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PubMed2000

Preparation of Thermus thermophilus holo-chaperonin-immobilized microspheres with high ability to facilitate protein refolding.

Carboxylated poly(styrene/acrylamide) (P(St/AAm)-H) microspheres with different acrylamide contents were prepared by emulsifier-free emulsion polymerization. Thermus thermophilus holo-chaperonin (cpn) was covalently immobilized onto these microspheres with high yield. The T. thermophilus holo-cpn-immobilized microspheres were used for refolding of guanidine hydrochloride (Gdn-HCl)-denatured enzymes and showed sufficiently high ability to facilitate refolding of Leuconostoc mesenteroides glucose-6-phosphate dehydrogenase (G6PD) and pig heart lactate dehydrogenase (LDH) at 30 degrees C and Bacillus stearothermophilus LDH at 60 degrees C. The specific ability of T. thermophilus holo-cpn-immobilized microspheres increased with increasing immobilization amount and reached plateau at around 10-15 mg/m(2). When the immobilization amounts of T. thermophilus holo-cpn were approximately 10 mg/m(2), the microspheres retained sufficiently high ability to facilitate protein refolding during repeated use. Therefore, the P(St/AAm)-H microspheres on which approximately 10 mg/m(2) of T. thermophilus holo-cpn is immobilized are very effective for refolding of various (Gdn-HCl)-denatured enzymes over a wide temperature range.

Acrylic Resins↗
PubMed2000

In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: induction of tumor regression and potent antitumor immunity.

An alternative technology for the local and sustained delivery of cytokines to tumors for cancer immunotherapy was evaluated and shown here to induce tumor regression, suppression of metastasis, and development of systemic antitumor immunity. Treatment of tumor-bearing BALB/c mice with a single intratumoral injection of biodegradable polylactic acid microspheres loaded with recombinant interleukin-12 (IL-12) promoted complete regression of the primary tumor and prevented the metastatic spread to the lung. Mice that experienced tumor regression after being treated rejected a subsequent challenge with live tumor cells, which indicated the development of systemic antitumor immunity. In situ tumor vaccination, ie., injection of IL-12 microspheres into existing tumors, was superior to vaccination of mice with mixtures of tumor cells (live or irradiated) and IL-12 microspheres in inducing systemic antitumor immunity. The sustained release of IL-12 from the microspheres was superior to bolus injection of free IL-12, and intratumoral delivery of microspheres was more effective than other routes of administration. These studies establish the utility of biodegradable polymer microspheres as a clinically feasible alternative to systemic cytokine therapy and cytokine gene-modified cell vaccines for the treatment of neoplastic disease.

Absorbable Implants↗
PubMedDate not supplied

Controlled-release of doxorubicin from poly(lactide-co-glycolide) microspheres significantly enhances cytotoxicity against cultured AIDS-related Kaposi's sarcoma cells.

Subsequent to the introduction of highly active antiretroviral therapy (HAART), there has been a reduction in HIV viral titers and a concomitant decrease in AIDS-related Kaposi's sarcoma. However, as failure rates of HAART approach 30%, concerns arise regarding resurgence in AIDS-KS. Current AIDS-KS therapies fail to provide sustained remissions and yet also result in significant morbidity. Although partially effective, systemic chemotherapy is particularly debilitating to AIDS patients. In this report, we examined the co-incubation of AIDS-KS cells with doxorubicin which was slowly delivered from biodegradable, locally injectable, controlled-release poly(lactide-co-glycolide) (PLGA) microspheres. Local drug delivery systems such as PLGA microspheres can sustain therapeutic intralesional concentrations while minimizing deleterious systemic side effects, providing a pharmacologic advantage at the treatment site. Our data show that controlled release from PLGA microspheres augments doxorubicin cytotoxicity towards AIDS-KS cells without increasing toxicity in nonlesional cells from the AIDS-KS donors. Electron microscopic analysis revealed that PLGA microspheres possess a strong affinity for cell membranes, facilitating doxorubicin delivery to redox-sensitive cell membrane sites. Consistent with their speculated endothelial cell lineage, some of the AIDS-KS cells appeared to engulf microspheres via phagocytosis. Our results suggest that PLGA controlled-release doxorubicin microspheres have potential clinical applicability in management of AIDS-KS.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Acute effect of tetrandrine pulmonary targeting microspheres on hypoxic pulmonary hypertension in rats.

OBJECTIVE: To assess the effect of tetrandrine (Tet) pulmonary targeting microspheres on hypoxic pulmonary hypertension and evaluate its selective action on pulmonary circulation. METHODS: Twenty rats were exposed to hypoxic conditions for 3 weeks. Ten rats were used as normoxic controls. We administered Tet pulmonary targeting microspheres to 10 hypoxic rats and Tet aqueous solution to 10 hypoxic rats and the 10 control rats. Mean pulmonary arterial pressure (mPAP) was measured by a right cardiac catheterization, and mean systemic blood pressure (mSBP) was measured by left femoral catheterization. RESULTS: Rats exposed to hypoxia developed pulmonary hypertension. The decrease in mPAP in rats treated with Tet pulmonary targeting microspheres was significantly greater than that in rats receiving Tet aqueous solution (P < 0.05), and the effects were longer with Tet pulmonary targeting microspheres. Moreover, Tet pulmonary targeting microspheres, unlike Tet aqueous solution, did not decrease mSBP. CONCLUSION: Tet pulmonary targeting microspheres were more effective than Tet aqueous solution treating hypoxic pulmonary hypertension and acted selectively on the pulmonary circulation.

Alkaloids↗
PubMed1999

[Study of relative factors which influenced the embolic level of microspheres in the hamster lingual carcinoma].

OBJECTIVE: To study the relative factors which influence the embolic level of microspheres in the hamster lingual carcinoma. METHODS: Micropicture analysis instrument was used to measure the embolic level of microspheres which were poured through ascending aorta. RESULTS: The optimum pressure of embolization was 30 kPa. The embolic level approached to remote site of the lingual artery as tongue cancer developed. In early invasive cancer period, the embolic level of microspheres was at arteriole level where microspheres block "the total values" which controlled the tumor microcirculation. The optimum embolic result and less offshoot microcirculation were obtained at this time. When in later period, microspheres mainly embolized the meta-arteriole. As the microvessels dilated, the dose of microspheres must be increased to get the best embolic result. CONCLUSION: The experimental data for clinical choice of optimum pouring pressure, optimum opportunity and optimum cases.

Albumins↗
PubMed2002

[In vitro drug release profiles and mucoadhesive property of bioadhesive microspheres of metronidazole].

AIM: To prepare bioadhesive microspheres of metronidazole (Metro) with prolonging resident time in the stomach and sustaining drug release. METHODS: The microspheres were prepared by a drying-in-liquid method. The appearance, particle size and drug release in vitro were examined. The factors influencing bioadhesive property and drug release, such as ethyl cellulose (EC)/carbopol 934P (CP) ratio, particle size and Metro content were investigated. RESULTS: The average diameter of the Metro-EC-CP microspheres was 559.9 microns. The release profiles of metronidazole were shown to fit to first-order equations well. With the increase of CP content in the Metro-EC-CP microspheres, the microspheres showed better mucoadhesion and faster drug release. The drug release rate decreased with the increase of particle size and the decrease of Metro content. CONCLUSION: The Metro-EC-CP microspheres have a sound mucoadhsive property and sustained drug release when the ratio of EC and CP was 17:3 and Metro content was 25%. The drug release was shown to last for 8 h in 0.1 mol.L-1 hydrochloric acid.

Acrylates↗
PubMed2001

[The FTIR and DR-FTIR characterization of studies on the surface functionalization reactions of vinyl acetate-divinylbenzene copolymeric microspheres].

A series of vinyl acetate (VAc)-divinylbenzene (DVB) copolymeric microspheres were prepared by suspension copolymerization. The surface hydroxyl group onto the VAc-DVA copolymeric microspheres can be obtained by saponifiction reaction on their surface. By reaction between the reactive chorine group of a dye and the hydroxyl groups on the VAc-DVB copolymeric microspheres, cibacron blue F3G-A, as an affinity ligand, was covalently immobilized on the surface of the VAc-DVB copolymeric microspheres. The characterization of surface functionalizationed VAc-DVB copolymeric microspheres was studied by means of FTIR and diffuse reflectance FTIR spectroscopy. The results indicate that DR-FTIR spectra give out more detailed information of the modified microspheres' surface than FTIR spectra does.

Enzyme Inhibitors↗
PubMed1992

Poly (lactic/glycolic acid) microspheres containing antigen as a novel and potential agent of immunotherapy for allergic disorders.

In order to establish a safer and simpler antigen administration method in immunotherapy, we prepared biodegradable microspheres containing antigen and evaluated its safety and efficacy using guinea pigs. Poly (lactic/glycolic acid); (LGA) microspheres containing ovalbumin (OA) were fabricated by solvent evaporation. Over 70% of the OA was released from the microspheres within 3 days, and release was completed within 14 days in vivo. The local tissue reactions to the OA-LGA microspheres were apparently weaker than those to OA-alum. Repeated injections of high dose OA-LGA microspheres to OA-sensitized guinea pigs (high-LGA group) for 8 weeks at intervals of 2 weeks elicited an excellent therapeutic effect, i.e. a significant increase in the threshold value of antigen inhalation test, with a significant increase in IgG2 blocking antibody. The therapeutic efficacy of the high-LGA group was comparable to the conventional immunotherapy model (conventional group) and was superior to the antigen-alum model (alum group). We concluded that administration of antigen-LGA microspheres could become a new immunotherapeutic method for allergic disorders, being safer and requiring a lower frequency of antigen injections than the conventional method.

Animals↗
PubMed1992

Biodegradable microspheres containing adriamycin in the treatment of proliferative vitreoretinopathy.

The use of biodegradable polymer microspheres containing adriamycin for the treatment of proliferative vitreoretinopathy (PVR) in an experimental rabbit model was investigated. A single injection of microspheres containing 10 micrograms of adriamycin effectively decreased traction retinal detachment to 10% (n = 10), whereas 50% of eyes injected with blank microspheres (n = 10) developed retinal detachment (P < 0.05). A single injection of microspheres, containing 3 micrograms of adriamycin, did not suppress retinal detachment. Electroretinographic and histologic studies confirmed that the 10 micrograms injection of adriamycin in microspheres was not toxic to the retina, although the injection of the same amount of free adriamycin caused retinal necrosis and detachment. Thus, microspheres containing adriamycin hold promise as a new treatment modality for PVR.

Animals↗
PubMed1992

Injectable microspheres with controlled drug release for glaucoma filtering surgery.

The authors evaluated the effects of biodegradable poly (lactic acid) microspheres that provided the controlled release of the antimetabolic agent adriamycin (ADR) to prevent post surgical fibrosis after glaucoma filtering surgery. Fifty six eyes of 28 rabbits underwent posterior lip sclerotomy and received a 0.2 ml subconjunctival injection that contained microspheres 90 degrees from the filtering site immediately after surgery. Microspheres containing ADR (100 or 200 micrograms) were randomly administered to one eye. The fellow eyes served as controls and received microspheres without the drug. Intraocular pressure in the eyes treated with the microspheres that contained the drug was significantly lower than that in the control eyes from days 7-12 in the 100 micrograms group and from days 6-16 in the 200 micrograms group (P < .05). Eyes that received ADR had a significantly longer patent filtering bleb compared with the control eyes (P < .05). No corneal complications were observed in the eyes treated with 100 micrograms of ADR and the control eyes. Peripheral corneal opacities (25%) and epithelial erosion (17%) were observed in the eyes that received the 200 micrograms dose, but the cornea returned to normal after 4 wk. These results suggest that controlled-drug-release microspheres with an antimetabolic agent may be promising for preventing fibrosis after surgery.

Animals↗
PubMedDate not supplied

Preparation and in vitro transfection efficiency of chitosan microspheres containing plasmid DNA:poly(L-lysine) complexes.

PURPOSE: Studies on DNA complexes with cationic polymers are prompted by the search for nonviral DNA carriers for gene therapy. Among them, poly(L-Lysine) (PLL) has been extensively studied. On the other hand, these systems deliver DNA as a bolus without long-term release. The aims of this study were to encapsulate plasmid DNA:poly(L-lysine) (pDNA:PLL) complexes into chitosan microspheres as an alternative to the PLL based gene delivery and investigate its in vitro release and transfection characteristics as well as plasmid DNA integrity and stability against serum and DNase I challenge. METHODS: pUC18 plasmid DNA that encoded beta-galactosidase was used as a model. The microspheres were prepared by complex coacervation method and the release and in vitro transfection properties were investigated. pDNA:PLL complexes were prepared at two different mass ratios. In vitro release studies were performed at 37 +/- 0.5 degrees C and drug release was monitored both spectrophotometrically and fluorometrically. Structural integrity of the pDNA:PLL complexes were determined by Southern blotting analysis. Protective effect of encapsulation of pDNA:PLL complexes against DNase I and serum treatment were also studied. In vitro transfection studies were performed by using 3T3 cell line. RESULTS: According to our in vitro release data, the mass ratio of pDNA:PLL significantly affected the release of pDNA:PLL complexes from chitosan microspheres, and the structure of the plasmid DNA did not change during the experiments. pDNA:PLL-loaded chitosan microspheres indicated high stability against fetal bovine serum and DNase I treatment for a week. In vitro transfection data showed that pDNA:PLL-loaded chitosan microspheres could be effectively transfected 3T3 cells in vitro. CONCLUSION: As a conclusion, pDNA:PLL complexes could be encapsulated into chitosan microspheres with maintaining their structural and functional integrity and this system may be a good alternative for polycation based gene carriers.

3T3 Cells↗
PubMed2003

Influence of polymers weight ratio and pH of polymers solution on the characteristics of chitosan-carboxymethyl cellulose microspheres containing theophylline.

Optimization of formulation for chitosan-carboxymethyl cellulose (CH-CMC) microspheres that contain a drug of narrrow therapeutic index was the interest of this study. Theophylline (TPH) was chosen as a model drug. The effects of chitosan:sodium carboxymethyl cellulose (CH:SCMC) weight ratio (X1) and pH of polymers solution (X2) as independent variables on the physical characteristics of the microspheres as well as release profile of TPH from microspheres prepared by the emulsion coacervation-phase separation technique were studied. The influence of each of the two variables on responses such as angle of repose, compressibility index, incorporation efficiency particle size, initial drug release, time for 50% drug release (T50%) and % drug released in 8 hours was investigated. Generally, the increase in CH:SCMC weight ratio showed to increase the incorporation efficiency of the drug, increase the particle size and decrease the flowability of the microspheres. The increase of CH:SCMC ratio was also responsible to get low initial drug release, slow drug release (long T50%) and incomplete total drug released in 8 hours. On the other hand, high and low pHs of polymers solution were responsible to decrease drug incorporation in the microspheres and to produce small particles while, good flowability was obtained at pHs 2.5 and 4. A full factorial experimental design was employed to investigate the effect of the two independent variables on the responses. The results were analyzed by a general quadratic equation and response surfaces generated. From the obtained regression, it was concluded that the effect of CH:SCMC polymers ratio is more significant in changing the values of flowability particle size and drug release in 8 hours while pH values were more significant in changing the values of initial drug release and T50%. On the other hand the interaction coefficients of the two variables showed synergistic effect on flowability and drug release in 8 hours while, there were antagonist effects on particle sizes and T50%. From the optimization studies it is possible to choose the conditions required for the preparation of microspheres with the desired characteristics.

Bronchodilator Agents↗
PubMed2004

Radioactive microspheres in therapeutics.

Microspheres as a drug delivery system hold great promise in reaching the goal of controlled drug delivery as well as site specific delivery. In the last few decades, scientific and technological advancements have been made in the research and development of radiolabeled microspheres. These are used successfully for the treatment of various cancers and tumors. Since response to chemotherapy and external radiotherapy is not so effective and hazardous too, so an alternative to this is internal radiation therapy. These radiolabeled microspheres are very stable and have a proven efficacy in the field of primary as well as metastatic cancers. Radioactive microspheres can be selectively targeted to various tumors without undue radiation to the nontumorous tissues. The radioactive microspheres are injected to halt tumor growth via the blood supply, thereby enabling surgical removal once the tumor size decreases. This review provides an outlook to various aspects of radioactive microspheres and their role in treatment of various tumors and cancers.

Albumins↗
PubMed1992

Three-dimensional tumor dosimetry for hepatic yttrium-90-microsphere therapy.

The nonuniformity of dose deposition for hepatic 90Y-microsphere therapy is believed to play an important role in the relative sparing of normal liver tissues. To help study this issue, three-dimensional dose calculations have been performed for the VX2 tumor model in the rabbit treated with hepatic arterial administration of 90Y-glass microspheres (90Y-MS). Colored, nonactivated spheres of similar size to 90Y-MS were injected into the hepatic artery to mimic the treatment deposition of 90Y-MS. Sample blocks of treated liver were serially sectioned (200 microns thickness), fixed and photographed showing the position of the colored microspheres. The microsphere positions were digitized into a three-dimensional treatment planning system, and three-dimensional dose calculations were performed. A 2-mm diameter liver tumor nodule receiving 15 times more microspheres than nearby normal liver resulted in tumor-to-normal-tissue (TNT) calculated dose ratios of 2.6 (average dose) and 1.9 (minimum dose). The nonuniform microsphere distribution resulted in a dose gradient over the nodule with a minimum value which was less than one half the average dose. The relative dose deposition in the vicinity of the tumor nodule does not fully reconcile the known liver tolerance dose derived from uniform irradiation with the large calculated average doses tolerated with this type of therapy.

Animals↗
PubMed2005

Chitosan hydrochloride based microspheres of albendazole for colonic drug delivery.

Microspheres of chitosan hydrochloride (CH) were prepared in order to deliver albendazole specifically into the colon. Microspheres were prepared by an emulsion method using different ratios of drug and CH (1:1 to 1:5), agitation speeds (500 to 1500 rpm) and concentrations of glutaraldehyde in toluene as the cross-linking agent (0.25 to 1.0% w/v). The effect of polymer concentration, stirring rate and concentration of cross-linking agent on the particle size and drug loading was studied. With an increase in CH concentration, the average particle size was increased. Increased agitation speed reduced the size of the microspheres but higher agitation speed resulted in irregularly shaped microspheres. Increasing the concentration of cross-linking agent produced more regularly shaped microspheres of smaller size. The drug loading was highest at a drug: CH ratio of 1:3, stirring speed 1000 rpm and 0.75% w/v concentration of cross-linking agent. The effect of CH concentration on in vitro drug release from the microspheres was evaluated in simulated g.i.t fluids. A comparative in vitro drug release study of the optimized formulation was carried out in simulated colonic fluid, with and without 2% rat caecal content. The drug release in 24 h was 48.9% in colonic fluid without rat caecal content, and 76.5% in colonic fluid with rat caecal contents.

Albendazole↗
PubMed2005

[Photoluminescence spectra of trivalent neodymium doped TiBa glass microspheres].

In this work, TiBa glass microspheres doped with Nd3+ for morphology-dependent resonances of emission were designed and prepared. The emission spectra of TiBa glass plate and TiBa glass microspheres (45 and 13 microm in diameter) under 514 nm excitation were measured. The authors observed many regularly spaced, sharp peaks in the emission spectra of a Nd3+-doped glass microsphere. Based on the Mie scattering theory, the wavelength separation between the adjacent resonant peaks for the 45 microm sphere was calculated to be 3.0 for 810 nm. This value agrees well with the observed peak separation (3.1 nm), which indicates the contribution of the whispering gallery modes. The emission intensities of a Nd3+-doped TiBa glass microsphere (13 microm in diameter) in the 901.69 nm region were plotted against the excitation laser power. The emission intensities of the microsphere exhibit the linear dependence at the low excitation power (<2 mW). The 901.69 nm emission intensity of the microsphere steeply increases at the excitation power of 2 mW, which can be ascribed to the laser operation.

Glass↗
PubMed2005

Floating microspheres of cimetidine: formulation, characterization and in vitro evaluation.

The present study involves preparation and evaluation of floating microspheres with cimetidine as model drug for prolongation of gastric residence time. The microspheres were prepared by the solvent evaporation method using polymers hydroxypropylmethyl cellulose and ethyl cellulose. The shape and surface morphology of prepared microspheres were characterized by optical and scanning electron microscopy, respectively. In vitro drug release studies were performed and drug release kinetics was evaluated using the linear regression method. Effects of the stirring rate during preparation, polymer concentration, solvent composition and dissolution medium on the size of microspheres and drug release were also observed. The prepared microspheres exhibited prolonged drug release (approximately 8 h) and remained buoyant for > 10 h. The mean particle size increased and the drug release rate decreased at higher polymer concentration. No significant effect of the stirring rate during preparation on drug release was observed. In vitro studies demonstrated diffusion-controlled drug release from the microspheres.

Cimetidine↗
PubMed1991

Controlled release microspheres based on Eudragit L100 for the oral administration of erythromycin.

The use of Eudragit L100, a copolymer based on methacrylic acid and methacrylic acid methyl ester, in preparing erythromycin microspheres is described. The microspheres were simply prepared in liquid paraffin by solidifying an Eudragit L100 in ethanol solution. When gelatin was incorporated in the solidifying solution, the resultant microspheres were more spherical and had a smooth surface. The size of the microspheres could be controlled by varying the Eudragit L100 concentration in ethanol, and erythromycin was incorporated with 60-70% efficiency. The degradation of erythromycin by acid was markedly protected when the erythromycin microspheres were coated with the polymer. The in vitro release rate of erythromycin from the microspheres was also modified by the coating process. The feasibility of preparing formulations of erythromycin for oral administration, which release the drug at a controlled rate, and protect the drug from gastric acid, is thus demonstrated.

Acrylic Resins↗