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PubMed2005

Preparation, characterization and in vitro release of gentamicin from PHBV/wollastonite composite microspheres.

Composite microspheres have been prepared from bioactive wollastonite (W) and biodegradable poly (hydroxybutyrate-polyhydroxyvalerate) (PHBV) in the present study. Gentamicin was encapsulated into the microspheres by the absorption method and the in vitro release of the gentamicin from the microspheres was performed in distilled water, modified simulated body fluid (SBF) and phosphate buffered saline (PBS) at 37 degrees C for 22 days, respectively. The results showed that the release behavior of gentamicin from PHBV/W composite microspheres was similar to that from the pure PHBV microspheres when the experiment was performed in distilled water. However, in the PBS and SBF solutions, gentamicin released from the PHBV/W composite microspheres at a relatively lower rate as compared to that of the pure PHBV microspheres and 90% of the total amount of gentamicin released from the composite microspheres after soaking for 22 days, which was much longer than that for the release of the same amount gentamicin from the pure PHBV microspheres (8 days). Scanning electron microscopy (SEM) and energy-dispersive spectrometer (EDS) analysis on the microspheres after release in SBF and PBS revealed that a microporous apatite layer was formed on the composite microspheres surface, which resulted in a controlled release behavior of the gentamicin from the PHBV/W composite microspheres. All of these results provided the possibility that the PHBV/W composite microspheres could be applied as alternative drug controlled release systems, especially as bone fillings for bone repair due to their advantages of controlled releasing antibiotics and apatite-formation ability, through which the implanted microspheres could chemically bond to the surrounding tissue in vivo.

Algorithms↗

PubMedDate not supplied

Novel, fluorescent, magnetic, polysaccharide-based microsphere for orientation, tracing, and anticoagulation: preparation and characterization.

A fluorescent, magnetic composite poly(styrene-maleic anhydride) microsphere, suitable for conjugation with polysaccharide, was synthesized using magnetite/europium phthalate particles as seeds by copolymerization of styrene and maleic anhydride. The magnetite/europium phthalate particles were wrapped up by poly(ethylene glycol), which improved the affinity between the seed particles and the monomers. The composite microspheres obtained, with a diameter of 0.15-0.7 microm, contain 586-1013 microg of magnetite/g of microsphere and 0.5-16 mmol surface anhydride groups/g of microsphere. Heparin was conjugated with the reactive surface anhydride groups on the surface of the microspheres by covalent binding to obtain a fluorescent, magnetic, polysaccharide-based microsphere. The microspheres not only retain their bioactivities but also provide magnetic susceptibility and fluorescence. They can be used as a carrier with magnetic orientation and fluorescence tracer for potent drug targeting. The orientation, tracer, and anticoagulation of the fluorescence, magnetic, polysaccharide-based microspheres were studied. The anticoagulant activity of the microspheres and heparin binding capacity reached 54,212.8 U and 607.1 mg/g of dry microspheres. The activity recovery was 50.2%. The anticoagulant activity of the microspheres increases with the increase of the conjugated heparin on the surface of the microspheres and the decrease of the microsphere size. Furthermore, The fluorescent, magnetic, polysaccharide-based microspheres can be easily transported to a given position in a magnetic field and traced via their fluorescence.

Anticoagulants↗

PubMed1993

Controlled delivery systems for proteins using polyanhydride microspheres.

A method to provide near-constant sustained release of high molecular weight, water-soluble proteins from polyanhydride microspheres is described. The polyanhydrides used were poly(fatty acid dimer) (PFAD), poly(sebacic acid) (PSA), and their copolymers [P(FAD-SA)]. P(FAD-SA) microspheres containing proteins of different molecular sizes--lysozyme, trypsin, heparinase, ovalbumin, albumin, and immunoglobulin--were prepared by a solvent evaporation method using a double emulsion. The microspheres containing proteins were spherical, with diameters of 50-125 microns, and encapsulated more than 80% of the protein, irrespective of the protein used. Enzymatic activity studies showed that encapsulation of enzymes inside polyanhydride microspheres can protect them from activity loss. When not placed inside polyanhydride microspheres, trypsin lost 80% of its activity in solution at 37 degrees C at pH 7.4 in 12 hr, whereas inside the polyanhydride microspheres the activity loss was less than 10% under these conditions. About 47% of the enzymatic activity of heparinase encapsulated in the microspheres was lost at 37 degrees C in 24 hr, while in solution it lost over 90% of its activity. The protein-loaded microspheres displayed near-zero-order erosion kinetics over 5 days as judged by the release of sebacic acid (SA) from the microspheres. The microspheres degraded to form SA and FAD monomers. All proteins were released at a near-constant rate without any large initial burst, irrespective of polymer molecular weight and protein loading. The period of protein release was longer than that of SA and continued protein release was observed even after the microsphere matrix had completely degraded. Differential scanning calorimetric studies demonstrated an interaction between protein and the FAD monomers produced with microsphere degradation. It is likely that the protein interaction with FAD monomers permits formation of water-insoluble protein aggregates which slowly dissolve and diffuse out of the matrix, leading to delayed protein release. For trypsin-loaded microspheres, trypsin lost 40% of its activity during microsphere preparation. Activity studies demonstrated that the sonication process was primarily responsible for activity loss. A reduction in the period of ultrasound exposure decreased the loss of protein activity to around 20%.

Decanoic Acids↗

PubMed2001

In vitro effects of transcatheter injection on structure, cell viability, and cell metabolism in fibroblast-impregnated alginate microspheres.

PURPOSE: To determine if microsphere-encapsulated cell preparations can be delivered through a microcatheter without compromising microsphere structure, cell viability, or metabolism. MATERIALS AND METHODS: Fibroblast-impregnated microspheres were fabricated by using 1.0% alginate and rabbit synovial fibroblasts. Fibroblast-impregnated alginate microspheres injected through microcatheters were analyzed in parallel with identical noninjected microspheres. The effects of transcatheter injection on structure and cell viability (percentage of viable cells per microsphere) were correlated with microsphere size. Structural effects were analyzed by using light microscopy, and 7-day percentage (ratio of live cells to dead cells) cell viability was assessed with confocal microscopy and fluorescent staining. In a second series of experiments, the metabolism of small microspheres was studied during a course of 7 days by using a spectrophotometric bioanalyzer. RESULTS: Transcatheter injection caused fracturing and/or fragmentation of large (800-1,000 microm) and medium (500-750 microm) microspheres, while small (250-400 microm) microspheres were structurally unaffected by transcatheter injection. Fracturing and fragmentation were associated with cell release from the alginate matrix. Although transcatheter injection reduced cell viability by 17%-23% in all size categories, it did not cause a detectable alteration in the rate of glucose metabolism. CONCLUSION: Transcatheter injection was physiologically well tolerated by fibroblasts encapsulated in alginate microspheres; however, when microsphere diameter exceeded the catheter diameter, fracturing and fragmentation of microspheres compromised the sequestration function of the microsphere vector.

Alginates↗

PubMed1988

Evaluation of nonradioactive, colored microspheres for measurement of regional myocardial blood flow in dogs.

Measurement of regional myocardial blood flow (RMBF) is crucial in experimental studies of myocardial ischemia and reperfusion in dogs. The standard measurement technique uses radioactive microspheres; however, not all institutions are able to dispose of radioactive waste and therefore cannot make use of this method. We tested a new, nonradioactive microsphere, labeled with colors instead of nuclides. Simultaneous blood flow measurements with two nuclide-labeled and two colored microspheres were performed after coronary occlusion in dogs. Both techniques show a within-method correlation of r greater than 0.98. Duplicate variability for paired RMBF values in 80 samples was 8.7 +/- 0.1% when computed with radioactive microspheres and 13.2 +/- 1.8% when computed with colored microspheres. There was a good correlation in the measurement of RMBF between the radioactive- and colored-microsphere methods (r = 0.98). The best-fitting linear regression line was expressed by the formula: Colored-microsphere RMBF = 1.11 (radioactive-microsphere RMBF)-0.02. When measured by colored microspheres, RMBF was approximately 8% higher than when computed with radioactive microspheres for blood flow values of 0-2 ml/min/g. When blood flow was increased pharmacologically to levels of 2-7.5 ml/min/g, colored microspheres yielded blood flow values 39% higher than the values computed by radioactive microspheres. We conclude that the nonradioactive, colored-microsphere method correlates with the radioactive technique, but at high flows, it yields values greater than those obtained with radioactive microspheres.

Animals↗

PubMed1996

Formulation of poly(DL-lactide-co-glycolide) microspheres and their ingestion by bovine leukocytes.

This study determined optimal parameters for producing controlled-release microspheres and examined their suitability for vaccines via ingestion by bovine leukocytes. Microspheres elicit an immune response when ingested by antigen-presenting cells and provide sustained exposure of antigen to sensitized cells. Ingestion of microspheres is determined by their size (< 10 microns), and antigen release is governed by composition. Poly(DL-lactide-co-glycolide) microspheres were prepared using different polymer concentrations, stir rates, emulsifier concentrations, and emulsifier molecular masses. Microspheres that were < 10 microns were prepared using a 6% 50:50 lactide to glycolide polymer solution emulsified at 12,000 rpm in a low molecular mass, 5% polyvinyl alcohol solution. Microspheres that were > 20 microns were prepared using a 10% 85:15 lactide to glycolide polymer solution emulsified at 1200 rpm in a low molecular mass, 3% polyvinyl alcohol solution. Small microspheres released 90% of the antigen after 7 d, and large microspheres released only 24% of the antigen after 56 d. Both monocytes and neutrophils selectively ingested small microspheres that were opsonized with normal bovine serum (heated and unheated). Ingestion of microspheres that had been opsonized with fetal bovine serum (heated and unheated) was minimal. Lymphocytes did not ingest microspheres. Ingestion of small microspheres by bovine monocytes and sustained release of antigen by large microspheres suggested that microspheres have the ability to produce a sustained immune response with a single injection.

Animals↗

PubMed2002

[Preparation of surface functional magnetic microspheres and their application in nucleic acid separation and enzyme immobilization].

OBJECTIVE: To Prepare surface functional magnetic microspheres for the separation of vascular endothelial growth factor (VEGF) nucleic acid and lactase enzyme immobilization. METHODS: Using suspension polymerization methods to copolymerize MA-styrene containing magnetite nanoparticles and GMA-styrene also containing magnetite nanoparticles, respectively. Both the carboxyl-modified magnetic microspheres and epoxy-modified magnetic microspheres were obtained. In addition, the chloromethyl-modified magnetic microspheres were prepared by seedy microemulsion. The magnetic microspheres bound with b-gamma IgG were determined by radioimmunoassay (RIA), and the separation of VEGF nucleic acid and lactase enzyme immobilization were performed by carboxyl-modified magnetic microspheres. RESULTS: Transmission electron microscopy (TEM), energy-dispersive spectroscopy (EDS) and infrared (IR) spectra showed that the products of polymer magnetic microspheres were monodispersed and that the magnetic particles were uniformly distributed in the microsphere with special functional group on the surface of the microsphere. RIA showed that three kinds of magnetic microspheres could be bound with b-gamma IgG and the absorption of b-gamma IgG reached 75 micrograms/mg, especially for the carboxyl-modified magnetic microspheres. The carboxyl-modified magnetic microspheres can be used for the separation of VEGF nucleic acid by coupling with corresponding primer. Moreover, the immobilized enzyme was proportional to the amount of the carboxyl-modified magnetic microspheres. CONCLUSIONS: The surface functional magnetic polymer microspheres can be bound with active bio-substance, and have a wide application prospect in the fields of biology and medicine.

Adsorption↗

PubMed1997

Sustained local drug delivery to the arterial wall via biodegradable microspheres.

This study was designed to evaluate the feasibility of applying locally delivered polylactic acid microspheres for drug delivery to the arterial wall. To study drug persistence, rhodamine-loaded microspheres were infused into one carotid artery of 14 rabbits and plain rhodamine solution into the other by using a porous balloon. To study tissue response, plain microspheres and dexamethasone-loaded microspheres were infused into the carotid arteries of another group of rabbits. To study the antiproliferative effects of locally delivered drug, 20 rabbits were subjected to overstretch balloon injury to both carotid arteries and divided into 4 groups: injury alone, plain microspheres, dexamethasone-loaded microspheres, and microspheres containing colchicine and dexamethasone. Fluorescent microspheres persisted in the vessel wall for 4 wk, whereas rhodamine without microspheres disappeared at 72 h. Histopathologic studies in arteries infused with unloaded microspheres showed inflammatory cell infiltrate with polymorphonuclear cells at 1 wk and macrophages and giant cells at 4 wk. Arteries infused with dexamethasone-loaded microspheres did not show any inflammatory cell infiltrate. Local delivery of dexamethasone or dexamethasone plus colchicine did not result in significant change in the intima-to-media ratio or in residual lumen following balloon injury. Polylactic acid microspheres may be used for prolonged delivery of drugs or other bioactive agents locally to the arterial wall. They induce an inflammatory reaction that is suppressable by dexamethasone in the microspheres. Dexamethasone or dexamethasone and colchicine delivered via this system, however, failed to reduce the degree of intimal hyperplasia after overstretch balloon injury to the rabbit carotid arteries.

Angioplasty, Balloon, Coronary↗

PubMed2003

Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration: in vitro and in vivo studies.

Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration.

Animals↗

PubMed2006

Gelatin-methotrexate conjugate microspheres as a potential drug delivery system.

Gelatin-methotrexate microspheres for intra-tumor administration have possibilities for minimizing systemic toxicities of methotrexate (MTX) and overcoming its resistance. Gelatin-MTX conjugates prepared by a carbodiimide reaction were crosslinked with glutaraldehyde to form microspheres (MTX:gelatin molar ratios of 2:1, 15:1, and 21:1). Microspheres were evaluated under in vitro tumor conditions at pH 6.5 and 37 degrees C with and without Cathepsin B (Cat B). Some microspheres were capped with an ethanolamine/cyanoborohydride procedure. SEM of broken microspheres revealed a hollow shell structure. Superficial Cat B degradation influenced some free MTX release but produced no conjugate fragment release. HPLC measured release of fragments (<10 kDa) was very little and release of free MTX was small. However, higher drug load microspheres released less free MTX than lower drug load, a substantial lag phase of free MTX release from capped microspheres changed to an initial rapid release in uncapped microspheres, and fragments were only released from uncapped microspheres. Opened unstable Schiff base crosslinks in uncapped microspheres may allow enzyme to produce conjugate fragments not observed in capped microspheres. Free MTX release may occur from dissolved uncrosslinked conjugate within the hollow microspheres. Important relationships and observations are described that will be useful for gelatin and perhaps other proteinaceous microspheres.

Antimetabolites, Antineoplastic↗

PubMed1995

Potentiality of gelatin microsphere as immunological adjuvant.

This paper describes a new attempt to enhance the production of antibody by delivery of an antigen to phagocytic antigen-presenting cells (e.g. macrophages) using gelatin microspheres. A model protein antigen, human gamma globulin (HGG), was incorporated into microspheres composed of gelatin which have an opsonic ability for macrophage phagocytosis. Subcutaneous injection of the microspheres induced the production of HGG-specific IgG antibody in the mouse serum to a great extent compared with that of HGG in soluble form or in Freund's incomplete adjuvant (FIA) form. There was an optimal concentration of cross-linking agent (glutaraldehyde) for the highest production of antibody. When gelatin microspheres were cross-linked at lower concentrations of glutaraldehyde, they were more extensively swollen in an aqueous solution, leading to an increase in the size of hydrated microspheres because of their lower cross-linking densities. The increased size of microspheres caused a decrease in their macrophage phagocytosis, whereas the release rate of HGG from the microspheres increased as the concentration of cross-linking agent became low. The balance of the two factors, the microsphere susceptibility to macrophage phagocytosis and the rate of HGG release, seemed to affect the efficacy of gelatin microspheres to enhance the antibody production. In addition, incorporation of HGG into gelatin microspheres enhanced the delayed-type hypersensitivity reaction. Moreover, the microspheres developed a strong secondary response in comparison with FIA. The gelatin microspheres induced a minimal inflammatory response around the injection site in contrast to FIA. These findings demonstrate that the gelatin microsphere is promising as an adjuvant to enhance both humoral and cellular immune responses to antigen.

Adjuvants, Immunologic↗

PubMed2004

Preparation of DNA-loaded polysulfone microspheres by liquid-liquid phase separation and its functional utilization.

DNA-loaded polysulfone (PSf) microspheres were fabricated by means of a liquid-liquid phase separation technique. The porous microspheres were then used to remove DNA-binding intercalating materials--ethidium bromide, acridine orange, and endocrine disruptors. The DNA-loaded PSf microspheres are stable in water. The stability of the DNA-loaded microspheres and/or the release rate of DNA from the microspheres can be controlled by manipulating the microsphere structure. Increasing the polymer concentration, which causes lower porosity and smaller pores on the outer surface of the microspheres, led to increased stability of the microspheres and decreased release rate of DNA. Additionally, the drying temperature also affected the stability of the microspheres. The DNA-loaded PSf microspheres could effectively accumulate harmful DNA-intercalating pollutants and endocrine disruptors, such as ethidium bromide, acridine orange, biphenyl, dibenzofuran, and dibenzo-p-dioxin. The amount of pollutants removed by the microspheres is dependent on the amount of incorporated DNA and on the microsphere structure. The DNA-loaded microspheres have the potential to be used in environmental applications.

DNA↗

PubMed2005

Development of a novel formulation containing poly(d,l-lactide-co-glycolide) microspheres dispersed in PLGA-PEG-PLGA gel for sustained delivery of ganciclovir.

The purpose of this work is to develop empirical equations for describing the in vitro ganciclovir (GCV) release from PLGA microspheres and also to develop and characterize a formulation containing GCV loaded PLGA microspheres dispersed in thermogelling PLGA-PEG-PLGA polymer gel. Effect of polymer chain length and polymer blending on GCV entrapment and release from PLGA microspheres is also examined. PLGA microspheres of GCV were prepared from two polymers PLGA 6535 (d,l-lactide:glycolideColon, two colons65:35, Mw=45,000-75,000 Da) and Resomer RG 502H (d,l-lactide:glycolideColon, two colons50:50, Mw=8000 Da) and a 3:1 mixture. PLGA-PEG-PLGA polymer was synthesized and characterized. In vitro GCV release studies were conducted with microspheres and microspheres dispersed in 23% w/v PLGA-PEG-PLGA solution. Polymer blended microspheres entrap more GCV (72.67+/-2.49%) than both PLGA 6535 (51.37+/-2.7%) and Resomer RG 502H (47.13+/-1.13%) microspheres. In vitro drug release data was fit to sigmoid equations and release parameters were estimated by nonlinear regression analysis. These equations effectively describe three different phases in GCV release from PLGA microspheres, initial diffusion, matrix hydration and degradation. The amount of drug release during the initial phase decreased for the blend microspheres indicating efficient packing between the PLGA 6535 and Resomer RG 502H in the microsphere matrix. Moreover, upon dispersion into the polymer gel, the rate of drug release during initial diffusion phases slowed relative to microspheres alone. In conclusion, this study reports the development of PLGA microspheres with high payloads and their PLGA-PEG-PLGA gel based formulations. Drug release equations have been developed that effectively describe the triphasic GCV release.

Algorithms↗

PubMed2002

Tissue engineered microsphere-based matrices for bone repair: design and evaluation.

The need for synthetic alternatives to conventional bone grafts is due to the limitations of current grafting materials. Our approach has been to design polymer-based graft substitutes using microsphere technology. The gel microsphere matrix and the sintered microsphere matrix were designed using the random packing of poly(lactide-co-glycolide) microspheres to create a three-dimensional porous structure. The evaluation of these methods dealt with analysis of effects of matrix composition and processing. Matrices were evaluated structurally by scanning electron microscopy and porosimetry, and biomechanically by compression testing. The evaluation revealed the high modulus of the gel microsphere matrix and the versatility of the sintered microsphere matrix. The gel microsphere matrix incorporated hydroxyapatite particles and had a Young's modulus of 1651 MPa, but structural analysis through SEM revealed a pore system less optimal for bone in-growth. The sintered microsphere matrices were fabricated without hydroxyapatite particles by thermally fusing polymeric microspheres into a three-dimensional array, possessing interconnectivity and a modulus range of 241 (+/-82)-349 (+/-89) MPa. The sintered microsphere matrix demonstrated a connected pore system and mechanical properties in the mid-range of cancellous bone. Porosimetry data indicated that matrix pore diameter varied directly with microsphere diameter, while pore volume was independent of microsphere diameter in the range of diameters examined. The microsphere-based matrices show promise as polymeric substitutes for bone repair.

Bone Regeneration↗

PubMed1999

Biodegradable recombinant human erythropoietin loaded microspheres prepared from linear and star-branched block copolymers: influence of encapsulation technique and polymer composition on particle characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate labeled dextran (FITC-dextran) loaded microspheres were prepared by a modified W/O/W double-emulsion technique. Biodegradable linear ABA block copolymers consisting of poly(L-lactide-co-glycolide) A blocks attached to central poly(ethyleneoxide) (PEO) B blocks and star-branched AB block copolymers containing A blocks of poly(L-lactide) or poly(L-lactide-co-glycolide) and star-branched poly(ethyleneoxide) B blocks were investigated for their potential as sustained release drug delivery systems. Microsphere characteristics were strongly influenced by the polymer composition. In the case of the linear block copolymers, a reduced lactic acid content in a linear block copolymer yielded smaller particles, a lower encapsulation efficiency, and a higher initial drug release both in the case of EPO and FITC-dextran. The investigation of the effects of several manufacturing parameters on microsphere formation showed that the process temperature plays an important role. Microsphere formation in a +1 degrees C environment resulted in higher drug loadings without increasing the amount of residual dichloromethane inside the particles. Other parameters such as the homogenization of the primary W/O emulsion and of the W/O/W double-emulsion have less impact on microsphere characteristics. Branched block copolymers containing star-shaped PEO also showed potential for the preparation of drug loaded microspheres. A certain amount of glycolic acid in the copolymer was necessary for the successful preparation of non-aggregating microspheres at room temperature. Again, the processing temperature strongly affected particle characteristics. Microsphere preparation at +1 degrees C allows the formation of microspheres from a polymer not containing glycolic acid, a result which could not be achieved at room temperature. Moreover, compared to microsphere formation at room temperature, the effective FITC-dextran loading was increased. Concerning the EPO loaded microspheres, the amount of EPO aggregated was comparable to that using the linear ABA polymers. A continuous release of the protein from these star-shaped polymers could not be achieved. In conclusion, apart from microsphere preparation in a +1 degrees C environment the choice of the polymer represents the main factor for a successful entrapment of proteins into biodegradable microspheres.

Biodegradation, Environmental↗

PubMed2001

Preparation and characterization of a composite PLGA and poly(acryloyl hydroxyethyl starch) microsphere system for protein delivery.

PURPOSE: To prepare and characterize a novel composite microsphere system based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acHES) hydrogel for controlled protein delivery. METHODS: Model proteins, bovine serum albumin, and horseradish peroxidase were encapsulated in the acHES hydrogel, and then the protein-containing acHES hydrogel particles were fabricated in the PLGA matrix by a solvent extraction or evaporation method. The protein-loaded PLGA-acHES composite microspheres were characterized for protein loading efficiency, particle size, and in vitro protein release. Protein stability was examined by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and monitoring the enzymatic activity. RESULTS: Scanning electron microscopy showed discrete PLGA microspheres containing many acHES particles. The composite microspheres were spherical and smooth in size range of 39-93 microm. The drug loading efficiency ranged from 51 to 101%. The composite microspheres showed more favorable in vitro release than conventional PLGA microspheres. The composite microspheres showed 20% less initial with a gradual sustained release compared to high burst (approximately 60%) followed by a very slow release with the conventional PLGA microspheres. The composite microspheres also stabilized encapsulated proteins from the loss of activity during the microsphere preparation and release. Proteins extracted from the composite microspheres showed good stability without protein degradation products and structural integrity changes in the size-exclusion chromatography and SDS-PAGE analyses. Horseradish peroxidase extracted from microspheres retained more than 81% enzymatic activity. CONCLUSION: The PLGA-acHES composite microsphere system could be useful for the controlled delivery of protein drugs.

Acrylic Resins↗

PubMed2003

PLG microsphere size controls drug release rate through several competing factors.

PURPOSE: Although the rate of drug release from poly(D,L-lactide-co-glycolide) (PLG) microspheres is often modulated by changing fabrication conditions or materials, the specific factors directly controlling the release profiles are often unclear. We have fabricated uniform rhodamine- and piroxicam-containing microspheres, 10 to 100 microm in diameter, to better understand how microsphere size controls drug release. METHODS: Drug distribution within the microspheres was examined using confocal fluorescence microscopy. The rate of polymer degradation was determined as the change in molecular weight, measured by gel permeation chromatography, during in vitro degradation experiments. Further, changes in the surface and interior morphology of the particles during in vitro degradation were investigated by scanning electron microscopy. RESULTS: Microsphere size greatly affected drug distribution. Small (approximately 10-microm) microspheres showed an essentially uniform drug distribution. Larger (approximately 100-microm) microspheres showed redistribution of drug to specific regions of the microspheres. Rhodamine partitioned to the surface and piroxicam partitioned to the interior of large PLG microspheres. Further, the rate of polymer degradation increased with microsphere size, possibly the result of a more acidic interior caused by increased accumulation of hydrolyzed polymer products in larger particles. Finally, larger microspheres developed a more porous interior structure during the drug release. CONCLUSION: Microsphere size affects drug release not only through changes in diffusion rates but also through secondary effects including drug distribution in the particle, polymer degradation rate, and microsphere erosion rates.

Lactic Acid↗

PubMed2001

Tumour embolization of the Vx2 rabbit head and neck cancer model with Dextran hydrogel and Holmium-poly(L-lactic acid) microspheres: a radionuclide and histological pilot study.

INTRODUCTION: Intra-arterial embolization of unresectable malignant tumours with biodegradable microspheres is an effective way of selective anti-tumour therapy. Promising candidates are Dextran hydrogel (Dex) microspheres for chemo-embolization and Holmium-166 poly(L-lactic acid) (166HoPLA) microspheres for radio-embolization. This study was performed to investigate the distribution of intra-arterially injected microspheres both in vivo and histologically in order to establish an optimal size of particles for embolization of head and neck tumours. MATERIAL: Twenty rabbits with Vx2 auricular tumours were embolized via the caudal auricular artery with 4 different batches of microspheres: Radioactive (166)HoPLA microspheres sieved between 20 and 50 microm and Dextran hydrogel microspheres sieved between 20 and 100 microm (Dex20), 30 and 100 microm (Dex30) or 50 and 100 microm (Dex50). Dex20 and Dex50 microspheres were labelled with 99mTechnetium in six cases. METHODS: The average particle size of the microspheres was determined. The proportion of microspheres entrapped in the tumour was measured with a gamma camera. The distribution of microspheres around the primary tumour and spill of particles over into lungs or other organs was analysed from histological sections. RESULTS: The mean particle diameter varied from 19 to 66 microm: (166)HoPLA 19+/-11 microm, Dex20 40+/-19 microm, Dex30 50+/-19 microm, Dex50 66+/-21 microm. The 19 microm(166)HoPLA particles proved inadequate for embolization as 51% spilled over into the lungs, whereas over 95% of the 40-66 microm Dex microspheres were retained within the primary tumour area. Particle density in lung tissues proved significantly lower for the Dex50 group. Stray emboli to the brain occurred in two rabbits. CONCLUSION: The results of this investigation show that both Dextran hydrogel and holmium-166 poly(L-lactic acid) microspheres are potential candidates for embolization of head and neck cancer. In future studies, arterio-arteriolar anastomoses which might confound treatment should be identified and occluded. Particles with a number weighted mean diameter of at least 40 microm and a volume weighted mean size up to 70 microm should be used.

Analysis of Variance↗