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PubMed2006

PEGylation of microspheres for therapeutic embolization: preparation, characterization and biological performance evaluation.

In this study, microspheres designed for embolization, defined as GF2000-Trisacryl MS (GF-MS) and DEAE-Trisacryl MS (DEAE-MS), were originally PEGylated using (3-amino propyl) triethoxy silane as coupling agent. Indomethacin was loaded into both PEGylated and non-PEGylated DEAE-MS, displaying ion-exchange ability, through a batch process with a respective capacity of 1.2 and 0.25 g/g. The morphology of naked and PEGylated MS was evaluated by scanning electron microscopy (SEM). Both micosphere resins surface looked like orange skin, although DEAE-MS showed a slightly rougher surface due to the copolymerization process. PEGylated microspheres have a most likely swelling surface owing to the presence of PEG hydrophilic chains. The mean diameters were of about 66 and 60 microm for GF-MS and DEAE-MS, respectively. Data obtained for PEGylated MS by Fourier Transform Infrared spectroscopy (FTIR) confirmed that microspheres were successfully PEGylated. Finally, complement activation in vitro was performed to evaluate the activating capacity of different microspheres. Both PEGylated GF-MS and DEAE-MS activated the complement system of about 33% less than their corresponding naked microspheres, while loading PEGylated DEAE-MS with indomethacin almost suppressed complement activation. This inhibiting role implies that PEGylation as well as loading the microspheres with anti-inflammatory drug has a compact effect on the interaction of microspheres with blood proteins.

Biocompatible Materials↗
PubMed2005

Preparation and electrochromic property of covalently bonded WO3/polyvinylimidazole core-shell microspheres.

Covalently bonded WO3/polyvinylimidazole (C-WO3/PVI) core-shell microspheres in sizes of 250 nm were prepared. The microstructures of C-WO3/PVI core-shell microspheres were characterized by TEM, IR, and XRD. It is found that the chemical and thermal stabilities of C-WO3/PVI core-shell microspheres are higher than those of pure WO3 nanoparticles and noncovalently bonded WO3/polyvinylimidazole (NC-WO3/PVI) core-shell microspheres. This is attributed to the strengthened interaction of the WO3 nanoparticle core and the PVI shell resulting from the interaction of covalent bonds. The electrochromic device made by the C-WO3/PVI core-shell microspheres was studied. It is suggested that the C-WO3/PVI core-shell microspheres exhibit better electrochromic properties than pure WO3 nanoparticles or NC-WO3/PVI core-shell microspheres.

Journal Article↗
PubMed2005

Chemoprevention of 4-NQO-induced oral carcinogenesis by co-administration of all-trans retinoic acid loaded microspheres and celecoxib.

All-trans retinoic acid (atRA) is one of the most potential chemopreventive agents for head and neck squamous cell carcinoma (HNSCC). However, the induced metabolism of atRA by cytochrome P450s in the liver limits its clinical applications. To overcome such limitation, we had developed atRA-loaded microspheres designed to release atRA for a long period. Unfortunately, the atRA-loaded microspheres severely induced inflammatory responses: that is, atRA released from the microspheres significantly induced the proliferation of fibroblasts and collagen deposition, thereby causing a permeability barrier for drugs from entering the blood stream. In the present study, the effects of celecoxib as an anti-inflammatory drug are investigated when it is concurrently used with atRA-loaded microspheres to treat 4-NQO-induced oral carcinogenesis. We investigated if it might influence the plasma concentration of atRA and its metabolism by preventing the fibroblast proliferation and collagen deposition, reduce the toxicity level of atRA, and improve the chemopreventive efficacy of atRA-loaded microspheres. The concurrently administered celecoxib prevented inflammatory responses and suppressed the number of fibroblasts and collagen deposition in the fibrous capsules for 14 days. The atRA concentration in plasma was also increased and the metabolism of atRA was significantly decreased within 2 weeks. In the 4-NQO-induced oral carcinogenesis study, the incidence of invasive SCC was above 44% when F344 rats were treated with atRA-loaded microspheres. However, the treatment using atRA-loaded microspheres and celecoxib concurrently could reduce the incidence of invasive SCC up to 28%, and three of 25 rats were found to have no tongue lesions. In conclusion, the concurrent use of celecoxib could maintain the atRA concentration in plasma at a higher level while reducing its metabolism by preventing inflammatory responses, thereby improving their chemopreventive effects against 4-NQO-induced oral carcinogenesis.

4-Nitroquinoline-1-oxide↗
PubMed1998

Preparation of casein-chitosan microspheres containing diltiazem hydrochloride by an aqueous coacervation technique.

Sustained release casein-chitosan microspheres containing diltiazem hydrochloride (DTZ) were prepared with colloidal coacervation technique in a completely aqueous environment. The interaction between chitosan solution in dilute acetic acid (5% v/v) and casein solution in 0.5 M sodium hydroxide was the basis for the microspheres formation. Formaldehyde was used for the surface hardening of the droplets by cross-linking and thus fixing the shape and surface morphology of the formed microspheres. The entrapment efficiencies of the microspheres were variables (14.5-53.7%) depending on the preparation conditions. The prepared microspheres exhibited an angle of repose values between 31.9-42.0 degrees indicating good free flowing nature, whereas DTZ powder as such was non-flowable. The dissolution profiles of DTZ from casein-chitosan microspheres showed retarded release pattern of the drug into distilled water. Casein and chitosan concentrations, initial drug concentration and stirring time were found to be the main parameters that affect the properties and the performance of the prepared microspheres. The retarded release of DTZ was increased by increasing casein concentration, and stirring time. On the other hand, increasing chitosan concentration and using high initial drug loading showed a fast drug release.

Animals↗
PubMed1997

Multiple emulsion technology for the design of microspheres containing peptides and oligopeptides.

This paper reviews the preparation and characterization of small poly(lactic-co-glycolic acid) microspheres (mean size lower than 10 µm) containing small peptides and prepared by a water-in-oil-in-water emulsion solvent evaporation technique. These microspheres were shown to encapsulate very efficiently a 33 amino acid peptide (V3 BRU) and in vitro release kinetics studies showed that such microspheres could be employed for both oral vaccination and controlled release. The encapsulation of a seven amino acid peptide (pBC 264) led on the contrary to a very low encapsulation efficiency. In order to increase the encapsulation of pBC 264, two strategies were adopted: (i) taking into account the solubility of pBC 264 at different pH, the inner aqueous phase was maintained at a basic pH where the peptide was soluble, while the external aqueous phase was acidic; (ii) ovalbumin was added to stabilize the inner emulsion. These two strategies allowed us to increase significantly the encapsulation rate of pBC 264. Nevertheless, the in vitro release kinetics of the peptide were strongly influenced by the presence of ovalbumin which seems to form pores in the microsphere structure. By contrast, when ovalbumin was replaced by Pluronic(R) F68, microspheres did not have pores, thus the release profile and the extent of the burst were much smaller. When microspheres were stereotactically implanted in the rat brain, in vivo release profiles were in good agreement with the release observed in vitro. In conclusion, these microspheres are well suited for the slow delivery of neuropeptides in the brain, a feature expected to facilitate the study of long term effects of these compounds.

Journal Article↗
PubMedDate not supplied

Long-term release and improved intracellular penetration of oligonucleotide-polyethylenimine complexes entrapped in biodegradable microspheres.

The aim of this work was to design a biodegradable delivery system for oligonucleotides providing both a sustained release and an improved intracellular penetration. To this purpose oligonucleotide/polyethylenimine (ON/PEI) complexes at nitrogen to phosphate (N/P) molar ratios of about 15 or 40 were encapsulated into poly(lactide-co-glycolide) microspheres by the multiple emulsion-solvent evaporation technique. ON/PEI complexes were efficiently entrapped inside microspheres. The introduction of salts within the external aqueous phase allowed an improvement of microsphere characteristics. In particular, the use of sodium chloride led to a reduced microsphere porosity and a more homogeneous ON distribution inside the polymeric matrix. These effects were attributed to the reduced flux of water from the external aqueous phase toward the internal aqueous droplets, due to the osmotic effect of sodium chloride. Both, the reduced porosity and the improved ON distribution inside the matrix, were considered responsible for the lower burst effect and the slower ON release rate from microsphere prepared with sodium chloride. ON/PEI complexes encapsulated inside microspheres were also protected toward enzymatic degradation in fetal calf serum. Interestingly, ON/PEI complexes slowly released from microspheres efficiently penetrated inside HeLa cells and oligonucleotides were preferentially located in the nucleus.

Biodegradation, Environmental↗
PubMed2005

Interparticle interactions and direct imaging of colloidal phases assembled from microsphere-nanoparticle mixtures.

We investigate the interparticle interactions, phase behavior, and structure of microsphere-nanoparticle mixtures that possess high size and charge asymmetry. We employ a novel Monte Carlo simulation scheme to calculate the effective microsphere interactions in suspension, yielding new insight into the origin of the experimentally observed behavior. The initial settling velocity, final sediment density, and three-dimensional structure of colloidal phases assembled from these binary mixtures via gravitational settling of silica microspheres in water and index-matched solutions exhibit a strong compositional dependence. Confocal laser scanning microscopy is used to directly image and quantify their structural evolution during assembly. Below a lower critical nanoparticle volume fraction (phi(nano) < phi(L,C)), the intrinsic van der Waals attraction between microspheres leads to the formation of colloidal gels. These gels exhibit enhanced consolidation as phi(nano) approaches phi(L,C). When phi(nano) exceeds phi(L,C), an effective repulsion arises between microspheres due to the formation of a dynamic nanoparticle halo around the colloids. From this stable fluid phase, the microspheres settle into a crystalline array. Finally, above an upper critical nanoparticle volume fraction (phi(nano) > phi(U,C)), colloidal gels form whose structure becomes more open with increasing nanoparticle concentration due to the emergence of an effective microsphere attraction, whose magnitude exhibits a superlinear dependence on phi(nano).

Journal Article↗
PubMed2005

Phase behavior and 3D structure of strongly attractive microsphere-nanoparticle mixtures.

We investigate the phase behavior and 3D structure of strongly attractive mixtures of silica microspheres and polystyrene nanoparticles. These binary mixtures are electrostatically tuned to promote a repulsion between like-charged (microsphere-microsphere and nanoparticle-nanoparticle) species and a strong attraction between oppositely charged (microsphere-nanoparticle) species. Using confocal fluorescence scanning microscopy, we directly observe the 3D structure of colloidal phases assembled from these mixtures as a function of varying composition. In the absence of nanoparticle additions, the charged-stabilized microspheres assemble into a polycrystalline array upon sedimentation. With increasing nanoparticle volume fraction, nanoparticle bridges form between microspheres, inducing their flocculation. At even higher nanoparticle volume fractions, the microspheres become well coated with nanoparticles, leading to their charge reversal and subsequent restabilization. We demonstrate how this fluid-gel-fluid transition can be utilized to control the morphology of the colloidal phases formed under gravity-driven sedimentation.

Journal Article↗
PubMed1997

The stabilization and encapsulation of human growth hormone into biodegradable microspheres.

PURPOSE: To produce and evaluate sustained-acting formulations of recombinant human growth hormone (rhGH) made by a novel microencapsulation process. METHODS: The protein was stabilized by forming an insoluble complex with zinc and encapsulated into microspheres of poly (D,L-lactide co-glycolide) (PLGA) which differed in polymer molecular weight (8-31 kD), polymer end group, and zinc content. The encapsulation procedure was cryogenic, non-aqueous, and did not utilize surfactants or emulsification. The rhGH extracted from each of these microsphere formulations was analyzed by size-exclusion, ion-exchange and reversed-phase chromatography, SDS-polyacrylamide gel electrophoresis, peptide mapping, and cell proliferation of a cell line expressing the hGH receptor. In addition, the in vivo release profile was determined after subcutaneous administration of the microspheres to rats and juvenile rhesus monkeys. RESULTS: Protein and bioactivity analyses of the rhGH extracted from three different microsphere formulations showed that the encapsulated protein was unaltered relative to the protein before encapsulation. In vivo, microsphere administration to rats or monkeys induced elevated levels of serum rhGH for up to one month, more than 20-fold longer than was induced by the same amount of protein injected subcutaneously as a solution. The rate of protein release differed between the three microsphere formulations and was determined by the molecular weight and hydrophobicity of the PLGA. The serum rhGH profile, after three sequential monthly doses of the one formulation examined, was reproducible and showed no dose accumulation. CONCLUSIONS: Using a novel process, rhGH can be stabilized and encapsulated in a solid state into PLGA microspheres and released with unaltered properties at different rates.

Administration, Cutaneous↗
PubMed1994

Dose and load studies for subcutaneous and oral delivery of poly(lactide-co-glycolide) microspheres containing ovalbumin.

Poly(lactide-co-glycolide) microspheres containing different loads of OVA (0.05, 0.1, 0.5 and 1.0% w/w) were manufactured by a w/o/w emulsion/solvent evaporation method. Low load efficiencies of less than 20% were observed. Normal size distributions with mean volume diameters ranging from 3.7 to 4.7 microns were obtained for different batches. The in vitro release of OVA from different loaded microspheres showed an expected burst release with all batches. The in vivo dose study (1, 10, 25, 50 micrograms of OVA) was performed by subcutaneous and oral inoculation in mice by single (0 week) or double (0 and 3 weeks) administration of PLGA 50/50 microspheres containing 0.1% OVA. Subcutaneous administration showed an immune response (serum Ig levels by ELISA) statistically (Fisher's paired t-test; P < 0.05) above OVA saline negative controls at 3, 6 and 12 weeks after administration. Oral administration of microspheres produced statistically higher systemic immune responses at the higher doses. Single and double inoculation orally and subcutaneously produced similar serum antibody levels. The in vivo load study was performed by subcutaneous and oral administration to mice of 25 micrograms OVA contained in various loaded (0.05, 0.1, 0.5 and 1.0% w/w) microspheres. Serum immune responses at 3, 6, and 12 weeks after inoculation were statistically above OVA saline controls and were inversely proportional to the OVA load using either route. This observation suggested a relationship between the number of microspheres delivered and the in vivo serum response. Single subcutaneous administration of 0.05 or 0.1% OVA loaded PLGA 50/50 microspheres induced larger immune responses compared with complete Freund's adjuvant.

Administration, Oral↗
PubMedDate not supplied

In vitro evaluation and intra-articular administration of biodegradable microspheres containing naproxen sodium.

The dispersion of non-steroidal antiinflammatory drugs (NSAIDs) into biodegradable polymeric matrices have been accepted as a good approach for obtaining a therapeutic effect in a predetermined period of time meanwhile minimizing the side effects of NSAIDs. In the present study, it was aimed to prepare Naproxen Sodium (NS), (a NSAID) loaded microsphere formulation using natural Bovine Serum Albumin (BSA) and synthetic biodegradable polymers such as poly(lactide-co-glycolic acid) (PLGA) (50:50 MW 34,000 and 88,000 Da) for intra-articular administration, and to study the retention of the drug at the site of injection in the knee joint. NS incorporated microspheres were evaluated in vitro for particle size (the mean particle size; for BSA microspheres, 10.0 +/- 0.3 microm, for PLGA microspheres, 9.0 +/- 0.2 and 5.0 +/- 0.1 microm for MW 34,000 and 88,000 Da, respectively), yield value, drug loading, surface morphology and drug release. For in vivo studies, monoarticular arthritis was induced in the left knee joints of rabbits by using ovalbumin and Freund's Complete Adjuvant as antigen and adjuvant. A certain time (4 days) is allowed for the formation of arthritis in the knee joints, then the NS loaded microspheres were injected directly into the articular cavity. At specific time points, gamma scintigrams were obtained to determine the residence time of the microspheres in knee joints, in order to determine the most suitable formulation. This study indicated that PLGA, a synthetic polymer, is more promising than the natural type BSA microspheres for an effective cure of mono-articular arthritis in rabbits.

Animals↗
PubMed1987

Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation.

In an open, randomised crossover study enteric coated microspheres of pancreatin were compared with a standard preparation of enteric coated pancreatin over two consecutive 28 day treatment periods in 23 adults with steatorrhoea due to cystic fibrosis. Lipase intake was equal to the patients' previous requirements and was the same during the two months. Patients performed 72 hour faecal collections at the end of each month and completed diary cards daily throughout. Comparison of the month of treatment with enteric coated microspheres with the month of standard enteric coated tablets showed a significant increase in body weight on microsphere capsules (p less than 0.02). There was also a reduced frequency of bowel actions (p less than 0.001) and abdominal pain (p less than 0.05), and improvement in stool character (p less than 0.001) on microsphere capsules. Faecal fat excretion was reduced by 44% with the microsphere capsules (p less than 0.01), and 86% of patients showed an increased coefficient of fat absorption (mean increase 13%, 95% confidence limits 6.5-19.1%; p less than 0.001). Eighty one per cent of patients preferred microsphere capsules of the two treatments. Thus enteric coated microsphere capsules are more effective in treating steatorrhoea in cystic fibrosis than standard enteric coated tablets.

Adult↗
PubMed1988

Initial trial of slow-release testosterone microspheres in hypogonadal men.

The duration of hormone release from testosterone-loaded poly(DL-lactide-co-glycolide) microspheres was assessed in eight hypogonadal men. Eight weeks before receiving testosterone (T) microspheres, patients were withdrawn from their prior androgen therapy in order to minimize the contribution of that therapy to hormone levels measured following microsphere injection. Blood was obtained for hormone measurements immediately before and weekly for 14 weeks after the administration of the T microspheres. A biphasic release of hormone was observed; a significant increase in total T and free T concentration (compared to preinjection values) was observed during week 1 (P less than 0.01) and between weeks 6 and 11 after injection (P less than 0.05). A similar pattern was detected in estradiol and dihydrotestosterone concentrations, whereas T-binding globulin levels showed a small, reciprocal fall after the injection of microspheres (P = not significant [NS]). After receiving the T microspheres, seven of eight hypogonadal men reported the return of normal sexual function; the eight patient withdrew from the study after 5 weeks. It was concluded that T microspheres are a promising new method of androgen replacement therapy for hypogonadal men.

Adult↗
PubMed1999

Microencapsulation of human growth hormone within biodegradable polyester microspheres: protein aggregation stability and incomplete release mechanism.

Recombinant human growth hormone (rhGH) was encapsulated within poly(D,L-lactic-co-glycolic acid) microspheres by a double emulsion solvent evaporation method. A mixture of methylene chloride and ethyl acetate in varying volume ratios was used for the microsphere preparation. Protein release profiles from three different microsphere formulations demonstrated initial burst effects ranging from 28.2% to 54.7% after a 1-day incubation and exhibited no further significant releases up to 19 days. This was because the encapsulated rhGH with the microspheres was largely aggregated in a noncovalent fashion during the formulation. Nonaggregated water soluble rhGH species within the microspheres are likely to be responsible for the rapid release upon incubation. The initially released rhGH in the incubation medium, however, was composed of mostly monomer species with a small amount of dimer as probed by size-exclusion chromatography. Circular dichroism spectra of the initially released rhGH in the medium revealed that the conformation of the released rhGH was correctly folded relative to that of native rhGH, with little variation in alpha-helix contents depending on the formulations. The "nonrelease" mechanism after the initial burst release was attributed to nonspontaneously dissociable noncovalent protein aggregation and surface adsorption of rhGH present within the microspheres.

Acetates↗
PubMed2000

Flow cytometric, phase-resolved fluorescence measurement of propidium iodide uptake in macrophages containing phagocytized fluorescent microspheres.

BACKGROUND: Spectral interference (overlap) from phagocytosed green-yellow (GY) microspheres in the flow cytometric, red fluorescence emission measurement channel causes errors in quantifying damaged/dead alveolar macrophages by uptake of propidium iodide. METHODS: Particle burdens of uniform GY fluorescent microspheres phagocytosed by rat alveolar macrophages and the discrimination of damaged/dead cells as indexed by propidium iodide uptake were assessed with conventional and phase-sensitive flow cytometry. RESULTS: The fluorescence spectral emission from phagocytosed microspheres partly overlapped the propidium iodide red fluorescence emission and interfered with the measurement of damaged/dead cells when using conventional flow cytometry without subtractive compensation. This caused errors when estimating the percentage of nonviable, propidium iodide-positive, phagocytic macrophages. The interference was eliminated by employing phase-sensitive detection in the red fluorescence measurement channel based on differences in fluorescence lifetimes between the fluorescent microspheres and propidium iodide. Intrinsic cellular autofluorescence, whose fluorescence lifetime is approximately the same as that of the phagocytosed microspheres, also was eliminated in the phase-sensitive detection process. Because there was no detectable spectral interference of propidium iodide in the green fluorescence (phagocytosis) measurement channel, conventional fluorescence detection was employed. CONCLUSIONS: Phase-resolved, red fluorescence emission measurement eliminates spectral overlap errors caused by autofluorescent phagocytes that contain fluorescent microspheres in the analyses of propidium iodide uptake. Cytometry 39:45-55, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗
PubMed1985

Effects of intra-arterially infused biodegradable microspheres containing mitomycin C.

We prepared biodegradable microspheres containing about 5% mitomycin C (MMC) and of 45 +/- 8 microns in diameter. These preparations were infused into the rat hepatic artery as a preclinical model of intra-arterial infusion treatment for patients with inoperable hepatic tumor. The leaked MMC levels in the hepatic vein decreased below the assay limitation 2 hours after conventional MMC injection, whereas in the case of MMC microsphere the leaked drug levels were maintained at almost the same concentration for over 2 hours after infusion. The entrapped period of MMC microspheres within the hepatic artery was at least 2 weeks, and the necrobiotic foci due to antitumor effects of the condensed MMC released from the microspheres were observed in the area fed by these entrapped arterioles. This phenomenon was never observed in the case of conventional MMC and placebo microspheres. Intra-arterial infusion of MMC microspheres may be a promising clinical treatment for patients with malignant hepatic tumor.

Animals↗
PubMed2001

Multiplexed molecular interactions of nuclear receptors using fluorescent microspheres.

BACKGROUND: We describe a novel microsphere-based system to identify and characterize multiplexed interactions of nuclear receptors with peptides that represent the LXXLL binding region of coactivator proteins. METHODS: In this system, individual microsphere populations with unique red and orange fluorescent profiles are coupled to specific coactivator peptides. The coactivator peptide-coupled microsphere populations are combined and incubated with a nuclear receptor that has been coupled to a green fluorochrome. Flow cytometric analysis of the microspheres simultaneously decodes each population and detects the binding of receptor to respective coactivator peptides by the acquisition of green fluorescence. RESULTS: We have used this system to determine the binding affinities of human estrogen receptor beta ligand binding domain (ERbeta LBD) and human peroxisome proliferator activated receptor gamma ligand binding domain (PPARgamma LBD) to a set of 34 coactivator peptides. Binding of ERbeta LBD to a coactivator peptide sequence containing the second LXXLL motif of steroid receptor coactivator-1 (SRC-1(2) (676-700) is shown to be specific and saturable. Analysis of receptor binding to a multiplexed set of coactivator peptides shows PPARgamma LBD binds with high affinity to cAMP response element binding protein (CBP) peptides and to the related P300 peptide while ERbeta LBD exibits little binding to these peptides. Using the microsphere-based assay we demonstrate that ERbeta LBD and PPARgamma LBD binding affinities for the coactivator peptides are increased in the presence of agonist (estradiol or GW1929, respectively) and that ERbeta LBD binding is decreased in the presence of antagonist (raloxifene or tamoxifen). CONCLUSIONS: This unique microsphere-based system is a sensitive and efficient method to simultaneously evaluate many receptor-coactivator interactions in a single assay volume. In addition, the system offers a powerful approach to study small molecule modulation of nuclear receptor binding.

Amino Acid Motifs↗
PubMedDate not supplied

Adriamycin-loaded albumin microspheres: preparation, in vivo distribution and release in the rat.

Adriamycin-loaded bovine albumin microspheres have been prepared by a technique that allows preparation and administration to animals on the same day. Criteria adopted for injection were that microspheres should be stable and of a size such as to become trapped in capillary beds. These conditions were fulfilled by preparing microspheres using glutaraldehyde concentrations greater than 0.5 per cent and the appropriate combination of stirring speed and continuous phase viscosity. After systemic administration rats were sacrificed at intervals and major visceral organs examined for entrapped microspheres and serum for released drug. Microspheres sieved out in the first capillary bed encountered, the lung, then following biodegradation they disappeared at a rate dependent on the amount of cross-linking agent used in their preparation. In contrast to bolus injection, serum drug levels after microsphere administration indicated an initial rapid release followed by a more protracted phase lasting at least 24 h. This latter observation is consistent with drug release during biodegradation of carrier.

Animals↗