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PubMed2005

Direct fluorescent staining and analysis of proteins on microspheres using CBQCA.

BACKGROUND: General methods for accurate determination of microsphere surface protein loading are needed for applications from protein arrays to molecular assembly studies. Current methods include bulk absorption measurements of stained microspheres or use of known fluorescently tagged binding partners, which limit sensitivity and general applicability, respectively. METHODS: Microspheres bearing covalently coupled proteins were stained with 3-(4-carboxybenzoyl)quinoline-2-carboxaldehyde (CBQCA) using different incubation times and dye concentrations to determine optimal staining conditions. The CBQCA fluorescence of microspheres (measured by flow cytometry) bearing known amounts of protein were used to generate standard curves of CBQCA fluorescence response versus the amount of microsphere surface protein. CBQCA was also used to stain noncovalent protein interactions. RESULTS: Maximal labeling was attained within 1 h with 1 mM CBQCA. Linear fluorescence response occurred between 8 x 10(4) and 1 x 10(6) proteins/microsphere. CBQCA staining did not disturb noncovalent protein interactions. CONCLUSIONS: We have developed methods using CBQCA and flow cytometry to quickly and simply quantify the amount of protein on the surface of a microsphere. Importantly, this approach could be extended to other formats (e.g., chips). Further, because it does not disturb noncovalent protein-protein interactions, it may be possible to use this approach to detect protein interactions without the use of purified prestained probes.

Animals↗

PubMed2006

Effect of microsphere binding site density on the apparent affinity of an interaction partner.

BACKGROUND: Flow cytometric microsphere-based binding assays can be used to measure molecular interactions with high sensitivity. We have used multiplexed microsphere technology to explore the effect that binding site density has on the apparent affinity of a soluble interaction partner. METHODS: The interaction of a nuclear receptor, peroxisome proliferator-activated receptor gamma ligand binding domain (PPARgamma LBD), with a synthetic peptide derived from a nuclear receptor coactivator protein, PPARgamma coactivator-1 alpha (PGC-1alpha), is the interacting system being studied. The density of this peptide coupled to fluorescently unique microsphere populations is varied by co-incubating the biotinylated peptide and avidin-coated microsphere populations with increasing the amounts of free D-biotin. The discrete-density peptide-coupled microsphere populations are combined to conduct a multiplexed binding experiment with Alexa 532-labeled PPARgamma LBD, in the absence or presence of a small molecule ligand. RESULTS: As the immobilized binding site density of PGC-1alpha peptide on fluorescent microspheres is increased the measured apparent affinity for PPARgamma LBD is increased. CONCLUSIONS: The density of binding sites immobilized to a surface has a pronounced effect on the apparent affinity for soluble binding partners. By controlling and varying the binding site density it is possible to increase the sensitivity of an interaction assay. In multiplexed assay formats it should be possible to normalize intrinsically unequal binding interactions by individually optimizing the binding site density of the immobilized interaction partner. However, to quantitatively measure intrinsic affinities of molecular interactions, low binding site densities are required and multivalent reagents must be avoided.

Amino Acid Motifs↗

PubMed1994

Activation of human neutrophils by Arg-Gly-Asp-Ser immobilized on microspheres.

The adhesive interaction of cells with extracellular matrix components is essential for a variety of cellular functions, and is frequently mediated by a tetra peptide, Arg-Gly-Asp-Ser (RGDS), located within fibronectin and other proteins. In this study, the RGDS-mediated activation of polymorphonuclear leukocytes accompanied by phagocytosis was investigated using monodisperse polymeric microspheres carrying RGDS. The parent and Arg-Gly-Glu-Ser (RGES)-carrying microspheres, which have no adhesion activity, were employed as controls. The ingestion of microspheres into PMN was not enhanced by immobilizing RGDS. However, PMNs exhibited unique oxygen consumption and enhanced liberation of reactive oxygen when RGDS-carrying microspheres were phagocytosed. These PMN responses disappeared with the addition of soluble RGDS. Furthermore, cytochalasin D, which inhibits actin polymerization, showed a marked inhibitory effect on oxygen consumption in the RGDS-carrying microsphere system, as compared with those in other systems. These findings show that RGDS-carrying microspheres induced the biospecific activation of PMNs by the signal transduction via RGDS-integrin binding without alteration in the degree of phagocytosis.

Amino Acid Sequence↗

PubMed1994

In vivo and electron microscopic studies of rat liver after intravenous injection of polyamino acid microspheres.

In vivo and electron microscopy were used to study the hepatocellular responses of rat livers to intravenously injected polymeric microspheres. Two microsphere preparations with different surface characteristics and degradability were used in this study. In vivo microscopy revealed that both poly(benzyl L-glutamate) (PBLG) and poly(hydroxypropyl L-glutamine) (PHPG) microspheres caused disturbance in the microcirculation of rat liver up to 2 months after injection. The observed changes included stagnant flow and adherence of white blood cells to the endothelial lining of venules an sinusoids. Kupffer cell (KC) activation following phagocytosis of microspheres was evidenced by the enlargement of KCs and increased number of KCs taking up fluorescent latex particles. Electron microscopy of rat livers revealed a wide range of hepatocellular injury associated with the administration of PBLG and PHPG microspheres. These results indicate that a small amount of remaining microspheres is sufficient to induce continuous disturbance to hepatic microcirculation and that particulate drug carriers should be designed to be rapidly degraded so that the return to normal liver function is possible.

Animals↗

PubMed2004

Biodegradable radiation delivery system utilizing glass microspheres and ethylenediaminetetraacetate chelation therapy.

Dysprosium lithium-borate (DyLB) glass microspheres have been developed as a biodegradable radiation delivery vehicle for the treatment of rheumatoid arthritis and other diseases. Radioactive microspheres of these glasses are intended to be injected into a joint infected with rheumatoid arthritis to safely deliver a localized dose (100 Gy) of beta radiation. Once injected, the microspheres react nonuniformly with body fluids. The nonradioactive, lithium-borate component is dissolved from the glass, whereas the radioactive (165)Dy reacts with phosphate anions in the body fluids, and becomes "chemically" trapped in a solid, dysprosium phosphate reaction product that has the same size as the unreacted microsphere. The glass microspheres lose approximately 80% of their weight after nonuniform reaction (<1 day), but the dysprosium phosphate reaction product is slowly metabolized by the body over several months. Ethylenediaminetetraacetate (EDTA) chelation therapy can be used to dissolve the dysprosium phosphate reaction product in vitro in <2 h. The dysprosium phosphate reaction product which formed in vivo in the joint of a Sprague-Dawley rat was also dissolved by EDTA chelation therapy in <1 week, without causing any detectable joint damage. The combination of DyLB glass microspheres and EDTA chelation therapy provides a unique "tool" for the medical community because it can deliver a large dose (>100 Gy) of localized beta radiation to a treatment site within the body, followed by complete biodegradability.

Animals↗

PubMed2004

Three-month, zero-order piroxicam release from monodispersed double-walled microspheres of controlled shell thickness.

Double-walled microspheres represent an increasingly important class of drug delivery devices that provide enhanced control of drug delivery schedules. Clearly, the overall particle size and shell thickness are important parameters in modulating the drug release rates. Precision particle fabrication technology has been used to fabricate double-walled microspheres of predefined uniform diameters of 40-60 microm exhibiting a poly(D,L-lactide-co-glycolide) (PLG) core and poly(L-lactide) (PL) shell of controllable thickness from approximately 2 to 10 microm. The release of a model small-molecule drug, piroxicam, from uniform microspheres of pure PLG and PL is compared to the release from double-walled microspheres exhibiting different PL shell thicknesses. The presence of the PL shell enveloping a PLG core essentially eliminated the initial "burst" of piroxicam that was observed when the drug was released from pure PLG microspheres. In addition, increasing the PL shell thickness shifted the release profile from a biphasic shape for pure PLG microspheres to zero-order piroxicam release over 3 months for the thickest (approximately 10 microm) PL shell.

Drug Delivery Systems↗

PubMed2006

Synthesis and characterization of uniform radiopaque polystyrene microspheres for X-ray imaging by a single-step swelling process.

Uniform radiopaque polystyrene microspheres of approximately 2.3 +/- 0.2 microm were prepared by a single-step swelling of 2.3 +/- 0.2 microm polystyrene template microspheres, dispersed in an aqueous solution with methylene chloride emulsion droplets containing 2,3,5-triiodobenzoylethyl ester. After completing the swelling process, the methylene chloride was evaporated in order to lock the 2,3,5-triiodobenzoylethyl ester in the polystyrene microspheres. The influence of the weight ratio [2,3,5-triiodobenzoylethyl ester]/[polystyrene] on the % of entrapped 2,3,5-triiodobenzoylethyl ester was elucidated. Characterization of the radiopaque polystyrene microspheres was accomplished by light microscope, FTIR, TGA, SEM, XPS, and elemental analysis. The radiopacity of the microspheres was demonstrated by an imaging technique based on X-ray absorption usually used in hospitals. This novel method of encapsulation of 2,3,5-triiodobenzoylethyl ester within polystyrene microspheres by a single-step swelling process may be used as a model for encapsulation of various hydrophobic radiopaque drugs within uniform polystyrene template particles of various diameters for different X-ray imaging needs, e.g., blood pool, body organs, embolization, dental composition, implants, protheses, and nanocomposites.

Crystallization↗

PubMed2006

Drug entrapment in silica microspheres through a single step sol-gel process and in vitro release behavior.

A single step sol-gel process was used to precipitate silica microspheres containing ibuprofen or naproxen for controlled drug delivery applications. The drug release behavior from these systems was analyzed in vitro. Pure ibuprofen and naproxen exhibited linear release with time, while sol-gel silica entrapped drugs were released with a logarithmic time dependence starting with an initial burst effect followed by a gradual decrease. Microscopic analysis combined with gravimety and infrared spectroscopy indicated that some of the drug is entrapped as large crystals attached to silica microspheres while the rest is encapsulated inside the microspheres. Drug-loaded silica microspheres with no open porosity and with a narrow particle size distribution were obtained. Both erosion of the microspheres and diffusion through them contributed to drug release. Sol-gel precipitation of silica microspheres is a promising method for drug entrapment and controlled release.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1986

Laser Doppler flowmetry for bone blood flow measurement: correlation with microsphere estimates and evaluation of the effect of intracapsular pressure on femoral head blood flow.

Laser Doppler flowmetry (LDF) was used to measure bone blood flow in the rabbit femoral head and femoral condyles. To correlate the LDF output signal blood cell flux to in vivo blood flow, simultaneous measurements using LDF and 85Sr-labeled microspheres were made in an adult rabbit model. There was no correlation between the two methods for blood flow in the femoral condyles and the correlation between the two methods for blood flow in the femoral head does not achieve statistical significance. An LDF signal of 0.4 V was approximately equal to a microsphere measured flow rate of 0.4 ml blood/g bone/min. The strength of the correlation in the latter case may have been affected by (a) large arteriovenous shunts, (b) inadequate mixing of the microspheres with a left ventricular injection, and (c) insufficient numbers of microspheres present in the bone samples with which to satisfy the mathematical requirements of the microsphere method. When LDF was used to evaluate the effect of elevated intracapsular pressure on femoral head blood flow in skeletally mature rabbits, femoral head subchondral bone blood flow declined with increasing intracapsular pressure from a baseline value of 0.343 +/- 0.036 to a value of 0.127 +/- 0.27 at 120 cm of water pressure. The decline in femoral head blood flow was statistically significant at pressures of 40 cm of water or higher (p less than 0.001), and evaluation of sections of the proximal femora made from preterminal disulphine blue injections confirmed these findings. Intracapsular tamponade has an adverse effect on femoral head blood flow beginning well below central venous pressure and should be considered in the pathophysiology of posttraumatic and nontraumatic necrosis of the femoral head. Laser Doppler flowmetry was easy to use and appears to be a reproducible technique for evaluating femoral head blood flow, offering distinct advantages over the microsphere technique for measuring bone blood flow. Further studies of the in vivo calibration of the LDF method for bone blood flow are necessary for the method to have potential for clinical application.

Animals↗

PubMed1989

Canine bone blood flow estimated with microspheres.

Blood flow rate in the periosteal and endosteal cortices of the diaphysis of long bones was determined in eight anesthetized adult dogs using the radioactively labeled microsphere method. The flow rate in endosteal and periosteal cortices is not significantly different unless the endosteal cortex contains cancellous bone from the medullary cavity. The highest flow rate is in the ulna, with 6.50 ml/min/100 g for the endosteal cortex and 5.15 ml/min/100 g for the periosteal cortex. The lowest flow rate is in the femur, with 2.89 ml/min/100 g for the endosteal cortex and 2.29 ml/min/100 g for the periosteal cortex. The results of this study indicate that variation of blood flow does exist between bones of dogs. However, the flow rates of individual bone on the left and right sides in the same dog are not significantly different. This indicates that the data are reproducible and reliable, and differences are not an inaccuracy of the radioactively labeled microsphere method. The results also demonstrate that there are no significant differences in bone blood flow as measured with small numbers (fewer than 400 microspheres per sample) and large numbers (more than 400 microspheres per sample) of microspheres. The adequate number of microspheres in each bone sample is 150-250. Therefore, a dose of 0.5 x 10(6) spheres/kg body weight can be sufficient.

Animals↗

PubMed1990

Measurement of blood flow to the tibial diaphysis using 11-microns radioactive microspheres. A comparative study in the adult rabbit.

The commonly used size of microsphere for bone blood flow estimation is 15 microns, because it has appeared to be the smallest size that is not subject to significant nonentrapment in bone. Soft-tissue studies suggest that it is microspheres of 9-10 microns or less that pass through peripheral tissues and give low calculated flows, whereas many vessels passing into and within cortical bone are less than 15 microns in diameter. We have therefore performed a comparison between microspheres approximately 15 and 11 microns in average size. Blood flows to the cortex and marrow of the tibial diaphysis, and to the skeletal muscle of the anterior compartment, were obtained in six adult New Zealand White rabbits by the reference sample technique, injecting microspheres of 16.5 +/- 0.1 microns and 11.3 +/- 0.1 microns simultaneously. The calculated cortical flows averaged 2.07 and 2.51 ml/min/100 g, respectively, and the marrow flows 26.63 and 24.92 ml/min/100 g. Mean skeletal muscle flows were 15.57 and 14.54 ml/min/100 g, respectively. There were no significant differences between the calculated flows for the two sizes of microsphere. Thus, the smaller microspheres do not appear by this method to be subject to significant nonentrapment, and they are therefore suitable for blood flow measurement in these tissues.

Animals↗

PubMed2002

Poly(lactide-co-glycolide) microspheres for the controlled release of oligonucleotide/polyethylenimine complexes.

In this article, microspheres able to induce the controlled release of oligonucleotide/polyethylenimine complexes are proposed. A model oligonucleotide (the oligothymidilate pdT16) was encapsulated within poly(lactide-co-glycolide) microspheres alone or associated with polyethylenimine (PEI) at different nitrogen/phospate (N/P) ratios. Microspheres were prepared by the multiple emulsion-solvent evaporation technique and characterized for morphology, diameter, encapsulation efficiency, and release kinetics. The introduction of PEI in the internal aqueous phase resulted in the formation of a soluble complex with pdT16 and in a strong increase of the oligonucleotide encapsulation efficiency. PEI affected microsphere morphology inducing the formation of very porous particles yielding to an accelerated release of pdT16. When incubated with HeLa cells, microspheres encapsulating pdT16/PEI complexes allowed both a reduction of the complex toxicity and an improvement of the intracellular penetration of the released oligonucleotide. We conclude that biodegradable microspheres encapsulating oligonucleotides/PEI complexes have a great potential as controlled release system because they allow the sustained release of an oligonucleotide carrier that crosses biological membranes and locates in nucleus.

Biocompatible Materials↗

PubMed2005

Pharmacokinetic study of methotrexate following intra-articular injection of methotrexate loaded poly(L-lactic acid) microspheres in rabbits.

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated following intra-articular injection of either MTX solution or controlled release MTX loaded microspheres in healthy rabbit joints. MTX solution or MTX loaded microspheres (size 30-100 mum) (10 mg MTX) was injected into the right knee joint cavity of rabbits. Blood samples were taken at predetermined times from the jugular vein. Urine samples were also collected over time periods up to 24 h. The major organs and synovial tissues were removed for analysis 6 and 24 h post-injection (n = 4). MTX and 7-OH-MTX concentrations in the plasma and major organs were determined by HPLC. The MTX plasma area under the concentration-time curve (AUC) for rabbits injected with MTX solution was seven fold higher than that of the rabbits injected with MTX microspheres, while t(1/2) and mean residence time (MRT) were not significantly different between two treatment groups. Four fold more MTX was excreted in the urine from rabbits injected with MTX solution compared to those injected with MTX loaded microspheres 24 h following intra-articular injection. The concentration of MTX in the synovial tissues following intra-articular injection was significantly higher in the rabbits injected with microspheres than in the rabbits injected with MTX solution. MTX solution was rapidly cleared from the joint cavity while MTX encapsulated microspheres retained MTX in the joint cavity.

Alanine Transaminase↗

PubMed2006

An investigation into the interaction between taste masking fatty acid microspheres and alkaline buffer using thermal and spectroscopic analysis.

Fatty acid-based microspheres may be used for the controlled delivery and taste masking of therapeutic agents, although the mechanisms involved in the release process are poorly understood. In this investigation, microspheres composed of high purity stearic and palmitic acid were prepared using a spray-chilling protocol. In addition, samples of binary fatty acid systems, fatty acid salts and acid-soaps were prepared to allow comparison with the microspheres. The interaction with alkaline buffer, into which release is known to be rapid, was studied using DSC and powder XRD with a view to examining the physicochemical changes undergone by the microspheres as a result of exposure to this medium. New species were identified for the postimmersion microsphere systems; similarities between the thermal and spectroscopic properties of these materials and the acid-soap references indicated the formation of acid-soaps during the exposure to the medium. The data indicate that simple exposure to buffer may result in the formation of acid soaps. This in turn has implications for understanding not only the release of drugs from the microspheres but also the biological fate of fatty acids on ingestion.

Alkalies↗

PubMed1989

Preparation of controlled-release microspheres of ibuprofen with acrylic polymers by a novel quasi-emulsion solvent diffusion method.

A novel quasi-emulsion solvent diffusion method to prepare the controlled-release microspheres of ibuprofen with acrylic polymers has been developed. An ethanol solution of ibuprofen and acrylic resin was poured into aqueous medium with stirring. The finely dispersed ethanolic droplet-like coacervates formed in aqueous medium were gradually solidified and transformed into microspheres during agitation. The size of microspheres was determined by the concentrations of drug and polymer and the agitation speed of the system. The flowability, the packability, and the compressibility of the resultant microspheres were much improved compared with the raw crystals of the drug. The drug release rate from the microspheres could be controlled by the type and the concentration of polymer formulated. A unique principle of the present method and the resultant microspheres, having a matrix- or sponge-like texture, can provide characteristic advantages compared with a conventional reservoir-type device drug, like a microcapsule.

Acrylates↗

PubMed1990

Effect of surface geometry and morphic features on the flow characteristics of microsphere suspensions.

In this paper we present a study on the effect of surface ruggedness of microspheres on the rheological behavior of their suspensions. For this purpose, different types of ragweed pollen grains were selected as models of natural microspheres. A computer-image processing system based on Fourier and fractal analysis of the contour was used to quantitate the micromorphology and surface roughness. The viscosity of suspensions, prepared by the dispersion of the different types of microspheres in heavy liquid paraffin, was determined. It was found that an increase in surface roughness causes an increase in the viscosity of the suspension. Additional resistance to flow could be attributed to internal friction within the suspension due to an increase in the area of contact (during collision or aggregation) among the microspheres, and between microspheres and liquid environment. These findings suggest that the surface geometry of solid particles (e.g., microcapsules, beads, and microspheres) could have a significant effect on the performance of these microparticles in suspension.

Fourier Analysis↗

PubMed1992

In vitro and in vivo release of poly(DL-lactic acid) microspheres containing neurotensin analogue prepared by novel oil-in-water solvent evaporation method.

Poly(DL-lactic acid) (PLA) microspheres containing a neurotensin analogue [NA; H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt.3HCl] were prepared by a novel oil-in-water (o/w) solvent evaporation method, and the release behaviors were evaluated in vitro. About 20% of the loaded NA was released initially, and the subsequent release lasted for a month from microspheres prepared with PLA of molecular weight 2000 (PLA 2000). A smaller initial release from PLA 4000 and PLA 6000 microspheres was found, but a lag time of 2-3 weeks during which the drug was not released was observed with PLA 4000 and PLA 6000 microspheres. The addition of relatively hydrophilic monoglycerides decreased the lag time, and a fairly constant release of NA was achieved. The pharmacokinetic behavior of NA from PLA 2000 microspheres was studied in rats. The release of the drug after a subcutaneous injection exhibited pseudo-zero-order kinetics for 1 month. The initial release of the drug from the microspheres was reflected in a sharp increase of the plasma levels of the de-ester form of NA [H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OH], and the subsequent steady-state levels agreed well with the predicted levels obtained from analysis of constant-infusion kinetics.

Amino Acid Sequence↗

PubMed2006

Magnetic IDA-modified hydrophilic methacrylate-based polymer microspheres for IMAC protein separation.

Preparation of a new type of magnetic non-porous poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate) microspheres with hydrophilic properties containing coupled iminodiacetic acid (IDA) is described. The prepared microspheres were used for the immobilization of Ni(II) or Fe(III) ions to show their application in protein binding studies. Human IgG was bound to magnetic Ni(II)-IDA-modified microspheres and conditions of its adsorption and elution were optimized. Non-specific binding of the protein to magnetic microspheres in the absence of Ni(II) ions was low. Fe(III) ions immobilized on magnetic IDA-modified microspheres were used for the specific binding of porcine pepsin, as a model phosphoprotein. The ability of phosphate buffer to release the adsorbed enzyme from the microspheres and a low adsorption of the dephosphorylated protein indicate the participation of phosphate groups in the pepsin interaction. The elaborated method represents a rapid technique that can be used not only for the separation of proteins but also for analytical purposes.

Adsorption↗