and morphology. They were of spherical shape with hydrodynamic diameter of about 100 or 200 nm depending on the polylactic acid used. Their high encapsulation efficiency (~90%) indicated that triclosan is easily incorporated into the nanoparticles. The nanoparticles displayed slow and sustained triclosan release patterns (diffusion coefficient about 10^?22 m²/s) and the β-cyclodextrin polymer coating was stable under simulated physiological conditions. All these data indicated that these novel core–shell nanoparticles might provide a promising carrier system for controlled release of triclosan and other hydrophobic drugs after systemic administration.     

Promising Nanocarriers to Enhance Solubility and Bioavailability of Cannabidiol for a Plethora of Therapeutic Opportunities

In recent years, the interest in cannabidiol (CBD) has increased because of the lack of psychoactive properties. However, CBD has low solubility and bioavailability, variable pharmacokinetics profiles, poor stability, and a pronounced presystemic metabolism. CBD nanoformulations include nanosuspensions, polymeric micelles and nanoparticles, hybrid nanoparticles jelled in cross-linked chitosan, and numerous nanosized lipid formulations, including nanostructured lipid carriers, vesicles, SNEEDS, nanoemulsions, and microemulsions. Nanoformulations have resulted in high CBD solubility, encapsulation efficiency, and stability, and sustained CBD release. Some studies assessed the increased C_max and AUC and decreased T_max. A rational evaluation of the studies reported in this review evidences how some of them are very preliminary and should be completed before performing clinical trials. Almost all the developed nanoparticles have simple architectures, are well-known and safe nanocarriers, or are even simple nanosuspensions. In addition, the conventional routes of administration are generally investigated. As a consequence, many of these studies are almost ready for forthcoming clinical translations. Some of the developed nanosystems are very promising for a plethora of therapeutic opportunities because of the versatility in terms of the release, the crossing of physiological barriers, and the number of possible routes of administration.     

Electrocatalysis by Polyoxometalate-Protected Gold Nanoparticles

Electrocatalysis by polyoxometalate (POM)-monolayer protected gold nanoparticles is herein demonstrated using a newly discovered phenomenon that makes it possible to observe the electrochemistry of dilute aqueous solutions of these colloidal nanostructures. To preserve the integrity of the gold nanoparticles’ electrostatically-stabilized POM-monolayer structures, deposition and drying of the POM-protected metal(0) NPs on the electrode surface must be avoided. Overcoming this constraint, we here show that POM-monolayer protected gold nanoparticles can be induced to reversibly associate with electrode surfaces, resulting in dramatic current amplification and well behaved, quasi-reversible cyclic voltammetric behavior at remarkably small electrolyte concentrations, thus making it possible to investigate electrocatalysis by dilute aqueous solutions of POM-protected gold NPs.     

Thermoresponsive Copolymer/SiO2 Nanoparticles with Dual Functions of Thermally Controlled Drug Release and Simultaneous Carrier Decomposition

The preparation of thermoresponsive drug carriers with a self‐destruction property is presented. These drug carriers were fabricated by incorporation of drug molecules and thermoresponsive copolymer, poly(N‐isopropylacrylamide‐co‐acrylamide), into silica nanoparticles in a one‐pot preparation process. The enhanced drug release was primarily attributed to faster molecule diffusion resulting from the particle decomposition triggered by phase transformation of the copolymer upon the temperature change. The decomposition of the drug carriers into small fragments should benefit their fast excretion from the body. In addition, the resulting drug‐loaded nanoparticles showed faster drug release in an acidic environment (pH 5) than in a neutral one. The controlled drug release of methylene blue and doxorubicin hydrochloride and the self‐decomposition of the drug carriers were successfully characterized by using TEM, UV/Vis spectroscopy, and confocal microscopy. Together with the nontoxicity and excellent biocompatibility of the copolymer/SiO₂ composite, the features of controlled drug release and simultaneous carrier self‐destruction provided a promising opportunity for designing various novel drug‐delivery systems.     

Protein-loaded PLGA–PEO blend nanoparticles: encapsulation, release and degradation characteristics

The aim of this work was to study the variables that affect the encapsulation and release of proteins from nanoparticles based on poly(lactic-co-glycolic acid; PLGA)–poloxamer and PLGA–poloxamine blend matrices, using bovine serum albumin (BSA) and immuno-γ-globulin (IgG) as model proteins. The nanoparticles were prepared by a solvent diffusion technique, and the studied variables were (1) PLGA molecular weight, (2) type of PEO-block copolymers, (3) protein loading, (4) pH and, (5) volume of the protein solution. Our results showed that the proteins can be efficiently incorporated into and released from the blend matrices. The type of the PEO derivative and the pH of the internal aqueous phase were the most important factors influencing protein encapsulation and release kinetics. Moreover, comparative degradation study of PLGA, PLGA–poloxamer and PLGA–poloxamine nanoparticles confirmed that the degradation and release characteristics of polyester particles can be improved by the incorporation of polyoxyethylene derivatives with different hydrophilia–lipophilia balance.     

Preparation, characterization and application of pyrene-loaded methoxy poly(ethylene glycol)–poly(lactic acid) copolymer nanoparticles

Pyrene-loaded biodegradable polymer nanoparticles were prepared by incorporating pyrene into the polymer nanoparticles formulated from amphiphilic diblock copolymer, methoxy poly(ethylene glycol)–poly(lactic acid) (MePEG–PLA). Their morphological structure and physical properties were characterized by nuclear magnetic resonance (NMR), dynamic light scattering, fluorescence spectroscopy, transmission electronic microscopy and zeta potential measurements. Further, MePEG–PLA nanoparticles containing pyrene as fluorescent marker were administered intranasally to rats, and the distribution of nanoparticles in the nasal mucosa and the olfactory bulb were visualized by fluorescence microscopy. NMR results confirmed that MePEG–PLA copolymer can form nanoparticles in water, and hydrophilic PEG chains were located on the surface of the nanoparticles. The particle size, zeta potential and pyrene loading efficiency of MePEG–PLA nanoparticles were dependent on the PLA block content in the copolymer. Following nasal administration, the absorption of nanoparticles across the epithelium was rapid, with fluorescence observed in the olfactory bulb at 5 min, and a higher level of fluorescence persisted in the olfactory mucosa than that in the respiratory mucosa. These results show that pyrene could serve as a useful fluorescence probe for incorporation into polymer nanoparticles to study tissue distribution and MePEG–PLA nanoparticles might have a great potential as carriers of hydrophobic drugs.     

Role of Capping Ligands on the Nanoparticles in the Modulation of Properties of a Hybrid Matrix of Nanoparticles in a 2D Film and in a Supramolecular Organogel

We incorporate various gold nanoparticles (AuNPs) capped with different ligands in two‐dimensional films and three‐dimensional aggregates derived from N‐stearoyl‐L ‐alanine and N‐lauroyl‐L ‐alanine, respectively. The assemblies of N‐stearoyl‐L ‐alanine afforded stable films at the air–water interface. More compact assemblies were formed upon incorporation of AuNPs in the air–water interface of N‐stearoyl‐L ‐alanine. We then examined the effects of incorporation of various AuNPs functionalized with different capping ligands in three‐dimensional assemblies of N‐lauroyl‐L ‐alanine, a compound that formed a gel in hydrocarbons. The profound influence of nanoparticle incorporation into physical gels was evident from evaluation of various microscopic and bulk properties. The interaction of AuNPs with the gelator assembly was found to depend critically on the capping ligands protecting the Au surface of the gold nanoparticles. Transmission electron microscopy (TEM) showed a long‐range directional assembly of certain AuNPs along the gel fibers. Scanning electron microscopy (SEM) images of the freeze‐dried gels and nanocomposites indicate that the morphological transformation in the composite microstructures depends significantly on the capping agent of the nanoparticles. Differential scanning calorimetry (DSC) showed that gel formation from sol occurred at a lower temperature upon incorporation of AuNPs having capping ligands that were able to align and noncovalently interact with the gel fibers. Rheological studies indicate that the gel–nanoparticle composites exhibit significantly greater viscoelasticity compared to the native gel alone when the capping ligands are able to interact through interdigitation into the gelator assembly. Thus, it was possible to define a clear relationship between the materials and the molecular‐level properties by means of manipulation of the information inscribed on the NP surface.     

In Situ Formation of Gold Nanoparticles within a Polymer Particle and Their Catalytic Activities in Various Chemical Reactions

Composite materials consisting of nanoscale gold particles and protective polymer shells were designed and tested as catalysts in various chemical reactions. Initially, the systematic incorporation of multiple gold nanoparticles into a poly(N-isopropylacrylamide) particle was achieved by an in situ method under light irradiation. The degree of gold nanoparticle loading, along with the structural and morphological properties, was examined as a function of the amount of initial gold ions and reducing agent. As these gold nanoparticles were physically-embedded within the polymer particle in the absence of strong interfacial interactions between the gold nanoparticles and polymer matrix, the readily-accessible surface of the gold nanoparticles with a highly increased stability allowed for their use as recyclable catalysts in oxidation, reduction, and coupling reactions. Overall, the ability to integrate catalytically-active metal nanoparticles within polymer particles in situ allows for designing novel composite materials for multi-purpose catalytic systems.     

Photoactivated Nitrene Chemistry to Prepare Gold Nanoparticle Hybrids with Carbonaceous Materials

Photolysis of organic solvent soluble aryl azide‐modified gold nanoparticles (N₃‐AuNPs) with a core size of 4.6±1.6 nm results in the generation of interfacial reactive nitrene intermediates. The high reactivity of the nitrenes is utilized to tether the AuNP to the native surface of carbon nanotubes, and reduce graphene oxide and micro‐diamond powder, likely via addition to π‐conjugated carbon skeleton or insertion into the functionalities at the surface, to yield the desired hybrid material without the need for pretreatment of the surface. The AuNP‐covalent hybrid materials are robust in that they survive vigorous washing and sonication. In the absence of photolysis no attachment occurs with the same N₃‐AuNP. The nanohybrid AuNP‐nanohybrid materials are characterized using a combination of TEM, powder XRD, XPS and UV/Vis and IR spectroscopies. All of the characterization studies confirm the uniform incorporation of the AuNP on the irradiated substrates.     

纳米金的绿色合成与CTAB对金纳米聚集体的解聚集作用

室温下利用鞣酸(TA)既作还原剂又作保护剂,通过绿色还原方法制备了鞣酸包裹的金纳米粒子,并通过紫外可见光谱(UV-Vis)、透射电镜(TEM)、X射线衍射(XRD)、红外光谱(FTIR)等分别进行了表征和分析。结果表明,随着nTA/nHAuCl4比率的增加,紫外可见光谱显示鞣酸稳定的金溶胶最大吸收波长明显增大且吸收带变宽,而最大吸光率逐渐减小。TEM观察证实增加鞣酸用量会导致溶胶体系中花状金纳米聚集体的形成。实验发现,阳离子型表面活性剂十六烷基三甲基溴化铵(CTAB)对鞣酸保护的金纳米聚集体具有强烈的解聚集作用,在剧烈搅拌的条件下CTAB能使金纳米聚集体成功解聚为单分散状态的金纳米粒子,提高体系温度可明显促进CTAB对金纳米聚集体的解聚集作用。