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PubMed2007

Chitosan phthalate microspheres for oral delivery of insulin: preparation, characterization, and in vitro evaluation.

Chitosan phthalate polymer was synthesized and its microspheres were prepared by emulsion phase separation technique. The characterization of microspheres was determined by means of FTIR spectroscopy, electron microscopy, particle size, and zeta potential. The insulin was loaded to the microspheres by passive absorption technique. The peptic and tryptic enzymes degradation of insulin in microspheres was investigated. The in vitro release behavior of the microspheres was investigated under different pH conditions (pH 2.0 and pH 7.4). The degree of phthalate substitution in the synthesized polymer was 20%. The prepared microspheres were spherical with an average diameter 46.34 micro m. The insulin-loading capacity was 62%. Chitosan phthalate microspheres protect the insulin from gastric enzymes degradation that may enhance the oral stability of insulin. The encapsulated insulin was quickly released in a phosphate buffer saline (pH 7.4), whereas a small amount of insulin was released under acidic condition (0.1N HCl; pH 2.0) because under acidic conditions, carboxylic groups present in the system exist in nonionized form and are poorly hydrophilic. However, in alkaline conditions, it exists in ionized form and is considerably hydrophilic. The results suggest that chitosan phthalate microspheres may be used as a potential carrier for oral insulin delivery.

Administration, Oral↗
PubMed2001

Improved dissolution and cytotoxicity of camptothecin incorporated into oxidized-cellulose microspheres prepared by spray drying.

Oxidized celluloses (OC) containing 7, 13, and 20% carboxylic content (OC-7, OC-13, and OC-20, respectively) have been converted into aqueous colloidal dispersions and used to prepare microspheres of the antineoplastic agent camptothecin (CPT) by spray drying. Plasticizers used were glycerin, polyethylene glycol 400 (PEG-400), and polyethylene glycol 6000 (PEG-6000). Irrespective of the carboxyiic content of OC and the nature of plasticizer employed, the size of microspheres varied from 1.25+/-0.40 to 1.52+/-0.47 microm. The release studies in pH 7.4 buffer revealed the dissolution of CPT to be faster from the microsphere formulations than from physical mixtures and free CPT. The times to release 50% CPT (T-50%) from microspheres prepared using OC-7, OC-13, and OC-20 were about 31, 37, and 19 h, respectively. The in vitro cytotoxicity results indicated OC-20/CPT microspheres to be more effective than free CPT against human-derived RPMI-8402 lymphoid and THP-1 myeloid leukemia cell lines. The ED50 values for the OC-20/CPT microspheres and free CPT were 1 x 10(-5) and 0.25 x 10(-1) microg/mL, respectively, against the RPMI-8402 line and 0.5 x 10(-2) and 0.75 microg/mL, respectively, against the THP-1 line. The higher activity of OC-20/CPT microspheres compared to that of the free drug is attributed to increased dissolution of CPT from microspheres.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Porcine insulin biodegradable polyester microspheres: stability and in vitro release characteristics.

The stability of porcine insulin in biodegradable polymers, i.e., poly(DL-lactide-co-glycolide) 50:50 (50:50 DL-PLGA) and poly(L-lactide) (L-PLA) was investigated. Insulin encapsulated microspheres were fabricated from both polymers using double-emulsion-solvent evaporation and emulsion-solvent evaporation techniques and subjected to accelerated stability studies at 40 degrees C and 75% relative humidity. Porcine insulin was found to degrade in all microsphere formulations with an average of < 50% of the initial loading amount remaining intact at the end of 4 weeks. The two major degradation products observed in these formulations were determined to be A-21 desamido insulin and covalent insulin dimer with trace amounts of high molecular weight transformation products. In vitro release studies in phosphate buffered saline at 37 degrees C resulted in very slow and incomplete (< 30% in 30 days) release kinetics for all microsphere formulations. Extraction and analyses of the unreleased insulin within the microspheres revealed that an average of approximately 11% of the encapsulated insulin remained intact. The degradation products observed consisted of approximately 15% of three distinct deamidated hydrolysis products including A-21 desamido insulin, approximately 22% covalent insulin dimer, and trace amounts of high molecular weight transformation products. The degradation of porcine insulin within biodegradable polyester microspheres during stability and release studies can be attributed to the gradual decrease in the pH within the microspheres due to progressive polymer hydrolysis resulting in the production of DL-lactic and glycolic acids. The encapsulation of an acid-base indicator, bromophenol blue, in 50:50 PLGA microspheres (as a probe to estimate pH within the microspheres during accelerated stability studies) indicated that the pH decreased to approximately 3.8 after 3 weeks.

Animals↗
PubMed2004

Effect of process variables on particle size of gelatin microspheres containing lactic acid.

Gelatin microspheres containing lactic acid were prepared by a polymerization technique using glutaraldehyde as the cross-linking agent. Because particle size distribution of microspheres is a vital factor in the characterization of microspheres, the present study was carried out to evaluate the effect of process variables on the microspheres size distribution. It was found that concentration of a gelatin solution is the most important parameter that influences the particle size of microspheres. By using different concentrations of gelatin solution, microspheres with different size ranges were prepared. Both the stirring rate of the system and the volume ratio of aqueous and oil phases exerted a great influence on microsphere-size distribution, whereas, cross-linking time and cross-linker concentration only affected the yield. Lower-phase volume ratios resulted in small uniform microspheres with smooth surfaces and a narrow size range. The effect of emulsifier concentration (span 80), below 1% (w/w, with respect to the weight of the oil phase), on particle size was appreciable. However, at higher concentrations, little effect was observed.

Cross-Linking Reagents↗
PubMed2006

In situ regeneration of adipose tissue in rat fat pad by combining a collagen scaffold with gelatin microspheres containing basic fibroblast growth factor.

This study is an investigation to evaluate in situ adipose tissue regeneration in fat pads. Gelatin microspheres with different water contents were prepared for the controlled release of basic fibroblast growth factor (bFGF). After a collagen sponge scaffold was incorporated by the microspheres containing 0, 0.01, 0.1, 1, and 10 microg of bFGF with or without syngeneic rat preadipocytes (1 x 10(5) cells/site) into a defect of rat fat pad, adipogenesis at the implanted site of scaffold was evaluated histologically. in situ formation of adipose tissue accompanied with angiogenesis was observed in the scaffold implanted with the microspheres containing 1.0 microg of bFGF, although the extent was less at the lower and higher bFGF doses. The in situ formation induced by the microspheres containing bFGF was significantly higher than that induced by free bFGF of the same dose. Adipogenesis was enhanced with time after implantation up to 4 weeks and thereafter leveled off. Such in situ adipogenesis was reproducibly induced by implantation of collagen scaffold incorporating gelatin microspheres containing 1 microg of bFGF, whereas addition of rat syngeneic preadipocytes did not promote the adipogenesis. The degradation of microspheres and the consequent FGF release became faster with an increase in the water content of gelatin microspheres. Less in situ formation of adipose tissue was observed at the lower water content of microspheres, which showed longer-term bFGF release. We conclude that combination of scaffold collagen with an appropriate controlled release of bFGF was essential to achieve the in situ formation of adipose tissue even without preadipocytes.

Adipose Tissue↗
PubMed2004

Gentamicin-loaded microspheres for reducing the intracellular Brucella abortus load in infected monocytes.

OBJECTIVES: The intracellular antibiotic efficiency of gentamicin-loaded microspheres in the context of Brucella-infected murine monocytes was examined in vitro with a view to developing improved therapies for the treatment of brucellosis. METHODS: Biodegradable microspheres made of end-group capped and uncapped poly(lactide-co-glycolide) 50:50 (PLGA 50:50 and PLGA 50:50H) and containing gentamicin sulphate were used to target Brucella abortus-infected J774 monocyte-macrophages. The infected cells were treated with 15 micro g of free or microencapsulated gentamicin and the efficacy of the treatments was measured after 24 h. RESULTS: The particle sizes were below 8 micro m and in vitro release of gentamicin from the microspheres followed a continuous (PLGA 50:50H) or a multiphasic (PLGA 50:50) pattern over 50 days. Treatment with gentamicin microencapsulated into the end-group uncapped PLGA 50:50H microspheres, decreased significantly the number of intracellular bacteria (typically by 2 log(10)) in comparison with untreated infected cells. Addition of 2% poloxamer 188 to the microsphere dispersion medium further reduced the infection (3.5 log(10)). Opsonization of the particles with non-immune mouse serum had no effect on the antibacterial efficacy of the microspheres. End-group capped PLGA 50:50 type microspheres containing the antibiotic were less effective at reducing intracellular bacteria ( approximately 1 log(10) reduction), although addition of poloxamer 188 to the dispersion medium again enhanced their intracellular antibacterial activity. Placebo PLGA 50:50 and PLGA 50:50H microspheres had no bactericidal activity. CONCLUSIONS: The results indicate that PLGA 50:50-microencapsulated gentamicin sulphate may be suitable for efficient drug targeting and delivery to reduce intracellular Brucella infections.

Animals↗
PubMed1988

Distribution of embryos and 500-microM microspheres in the rabbit oviduct: controls for acute motion analysis during transport.

Distributions of embryos and 500-micron diameter microspheres were measured in the cleared oviducts of 32 rabbits at 8 intervals post coitus (pc) and normalized to percentage of isthmic length. By 18 h pc, 46% of the embryos had entered the isthmus and were denuded of the cumulus, while 55% of the microspheres had entered the isthmus. By 24 h pc, all embryos and microspheres were in the isthmus. At 72, 78, and 84 h pc, 6.5, 37, and 93% of embryos and 21, 73, and 95% of microspheres were in the cornu, respectively. The mean positions of embryos and microspheres progressed at approximately 1% of isthmic length per hour between 24 and 72 h pc. Throughout isthmic transport, embryos and microspheres in individual oviducts were tightly grouped and had similar statistical distributions. Although microspheres began to transfer into the uterine horns earlier than embryos, the data suggest that 500-micron microspheres can be used in studies to quantify discrete movements within the oviduct prior to 72 h pc. The data further suggest that opposing forces may be generated by contractile events that keep embryos grouped and possibly control their rate of progress through the oviduct.

Animals↗
PubMed1996

Prolonged regional nerve blockade. Injectable biodegradable bupivacaine/polyester microspheres.

BACKGROUND: Biodegradable microspheres are a useful method of drug delivery because they are both injectable and biodegradable, eliminating the need for surgical implantation or removal. Previous work has characterized implantable preparations of local anesthetics in polymer pellets for prolonged regional anesthesia. In this article, the authors characterize injectable suspensions of bupivacaine-polymer microspheres and examine whether they can produce prolonged blockade of the sciatic nerve in rats. METHODS: Microspheres were prepared using polylactic-co-glycolic acid polymers loaded with 75% w/w bupivacaine by a solvent evaporation method. Bupivacaine release from microspheres was determined in vitro by ultraviolet spectroscopy and scintillation counting. Sensory and motor blockade of the rat sciatic nerve were assessed in vivo after injection of microsphere suspensions. RESULTS: Depending on the type of microspheres, the dose, and the additive used, mean duration of sciatic nerve block ranged from 10 h to 5.5 days. Incorporation of 0.05% w/w dexamethasone into the microspheres resulted in significant prolongation of block (up to 13-fold), and only preparations that contained dexamethasone produced blocks lasting beyond 1 day. Bupivacaine was released in a controlled manner in vitro. Dexamethasone does not substantially slow bupivacaine release from microspheres in vitro. CONCLUSIONS: Prolonged percutaneous blockade of peripheral nerves is feasible. The recovery from blockade is complete, and plasma bupivacaine levels are far below the range associated with systemic toxicity. The mechanisms underlying the dexamethasone block-prolonging effect are under investigation.

Anesthetics, Local↗
PubMed2005

In vivo efficacy and toxicity of intratumorally delivered mitomycin C and its combination with doxorubicin using microsphere formulations.

The efficacy and toxicity of intratumorally (i.t.) administered anticancer drugs mitomycin C (MMC) and doxorubicin (Dox) incorporated in polymeric microspheres were investigated. Biodegradable sulfopropyl dextran microspheres and their oxidized products were used to load Dox and MMC, respectively. EMT6 mouse mammary cancer cells were injected into the hind leg of BALB/c mice. MMC microspheres, alone or combined with Dox microspheres, were injected i.t. once tumors had reached around 0.3 g. The tumor-plus-leg diameter was measured daily and the delay in time for the tumor to grow to 1.13 g relative to control (TGD) was employed as an indication of therapeutic effect. General toxicity was determined by monitoring weight, appearance and behavior of the mice. Morphology and histology of tumor and heart tissues were also examined. An average 79% TGD was observed after i.t. injection of MMC microspheres. The i.t. co-administration of MMC and Dox microspheres resulted in a 185% TGD. The i.t. injections of the microsphere formulations did not result in visible signs of toxicity in animals. In contrast, systemic (i.e. i.p.) injections of MMC solutions caused considerable general toxicity. This study suggests that i.t. delivery of anticancer drugs by polymeric microspheres is an effective way of improving the therapeutic index for cancer chemotherapy of selected solid tumors under special conditions.

Animals↗
PubMedDate not supplied

Cytokines delivered by biodegradable microspheres promote effective suppression of human tumors by human peripheral blood lymphocytes in the SCID-Winn model.

A new technology for the local and sustained delivery of immunostimulatory molecules to the tumor environment for cancer immunotherapy was evaluated. The ability of cytokines delivered by biodegradable microspheres to promote the antitumor activity of human peripheral blood lymphocytes (PBL) was tested in a human PBL, human tumor, and SCID mouse (SCID-Winn) model. Co-engraftment of human recombinant IL-12-loaded microspheres with human PBL and tumors in SCID mice promoted complete tumor suppression in as many as 100% of the mice, whereas microspheres loaded with polyethyleneglycol-interleukin-2 suppressed but did not eliminate the growth of tumor xenografts. Control microspheres (loaded with bovine serum albumin) in the presence of human PBL or cytokine-loaded microspheres in the absence of human PBL had no tumor-suppressive effect. Coincident with the enhancement of the human PBL-mediated antitumor activity in mice treated with IL-12-loaded microspheres was the production and release of human IFN-gamma indicating that IL-12 released from the microspheres results in the activation of the engrafted human PBL. The results establish that biodegradable microspheres represent an effective tool for the local and sustained delivery of cytokines to the tumor environment for cancer immunotherapy.

Adjuvants, Immunologic↗
PubMed2004

Effective treatment of osteomyelitis with biodegradable microspheres in a rabbit model.

Biodegradable microspheres were manufactured from a high molecular weight copolymer of 50% lactic and 50% glycolic acid and the antibiotic tobramycin. It was hypothesized that the microspheres would be more effective than polymethylmethacrylate beads in the local delivery of tobramycin and that the microspheres would not inhibit bone healing. Osteomyelitis was established in 40 New Zealand White rabbits using Staphylococcus aureus. All animals had irrigation and debridement of the infected radii four weeks after inoculation and were divided into five treatment groups: debridement alone, microspheres alone, microspheres containing tobramycin plus parenteral treatment with cefazolin, polymethylmethacrylate beads containing tobramycin plus parenteral cefazolin, and parenteral cefazolin. All animals were sacrificed after 4 weeks of treatment. The group treated with microspheres plus parenteral antibiotics was the only group to have a significantly higher percentage of animals without bacteria after 4 weeks of treatment when compared with the control group. Additionally, the animals treated with microspheres had a higher degree of bone healing in the defect than the animals treated with bone cement. The most effective treatment was biodegradable microspheres combined with parenteral antibiotic in this rabbit osteomyelitis model.

Animals↗
PubMed1988

Potentiation of antitumor activity of macrophages by recombinant interferon alpha A/D contained in gelatin microspheres.

Gelatin microspheres containing recombinant human interferon alpha A/D (A/D-IFN) (IFN-microspheres) potentiated the antitumor activity of mouse peritoneal macrophages (M phi) much more efficiently than free A/D-IFN. M phi acquired the inhibitory activity on tumor cell growth by the ingestion of IFN-microspheres without the aid of lipopolysaccharide (LPS), though LPS was required as a second signal for activating M phi primed with free IFN. The IFN-microspheres were much more efficient than free IFN plus LPS in respect of the IFN amount and the time required for M phi activation. Furthermore, M phi pretreated with the IFN-microspheres maintained their activated state for a much longer period than those pretreated with free A/D-IFN plus LPS. A monoclonal anti-IFN-alpha A antibody, which was capable of neutralizing A/D-IFN, did not interfere with the M phi activation by the IFN-microspheres. Even human IFN-alpha A was effective in activating murine M phi similarly to A/D-IFN, when given in the form of IFN-microspheres, though human IFN-alpha A in the free form was ineffective. These results argue that the mechanism of M phi activation by the IFN-microspheres is different from that by free IFN.

Animals↗
PubMed1989

In vivo effects of recombinant interferon alpha A/D incorporated in gelatin microspheres on murine tumor cell growth.

Intraperitoneal (ip) injections of gelatin microspheres containing a very small amount of recombinant human interferon alpha A/D (A/D-IFN) (IFN-microspheres) plus free A/D-IFN improved the survival of mice bearing ascitic Meth A-R1 cells which we had isolated as IFN-resistant cells under in vitro conditions. The dose of free A/D-IFN in one injection was 10,000 IU, which was insufficient by itself for manifesting in vivo antitumor activity. In these mice, in vivo R1 cell growth was suppressed and macrophage recruitment was enhanced in comparison with mice receiving other control agents. Administration of IFN-microspheres alone was also effective but less than that of IFN-microspheres plus free A/D-IFN. Peritoneal macrophages obtained from normal or R1-bearing mice receiving ip injection of IFN-microspheres with or without free A/D-IFN were activated to inhibit the in vitro growth of R1 cells. The intratumoral injection of IFN-microspheres strongly inhibited the growth of solid R1 tumors. Intravenous injection of IFN-microspheres was effective in preventing the pulmonary metastasis of B16 melanoma cells. These results indicate that the IFN-microsphere is much more effective against tumors than free A/D-IFN.

Animals↗
PubMedDate not supplied

The measurement of glomerular blood flow in the rat kidney: influence of microsphere size.

1. Radioactively labelled microspheres were used to determine glomerular blood flow in glomerular populations with distinct vascular characteristics. Two batches of microspheres (15 +/- 5.0 micrometer diameter and 7.0--10 micrometer diameter) were utilized. 2. The results show that the larger microspheres overestimate the superficial glomerular blood flow (414 +/- 61 nl/min, mean +/- s.e.m.) and underestimate the deep glomerular blood flow (98 +/- 10 nl/min), when compared with the data obtained with 7.0--10 micrometer diameter microspheres (317 +/- 30 nl/min and 209 +/- 23 nl/min, respectively). 3. The rheological artefact associated with the use of larger microspheres is confirmed by finding an uneven size distribution of microspheres lodged in the glomeruli. In each of three experiments, the mean diameter of 200 microspheres lodged in the superficial glomeruli (16.43 +/- 0.27 micrometer, 15.87 +/- 0.23 micrometer and 16.58 +/- 0.27 micrometer) was significantly greater than that found in the deep glomeruli (15.36 +/- 0.15 micrometer, 15.25 +/- 0.21 micrometer and 15.73 +/- 0.24 micrometer; P less than 0.01, less than 0.05 and less than 0.01, respectively). No such difference was detected when the 7.0--10 micrometer spheres were used. 4. Glomerular blood flow can be measured at all depths of the rat's cortex and the demonstrated rheological artefact associated with use of the larger spheres is circumvented with the use of 7.0--10 micrometer microspheres.

Animals↗
PubMed1998

Mucoadhesive microspheres containing amoxicillin for clearance of Helicobacter pylori.

In an effort to augment the anti-Helicobacter pylori effect of amoxicillin, mucoadhesive microspheres, which have the ability to reside in the gastrointestinal tract for an extended period, were prepared. The microspheres contained the antimicrobial agent and an adhesive polymer (carboxyvinyl polymer) powder dispersed in waxy hydrogenated castor oil. The percentage of amoxicillin remaining in the stomach both 2 and 4 h after oral administration of the mucoadhesive microspheres to Mongolian gerbils under fed conditions was about three times higher than that after administration in the form of a 0.5% methylcellulose suspension. The in vivo clearance of H. pylori following oral administration of the mucoadhesive microspheres and the 0.5% methylcellulose suspension to infected Mongolian gerbils was examined under fed conditions. The mucoadhesive microspheres and the 0.5% methylcellulose suspension both showed anti-H. pylori effects in this experimental model of infection, but the required dose of amoxicillin was effectively reduced by a factor of 10 when the mucoadhesive microspheres were used. In conclusion, the mucoadhesive microspheres more effectively cleared H. pylori from the gastrointestinal tract than the 0.5% methylcellulose suspension due to the prolonged gastrointestinal residence time resulting from mucoadhesion. A dosage form consisting of mucoadhesive microspheres containing an appropriate antimicrobial agent should be useful for the eradication of H. pylori.

Amoxicillin↗
PubMed2001

Treatment of tuberculosis using a combination of sustained-release rifampin-loaded microspheres and oral dosing with isoniazid.

Previously, we reported on the use of rifampin-loaded microspheres to effectively treat Mycobacterium tuberculosis-infected macrophages and mice. Using similar biocompatible polymeric excipients of lactide and glycolide copolymers, we have increased the rifampin loading of small microsphere formulations (1 to 10 microm) by fourfold. Improved formulations were evaluated individually and in combination with oral regimens of isoniazid for the treatment of Mycobacterium tuberculosis H37Rv-infected mice. Groups (10 mice per group) consisted of mice that received (i) oral dosages of isoniazid (25 to 0.19 mg/kg of body weight/day), (ii) two intraperitoneal injections of rifampin-loaded microspheres on days 0 and 7, (iii) a combination of small rifampin-loaded microspheres on days 0 and 7 and isoniazid orally for 25 days (12.5 to 0.39 mg/kg/day), (iv) placebo injections, and (v) no treatment. Treatment with rifampin-loaded microspheres alone resulted in significant reductions in the numbers of CFU in the lungs and spleens by day 26. A bioassay revealed that plasma rifampin levels from the microspheres exceeded the MICs by more than twofold throughout the 26-day experimental period. Susceptibility testing demonstrated continued sensitivity to rifampin during the treatment period. Whereas isoniazid alone significantly reduced the numbers of CFU for dosages ranging from 12.5 to 1.56 mg/kg, combination therapy with rifampin-loaded microspheres increased the effective range to 0.39 mg/kg. In many cases, complete elimination of CFU was obtained with the combination therapy, something not achieved with most of the single therapies. These results demonstrate the ability to use small microsphere formulations alone to achieve significant results in a murine tuberculosis model and also the ability to use them safely in combination with another antimycobacterial agent.

Administration, Oral↗
PubMed2004

Treatment of experimental visceral leishmaniasis with amphotericin B in stable albumin microspheres.

Hydrophilic albumin microspheres are proposed as a new delivery system for amphotericin B (AMB; AMB microspheres). The acute toxicity of AMB microspheres was lower than that of the AMB-deoxycholate (AMB-Doc) reference formulation in hamsters. Lethal doses in healthy and infected animals were improved at least eight times. Intravenous bolus administration of doses of AMB microspheres up to 40 mg/kg of body weight did not produce acute symptoms of toxicity. The efficacy of this new formulation was tested against Leishmania infantum-infected hamsters at doses of 2, 10, 20, and 40 mg/kg. With the 2-mg/kg dose, the activity of AMB, as assessed through the parasite load reductions in the liver and spleen and the evolution of antibody levels, was also improved (P < 0.05) by use of the AMB microsphere system. At the higher doses of 10, 20, and 40 mg/kg, reductions in parasite levels of more than 99% were achieved in the liver and spleen after the administration of AMB microspheres. A pharmacokinetic study was performed to study the serum, liver, and spleen AMB concentrations after administration of AMB microspheres and the reference formulation. Interestingly, a significant accumulation of AMB in the spleen and liver was observed after AMB microsphere administration. Our results suggest that this new formulation is a promising alternative to the conventional AMB-Doc formulation for the treatment of visceral leishmaniasis.

Amphotericin B↗
PubMed1997

Protective immunity against Salmonella typhimurium elicited in mice by oral vaccination with phosphorylcholine encapsulated in poly(DL-lactide-co-glycolide) microspheres.

Encapsulation of vaccines in biodegradable microspheres provides excellent mucosal immunogens with a high potential for immunization against bacterial infections. We tested the protective immunity elicited by intragastric vaccination with phosphorylcholine (PC) encapsulated in poly(DL-lactide-co-glycolide) (DL-PLG) microspheres against Salmonella typhimurium in a mouse model of invasive intestinal infection. We chose PC as the antigen because it was found to elicit an immune response after intestinal exposure of mice to PC-bearing S. typhimurium and because anti-PC immunity protects mice against Streptococcus pneumoniae, another PC-bearing microorganism. Mice were primed intragastrically on days 1, 2, and 3 and boosted on days 28, 29, and 30 with PC (280 microg) coupled to porcine thyroglobulin (PC-thyr) encapsulated in DL-PLG microspheres, free PC-thyr, or blank microspheres. A significant rise in anti-PC immunoglobulin A (IgA) titers, as measured by an enzyme-linked immunosorbent assay, was observed in the intestinal secretions after immunization with PC-loaded microspheres, compared to the titers of mice immunized with free PC-thyr or blank microspheres. This antibody response peaked 14 days after the last boost and correlated with a highly significant resistance to oral challenge by S. typhimurium C5 (P < 10(-3)). Control mice were primed intraperitoneally on day 1 with 15 microg of PC in complete Freund's adjuvant and boosted on days 10, 14, and 20 with the same dose without adjuvant but via the same route. In these mice, the levels of anti-PC IgA in intestinal secretions were equivalent to those of the mice intragastrically immunized with PC-loaded microspheres, but protection was significantly weaker, suggesting that either the IgAs were not functional or that other immune mechanisms are important in protection. Taken together, our results highlight the potential of antigen encapsulation in DL-PLG microspheres for eliciting protective immunity against invasive intestinal bacterial diseases and suggest that a similar strategy could be used against diseases caused by other PC-bearing microorganisms.

Administration, Oral↗