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PubMed2006

Nanoparticles in inflammatory bowel disease: particle targeting versus pH-sensitive delivery.

Tacrolimus proved its distinct mitigating potential in the treatment of inflammatory bowel disease (IBD). Due to the risk for severe adverse effects and to achieve increased efficiency and tolerability, a selective delivery to the site of inflammation is of interest. Tacrolimus nanoparticles (NP) were tested for their efficiency in local treatment of inflamed bowel tissue in IBD. Drug loaded NP were prepared from either biodegradable poly(lactide-co-glycolide) (PLGA) or pH-sensitive Eudragit P-4135F by using a simple oil/water emulsification method. Tests on the therapeutic effect were conducted using dextran sulfate model colitis in mice receiving tacrolimus formulations daily for 12 days. Clinical activity score and myeloperoxidase activity decreased while colon length increased significantly after administration of all tacrolimus containing formulations. Oral NP formulations were less efficient in mitigating the experimental colitis compared to subcutaneous drug solution (PLGA: 7.88 +/- 0.83; P-4135F: 7.48 +/- 0.42; subcutaneous: 5.27 +/- 0.68 U/mg) but superior to drug solution given by oral route (oral: 8.75 +/- 1.34; untreated colitis control: 9.95 +/- 0.92, all U/mg tissue). Tacrolimus solution groups (oral/subcutaneous) exhibited increased levels of adverse effects, whereas both NP groups demonstrated their potential to reduce nephrotoxicity. Both strategies showed similar mitigating effects while nephrotoxic adverse effects were slightly less expressed with pH-sensitive NP.

Administration, Oral↗
PubMed2005

In vitro and in vivo characterization of a novel biocompatible polymer-lipid implant system for the sustained delivery of paclitaxel.

Recently, a novel chitosan-based implantable formulation (chitosan-ePC) was developed to provide controlled, local release of paclitaxel (PTX) for the treatment of ovarian tumors. Hence, the objective of this study was to evaluate this delivery system in vitro in human ovarian SKOV-3 cells and in vivo in mice with intraperitoneal implants of drug-free or 14C-PTX-chitosan-ePC films. In vitro, 14C-PTX-chitosan-ePC implants (10 mg) provided zero-order constant release of 0.92+/-0.03 pg/day PTX over 5 days. Released PTX retained dose-dependent activity; effectively inhibiting SKOV-3 proliferation with an ED50 of 211 ng/ml of released PTX. Drug-free implants did not affect cell viability or cell morphology of SKOV-3 cells. A sustained, zero-order release of PTX was also seen in vivo over a 2 week period in mice implanted with 14C-PTX-chitosan-ePC films. Correlations between the in vitro and in vivo release of PTX was highly significant (R2 = 0.975). After 2-4 weeks, mice with chitosan-ePC implants did not demonstrate any signs of encapsulation, inflammation or infection. Overall, our in vitro and in vivo results demonstrated zero-order drug release and biocompatibility of the novel chitosan-ePC film. This indicates potential usefulness of chitosan-ePC implants in the sustained and local delivery of anti-neoplastic agents.

Animals↗
PubMed1996

Targeting to intestinal M cells.

The specialised, antigen-transporting, epithelial M cells in the follicle-associated epithelium (FAE) overlying gut-associated lymphoid tissues constitute the primary target for oral delivery of vaccines. Our studies have shown that polystyrene microspheres selectively bind to, and are efficiently transcytosed by, rabbit Peyer's patch M cells in closed intestinal loops. Binding of biodegradable poly(DL-lactide-co-glycolide) microspheres to rabbit Peyer's patch FAE is an order of magnitude lower than that of polystyrene microspheres. Although poly(DL-lactide-co-glycolide) microspheres are not selectively targeted to M cells, a high proportion of those which bind to M cells are transcytosed, supporting the potential of such microspheres as vehicles for oral vaccine delivery. Comparison of the binding of polystyrene microspheres by murine FAE revealed this to be markedly less extensive than by rabbit FAE. These data demonstrate that microsphere binding by M cells depends on the surface properties of both cells and microspheres and suggest that surface modification may enhance the efficacy of microsphere delivery vehicles. One such approach is the incorporation of molecules with inherent binding specificity for M cells. Lectin-binding studies have revealed that M cells exhibit pronounced regional and species variation in glycoconjugate expression. In murine intestine, certain lectins bind selectively to M cells either in Peyer's patches or caecum, or at both sites. Selective targeting to, and transcytosis of, lectin-conjugates by M cells in ligated segments of murine intestine have also been demonstrated. While several lectins display strong selectivity for rabbit caecal M cells, none to date have been identified with specificity for rabbit or rat Peyer's patch M cells. Knowledge of human M cells is limited and no lectin has yet been identified with specificity for these cells. However, at least one lectin exhibits binding specificity for FAE in the human ileum. In the future, knowledge of the regional patterns of M cell carbohydrate expression within a species may allow lectins to be utilised to target selectively antigenic material to the mucosal immune system at specific locations.

Administration, Oral↗
PubMed2005

Drug transport to brain with targeted nanoparticles.

Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50-300 nm generally). They cannot freely diffuse through the blood-brain barrier (BBB) and require receptor-mediated transport through brain capillary endothelium to deliver their content into the brain parenchyma. Polysorbate 80-coated polybutylcyanoacrylate nanoparticles can deliver drugs to the brain by a still debated mechanism. Despite interesting results these nanoparticles have limitations, discussed in this review, that may preclude, or at least limit, their potential clinical applications. Long-circulating nanoparticles made of methoxypoly(ethylene glycol)- polylactide or poly(lactide-co-glycolide) (mPEG-PLA/PLGA) have a good safety profiles and provide drug-sustained release. The availability of functionalized PEG-PLA permits to prepare target-specific nanoparticles by conjugation of cell surface ligand. Using peptidomimetic antibodies to BBB transcytosis receptor, brain-targeted pegylated immunonanoparticles can now be synthesized that should make possible the delivery of entrapped actives into the brain parenchyma without inducing BBB permeability alteration. This review presents their general properties (structure, loading capacity, pharmacokinetics) and currently available methods for immunonanoparticle preparation.

Animals↗
PubMed2006

Synthesis and characterization of the biodegradable polycaprolactone-graft-chitosan amphiphilic copolymers.

A novel synthetic approach to biodegradable amphiphilic copolymers based on poly (epsilon-caprolactone) (PCL) and chitosan was presented, and the prepared copolymers were used to prepare nanoparticles successfully. The PCL-graft-chitosan copolymers were synthesized by coupling the hydroxyl end-groups on preformed PCL chains and the amino groups present on 6-O-triphenylmethyl chitosan and by removing the protective 6-O-triphenylmethyl groups in acidic aqueous solution. The PCL content in the copolymers can be controlled in the range of 10-90 wt %. The graft copolymers were thoroughly characterized by 1H NMR, 13C NMR, FT-IR and DSC. The nanoparticles made from the graft copolymers were investigated by 1H NMR, DLS, AFM and SEM measurements. It was found that the copolymers could form spherical or elliptic nanoparticles in water. The amount of available primary amines on the surface of the prepared nanoparticles was evaluated by ninhydrin assay, and it can be controlled by the grafting degree of PCL.

Biocompatible Materials↗
PubMed2000

Restoration of segmental bone defects in rabbit radius by biodegradable capsules containing recombinant human bone morphogenetic protein-2.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) was encapsulated in biodegradable poly(DL-lactide-co-glycolide) (PLGA) capsules to regenerate bone by controlling the release rate of rhBMP-2. The rhBMP-2/PLGA capsules containing 12 microg of rhBMP-2 were implanted in seven 15-mm segmental defects of rabbits radii to examine the healing capacity of the rhBMP-2/PLGA capsules. For the control group, four segmental defects were left empty and two were implanted with ghost PLGA capsules. Healing of the defects was followed for 24 weeks and periodically evaluated by radiographs and histological examination. Mechanical testing was applied to three regenerated bone samples at 24 weeks postoperatively when the mature cortex was observed. Mechanical properties of regenerated bone were not significantly different from normal intact bone statistically. Histologically, the rhBMP-2/PLGA capsules disappeared completely during the process of bone regeneration. These results increased possibilities for clinical application of rhBMP-2/PLGA capsules.

Animals↗
PubMed2002

Long-circulating poly(ethylene glycol)-modified gelatin nanoparticles for intracellular delivery.

PURPOSE: The objective of this study was to develop and characterize long-circulating, biodegradable, and biocompatible nanoparticulate formulation as an intracellular delivery vehicle. METHODS: Poly(ethylene glycol) (PEG)-modified gelatin was synthesized by reacting Type-B gelatin with PEG-epoxide. The nanoparticles, prepared by pH and temperature controlled ethanol-water solvent displacement technique, were characterized for mean size, size distribution, and surface morphology. Electron spectroscopy for chemical analysis (ESCA) was used to confirm the surface presence of PEG chains. In vitro release of tetramethylrhodamine-labeled dextran (TMR-dextran, Mol. wt. 10,000 daltons) from the nanoparticle formulations was examined in PBS, with and without 0.2-mg/ml protease, at 37 degrees C. Relative cytotoxicity profile of control and PEGylated gelatin was evaluated in BT-20 a human breast cancer cell line. The nanoparticles were incubated with BT-20 cells to determine uptake and cellular distribution using confocal microscopy. RESULTS: Gelatin and PEGylated gelatin nanoparticles were found to be spherical in shape with a smooth surface in a size range of 200-500 nm and a unimodal size distribution. ESCA results showed an increase in the ether carbon (-C-O-) peak in the PEGylated gelatin nanoparticles due to the presence of PEG chains. The presence of PEG chains decreased the percent release of TMR-dextran in the presence of proteolytic enzyme due to steric repulsion. Cytotoxicity assays indicated that both gelatin and PEGylated gelatin were completely non-toxic to the cells. A large fraction of the administered control gelatin and PEGylated gelatin nanoparticles were found to be concentrated in the perinuclear region of the BT-20 cells after 12 hours indicating possible vesicular transport through initial uptake by endocytosis and endosomal processing. CONCLUSION: The results of this study show that PEGylation of gelatin may prove beneficial as long-circulating delivery system in vivo. Additionally, the nanoparticles could encapsulate hydrophilic macromolecules and are internalized by tumor cells.

Delayed-Action Preparations↗
PubMed1995

Novel PDLLA/PEG copolymer micelles as drug carriers.

In this study we attempted to develop a novel drug delivery system in the form of polymeric micelles. In order to obtain polymer chains with micelle forming abilities, we have proposed to produce copolymers by transesterification of poly(DL-lactic acid)(PDLLA)(as the hydrophobic segment) and polyethylene glycol (PEG) (as the hydrophilic segment). We first produced homopolymers of PDLLA with low molecular weights by condensation polymerization of DL-lactic acid. The PDLLA homopolymer with an average molecular weight of 1866 +/- 100 was then transesterified with PEG with a molecular weight range of 3300-4000. By changing the ratio of PEG to PDLLA, we were able to produce copolymers with different chain structures, and therefore, with different micelle forming abilities. FTIR, 1H-NMR, DSC, and GPC studies were performed to describe the structures of these PDLLA/PEG copolymers. Micelles of these copolymers were characterized by light scattering. We selected a model drug, i.e. adriamycin, and obtained the drug loadings to the PDLLA/PEG copolymer micelles. The maximum drug loading was about 12 mg g-1. We found that these micelles were degraded in phosphate buffer (pH 7.4 and temperature 37 degrees C) in about 5-6 weeks. We also investigated the release of adriamycin from these PDLLA/PEG micelles, and concluded that the drug release from these micelles was mainly 'degradation controlled'.

Biodegradation, Environmental↗
PubMed2002

In vivo biocompatibility and degradability of a novel injectable-chitosan-based implant.

A novel injectable-chitosan-based delivery system with low cytotoxicity was fabricated in the study. The chitosan microspheres with small particle size, low crystallinity and good sphericity were prepared by a spray-drying method followed by treating with a crosslinker. In the study, a naturally occurring crosslinking reagent (genipin), which has been used in herbal medicine and in the production of food dyes, was used to crosslink the chitosan microspheres. The glutaraldehyde-crosslinked counterparts were used as a control. Histological study of the genipin-crosslinked chitosan microspheres injected intramuscularly into the skeletal muscle of a rat model showed a less inflammatory reaction than its glutaraldehyde-crosslinked counterparts. The results of the scanning electron microscopic examination indicated that the glutaraldehyde-crosslinked chitosan microspheres retrieved at 12-week postoperatively were already degraded into a loose and porous structure. However, the degradation of the genipin-crosslinked chitosan microspheres was not significant after 20 weeks of implantation. The results of the study demonstrated that the genipin-crosslinked chitosan microspheres have a superior biocompatibility and a slower degradation rate than the glutaraldehyde-crosslinked chitosan microspheres. Accordingly, the genipin-crosslinked chitosan microspheres may be a suitable polymeric carrier for long-acting injectable drug delivery.

Animals↗
PubMed1999

Microparticles of novel branched copolymers of lactic acid and amino acids: preparation and characterization.

The preparation and characterization of microparticles produced from a new class of functionalized, biodegradable, comblike graft copolymers is presented. The copolymers are polyester-polyamino acid hybrids, composed of a poly(L-lactic acid-co-L-lysine) (PLAL) backbone, and poly(L-lysine), poly(D,L-alanine) or poly(L-aspartic acid) side chains extending from the lysine residues of PLAL. The microparticles have been characterized with regard to their surface properties, morphology, and size. Thus, electron spectroscopy for chemical analysis data and results of Zeta potential measurements suggest that the polyamino acid side chains tend to concentrate at the surface of the particles. Also, analyses by environmental scanning electron microscopy and confocal scanning laser microscopy indicate that particles carrying poly(lysine) chains have an unusual porous structure, most probably due to the combined effects of the amphiphilic, polyelectrolyte, and chemical nature of the composing copolymer, as well as of the particular preparation technique employed. The capabilities of the microparticles to serve as carriers in controlled drug release and delivery devices were demonstrated by encapsulation and release of rhodamine B, a low molecular weight drug model.

Aerosols↗
PubMed1998

Efficacy and pharmacokinetics of site-specific cefazolin delivery using biodegradable implants in the prevention of post-operative wound infections.

PURPOSE: The study objective was to evaluate the efficacy and pharmacokinetics of cefazolin delivered locally as a glyceryl monostearate (GMS) based biocompatible implant for prevention of post-operative wound infection in Sprague Dawley rats subcutaneously inoculated with Staphylococcus aureus. METHODS: For the efficacy and pharmacokinetic studies, 18 rats were subcutaneously inoculated with 4.5 x 10(7) CFU of S. aureus on the dorsum (6 per rat), and randomly assigned into three group of 6 rats each: (1) the control group, in which rats did not receive antibiotics, (2) the intermittent i.m. treatment group, in which rats received i.m. injections of 10 mg/kg cefazolin every 4 hr (total of 180 mg/kg in 3 days), and (3) the implant treatment group, in which rats were implanted subcutaneously with four Cefazolin-GMS implants in the vicinity of the inoculations. The implants were designed to deliver 180 mg/kg cefazolin over a 3 day period. For efficacy evaluation, the rats were euthanized one week post-inoculation and abscess count, weight and size were determined. RESULTS: Rats in the control group had developed 21 abscesses out of the 36 inoculations, indicating validity of the infection model. The local delivery of cefazolin resulted in complete eradication of the infection, since no abscesses formed in the rats in the implant group. In the IM treatment group, only one abscess was formed and no significant difference in efficacy between the two treatment groups was observed. The GMS implants sustained the release of cefazolin for a period of three days with only 3-fold fluctuations in plasma concentration (5.5-17.5 micrograms/ml). However, plasma concentrations after the intermittent IM administration of cefazolin fluctuated 110-fold between 44-0.4 micrograms/ml every 4 hr. The release rate of cefazolin from the implants was nearly zero order for the entire duration. Bioerosion of the implants was determined by examining the condition of the implants six weeks post-implantation. Two of the 12 implants had completely disappeared and the remaining implants were in a pasty form and had lost 20-80% of their weight. Absence of irritation or inflammation around the implants indicated biocompatibility of the GMS implants. CONCLUSIONS: Implantable system that provided a prolonged delivery of cefazolin was found to be effective against S. aureus infection, and demonstrated suitable pharmacokinetics and biocompatibility with significant bioerosion.

Animals↗
PubMed2002

Preparation, characterization and in vitro release of gentamicin from coralline hydroxyapatite-gelatin composite microspheres.

Composite microspheres have been prepared from bioactive ceramics such as coralline hydroxyapatite [CHA, Ca10(PO4)6(OH)2] granules, a biodegradable polymer, gelatin and an antibiotic, gentamicin. In our earlier work, we have shown a gentamicin release from CHA granules--chitosan composite microspheres. In the present investigation, an attempt was made to prepare the composite microspheres containing coralline hydroxyapatite and gelatin (CHA-G), which were prepared by the dispersion polymerization technique and the gentamicin was incorporated by the absorption method. The crystal structure of the composite microspheres was analyzed using X-ray powder diffractometer. The Fourier transformed infrared spectrum clearly indicated the presence of amide and hydroxyl groups in the composite microspheres. Scanning electron micrographs and optical micrographs show that the composite microspheres are spherical in shape and porous in nature. The particle size of composite microspheres was analyzed and the average size was found to be 16 microm. The thermal behavior of composite microspheres was studied using thermogravimetric analysis and differential scanning calorimetric analysis. The cumulative in vitro release profile of gentamicin from composite microspheres showed near zero order patterns.

Biocompatible Materials↗
PubMed2002

Biodegradable poly(ethylenimine) for plasmid DNA delivery.

Poly(ethylenimine) (PEI) has been known as an efficient gene carrier with the highest cationic charge potential. High transfection efficiency of PEI, along with its cytotoxicity, strongly depends on the molecular weight. Synthesis of cationic copolymers derived from the low molecular weight of PEI and hydrophilic poly(ethylene glycol) (PEG), which are water soluble and degradable under physiological conditions, was investigated for plasmid delivery. Hydrophilic PEG is expected to reduce the toxicity of the copolymer, improve the poor solubility of the PEI and DNA complexes, and help to introduce degradable bonds by reaction with the primary amines in the PEI. Considering the dependence of transfection efficiency and cytotoxicity on the molecular weight of the PEI, high transfection efficiency is expected from an increased molecular weight of the copolymer and low cytotoxicity from the introduction of PEG and the degradation of the copolymer into low molecular weight PEIs. Reaction conditions were carefully controlled to produce water soluble copolymers. Results from a gel retardation assay and zetapotentiometer indicated that complete neutralization of the complexes was achieved at the charge ratios of copolymer/pSV-beta-gal plasmid from 0.8 to 1.0 with the mean particle size of the polyplexes ranging from 129.8+/-0.9 to 151.8+/-3.4 nm. In vitro transfection efficiency of the synthesized copolymer increased up to three times higher than that of starting low molecular weight PEI, while the cell viability was maintained over 80%.

Cell Line↗
PubMed2005

Enhanced adhesion of ligand-conjugated biodegradable particles to colitic venules.

The expression of certain endothelial cell adhesion molecules (ECAMs) is increased in the vasculature of the inflamed bowel (e.g., colitis), thereby providing an opportunity for targeted drug delivery. We recently demonstrated that biodegradable particles conjugated with ligands to ECAMs exhibit significant selective adhesion to ECAM expressing endothelium. In the present study, we used a murine model of colitis to determine whether poly(lactic acid)-poly(ethylene glycol) particles conjugated with a VCAM-1 ligand (alpha-V) exhibit enhanced adhesion to colitic vasculature. In post-capillary venules of the colon, significantly more alpha-V particles accumulate in colitic mice relative to (i) control mice (i.e., selectivity) and (ii) particles bearing a control ligand (i.e., ligand efficiency). The selectivity and ligand efficiency of alpha-V particles were a function of the total number of particles infused. The highest selectivity observed within our test regime was 3, while ligand efficiency increased linearly with the number of particles injected to a value of 24. This work represents a significant step towards achieving a targeted drug delivery scheme for the treatment of inflammatory bowel disease and indicates that the efficiency of targeting is dependent on the dose regime.

Animals↗
PubMed2006

Osmotic-driven release kinetics of bioactive therapeutic proteins from a biodegradable elastomer are linear, constant, similar, and adjustable.

PURPOSE: The aim of the study is to determine whether a biodegradable elastomeric device that uses an osmotic pressure delivery mechanism can release different therapeutic proteins at a nearly constant rate in nanomolar concentrations with high bioactivity, given the same formulation conditions. Vascular endothelial growth factor (VEGF) and interleukin-2 (IL-2) were embedded in the device as sample therapeutic proteins, and their release and bioactivity were compared to that achieved previously with interferon-gamma (IFN-gamma). METHODS: A photo-cross-linkable biodegradable macromer consisting of acrylated star(epsilon-caprolactone-co-D,L-lactide) was prepared. VEGF, IL-2, and IFN-gamma were co-lyophilized with serum albumin and trehalose at different ratios and were then embedded into the elastomer by photo-cross-linking the lyophilized particles in a macromer solution. The protein mass and the bioactivity in the release supernatant were measured by enzyme-linked immunosorbent and cell-based assays. RESULTS: VEGF, IL-2, and IFN-gamma were released at the same, nearly constant rate of 25.4 ng/day for over 18 days. Using the optimum elastomer formulation, the release profiles of the proteins were essentially identical, and their rates were linear and constant. Cell-based bioactivity assays showed that 70 and 88% of the released VEGF and IL-2, respectively, were bioactive. The rate of protein release can be adjusted by changing the trehalose loading concentration in the elastomer matrix without altering the linear nature of the protein release kinetics. The elastomeric device degraded in PBS buffer within 85 days. CONCLUSIONS: The elastomer formulation shows promising potential as a sustained protein drug delivery vehicle for local delivery applications.

Cells, Cultured↗
PubMed2004

Effect of lactide/glycolide monomers on release behaviors of gentamicin sulfate-loaded PLGA discs.

In order to develop the desirable drug release patterns such as no lag time and exact zero-order release rate, gentamicin sulfate (GS)-loaded poly(D,L-lactide-co-glycolide) (PLGA) discs containing lactide monomer (LM) or glycolide monomer (GM) were prepared. LM or GM was applied for the controlling drug release pattern due to its non-toxic and biodegradable nature. Water absorption, mass loss, pH change, and morphology of discs were examined to study the effect of LM or GM addition. GS release showed near zero-order profile in the GS-loaded polymeric discs prepared in the presence of LM or GM (10%). The channel of GS-loaded PLGA containing LM or GM was formed by the dissolution of LM or GM. Water uptake of disc increased till 21 days from the beginning of the test. The pH variations of media declined in the same manner with the result of mass loss. The antibiosis of GS was also confirmed by bacterial inhibition zone test using the prepared polymeric discs. From these results, we expected that the polymeric discs containing LM or GM would be a good dosage form as a topically implantable device which can get rid of lag period from PLGA matrix.

Anti-Bacterial Agents↗
PubMedDate not supplied

A new biodegradable poly-amino acid: alpha,beta-poly[(N-hydroxypropyl/aminoethyl)-DL-aspartamide-co-L-lysine], a potential nonviral vector for gene delivery.

A new class of biodegradable poly-amino acid, alpha,beta-poly[(N-hydroxypropyl/aminoethyl)-DL-Aspartamide-co-L-Lysine] (PHAAL), was synthesized by ring-opening of poly[succinimide-co-lysine](PSL) with n-propanolamine and ethylene diamine after thermal copolycondensation of DL-Aspartic acid and L-lysine under reduced pressure. Different ratio feeds of PSL were obtained and characterized by 1H-NMR, Fourier transformed infrared spectroscopy, X-ray, thermogravimetric analysis and gel permeation chromatography experiments. As one of the polycationic materials, performed for gene delivery carrier, the PHAAL degradation experiment was carried out in PBS (10 mM, pH =7.4) and enzyme (papain, trypsine 1 mg/ml, 37 +/- 0.1 degree C) solution. PHAAL had lower cytotoxicity than polyethylenimine (25KDa) and poly-L-Lysine (30 KDa), in Hela, E.C.V.-304, Bcap 37 cell lines. Particle size and zeta, potential of PHAAL/DNA complexes were measured. Sizes ranged from 300-500 nm and zeta potentials were at -20 to 2,5 mV. The condensation ability of PHAAL for DNA was evaluated by agarose gel electrophoresis. The PHAAL could completely neutralize DNA at N/P ratio (w/w) 150:1.

Aspartic Acid↗
PubMed2006

Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum.

Drug delivery to the peritoneum is hampered by rapid clearance, and could be improved by application of controlled release technology. We investigated the suitability for peritoneal use of micro- and nanoparticles of poly(lactic-co-glycolic) acid (PLGA), a biodegradable polymer with generally excellent biocompatibility commonly used for controlled drug release. We injected 90 kDa PLGA microparticles, 5-250 microm in diameter, into the murine peritoneum, in dosages of 10-100 mg (n=3-5 per group). We found a high incidence of polymeric residue and adhesions 2 weeks after injection (e.g., 50 mg of 5-microm microparticles caused adhesions in 83% of animals). Histology revealed chronic inflammation, with foreign body giant cells prominent with particles>5 microm in diameter. Five micrometer microspheres made from 54, 57, and 10 kDa PLGA (gamma irradiated) caused fewer adhesions (16.7%) with a similar incidence of residue. Nanoparticles (265 nm) of 90 kDa PLGA also caused much fewer adhesions (6.3% of animals), possibly because they were cleared from the peritoneum within 2 days, and sequestered in the spleen and liver, where foamy macrophages were noted. The effect of sterilization technique on the incidence of adhesion formation is also studied.

Animals↗