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Results for “Biodegradable Delivery Systems”

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PubMed1995

A single administration of tetanus toxoid in biodegradable microspheres elicits T cell and antibody responses similar or superior to those obtained with aluminum hydroxide.

The use of biodegradable polymer microspheres as a single dose vaccine delivery system was investigated by using tetanus toxoid (TT). In order to compare the immunogenicity of TT-microspheres (TT-MS) with aluminum hydroxide (alum)-based TT, BALB/c mice were immunized with TT in different formulations including individual or mixtures of MS and TT-alum. All TT-MS formulations elicited high proliferative and antibody responses comparable to those obtained with TT-alum formulation. Antibody levels remained elevated over a long period of time. Certain individual MS preparations elicited lower antibody titers than the MS mixtures. More importantly, the proliferative and antibody responses induced by a single injection of three TT-MS mixtures with different particle sizes and degradation rates were similar to those obtained with three injections of TT-alum. In addition, TT-MS induce similar isotypesubclass antibodies to those TT-alum induced. These results raise the possibility to obtain optimal and long-lasting immune responses by single administration of the three TT-MS mixture formulations alone.

Aluminum Hydroxide↗

PubMed1990

A review: secondary ion mass spectrometry (SIMS) of polymeric biomaterials.

This paper comprises a short review of the application of secondary ion mass spectrometry (SIMS) to the surface chemical analysis of biomaterials, with the main emphasis on biomedical polymers. By the use of appropriate examples, the technique is shown to provide detailed information on the surface chemical structure of the top 1-2 nm of a range of biodegradable polymers, copolymers, surface modified materials and drug delivery systems. Semi-quantitative information on the surface composition of copolymeric materials can also be obtained. The molecular specificity of the technique can be exploited to identify the presence of additives (eg. drugs, peptides) or contaminants in the surfaces of biomaterials. This approach can be extended to situations where biomolecules of interest are covalently immobilised on biomaterial surfaces. Finally, SIMS imaging analysis is shown to provide a means of determining the lateral distribution of additive molecules in surfaces.

Biocompatible Materials↗

PubMed2006

The preservation of phenotype and functionality of dendritic cells upon phagocytosis of polyelectrolyte-coated PLGA microparticles.

Biodegradable microparticles (MP) represent a promising and efficient delivery system for parenteral vaccination. Recently, MP have also been explored as tool for the ex vivo antigen loading of professional antigen-presenting cells such as dendritic cells (DC) to be used as cellular vaccines. The purpose of this study was to investigate various polycationic coatings on poly(lactide-co-glycolide) (PLGA) MP, with regard to their effect on phenotypic and functional maturation of monocyte-derived DC (MoDC) that had previously been loaded with the MP in vitro. The preparation and concomitant coating of the PLGA was performed by means of a solvent extraction/evaporation method using a recently developed microextrusion-based technique. The polyelectrolytes tested for MP coating encompassed aminodextran, chitosan, poly(ethylene imine) (PEI), poly(L-lysine) and protamine. Uncoated and differently coated PLGA MP were fed to immature MoDC, which ingested efficiently the different MP types irrespective of their surface coating. The MP-loaded immature MoDC were then matured with the help of a cytokine/PGE-2 maturation cocktail. Here, the presence of the ingested MP did not affect the MoDC maturation in terms of expression of the surface markers CD80, CD83, CD86, HLA-DR and MMR, irrespective of the MP surface coating. Importantly, none of the PLGA MP types alone induced significant maturation of MoDC in the absence of the maturation cocktail. MP-loaded and subsequently matured MoDC expressed high levels of the chemokine receptor CCR7, whose functional activity was evidenced by the migration of MoDC towards CCL21, irrespective of the presence of ingested MP. Further, MP-loaded and subsequently matured MoDC also secreted comparable amounts of IL-10 and IL-12p70, irrespective of the presence of ingested MP except for PEI-coated PLGA MP, which enhanced significantly the secretion of IL-12p70 in mature MoDC. In conclusion, phenotypic and functional maturation of MoDC by means of a maturation cocktail remained unchanged irrespective of the presence of previously ingested differently coated PLGA MP. This offers interesting perspectives for using these particulate systems together with entrapped antigens for ex vivo loading of MoDC in view of cellular immunotherapy.

Cell Proliferation↗

PubMed2003

Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation.

In infected joint arthroplasty, high local levels of antibiotics are achieved through temporary implantation of non-biodegradable gentamicin-loaded polymethylmethacrylate beads. Despite their antibiotic release, these beads act as a biomaterial surface to which bacteria preferentially adhere, grow and potentially develop antibiotic resistance. In routine clinical practice, these beads are removed after 14 days, but for a variety of reasons, we were confronted with a patient in which these beads were left in situ for 5 years. Retrieval of gentamicin-loaded beads from this patient constituted an exceptional case to study the effects of long-term implantation on potentially colonizing microflora and gentamicin release. Gentamicin-release test revealed residual antibiotic release after being 5 years in situ and extensive microbiological sampling resulted in recovery of a gentamicin-resistant staphylococcal strain from the bead surface. This case emphasizes the importance of developing biodegradable antibiotic-loaded beads as an antibiotic delivery system.

Aged↗

PubMed2003

Biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol) block copolymers: characterization and their use as drug carriers for a controlled delivery system.

Poly(epsilon-caprolactone)-poly(ethylene glycol) (PECL) copolymers were synthesized from polyethylene glycol (PEG) and epsilon-caprolactone (epsilon-CL) using stannous octoate as catalyst at 160 degrees C by bulk polymerization. The effect of the molecular weight of PEG and the copolymer ratio on the properties of the copolymers was investigated by (1)H-NMR, IR, DSC and GPC. PCL and PECL microspheres containing human serum albumin were elaborated by solvent extraction method based on the formation of double w/o/w emulsion. Microspheres were characterized in terms of morphology, size, loading efficiency, and the efficiency of microspheres formation. The results show that the microspheres prepared from PECL-10 and PECL-15 copolymers achieved the highest loading efficiency (about 50%) among all copolymers. These results indicate that the properties of copolymers could be tailored by adjusting polymer composition. It is suggested that these matrix polymers may be optimized as carriers in the protein (antigen) delivery system for different purposes.

Calorimetry, Differential Scanning↗

PubMed2001

Brush-like branched biodegradable polyesters, part III. Protein release from microspheres of poly(vinyl alcohol)-graft-poly(D,L-lactic-co-glycolic acid).

Brush-like branched polyesters, obtained by grafting poly(lactic-co-glycolic acid), PLGA, onto water-soluble poly(vinyl alcohol) (PVAL) backbones, were investigated regarding their utility for the microencapsulation of proteins. Poly(vinyl alcohol)-graft-poly(lactic-co-glycolic acid), PVAL-g-PLGA, offers additional degrees of freedom to manipulate properties such as e.g. molecular weight, glass transition temperature and hydrophilicity. PLGA chain length was varied at a constant molecular weight (M(w)) of the PVAL backbone and secondly M(w) of the PVAL backbone was varied keeping the PLGA chain lengths constant. The most striking feature of these polymers is their high M(w). Microencapsulation of hydrophilic macromolecules, such as bovine serum albumin, ovalbumin, cytochrome c and FITC-dextran using a w/o/w double emulsion technique was investigated. Surface morphology, particle size, encapsulation efficiencies and protein release profiles were characterized as well. Microencapsulation of model compounds was feasible at temperatures of 0-4 degrees C with yields typically in the range of 60-85% and encapsulation efficiencies of 70-90%. Both, encapsulation efficiency and initial protein release (drug burst) were strongly affected by the glass transition temperature, T(g), of the polymer in contact with water, whereas the in vitro protein release profile depended on the PVAL-g-PLGA structure and composition. In contrast to PLGA, protein release patterns were mostly continuous with lower initial drug bursts. Shorter PLGA chains increased drug release in the erosion phase, whereas initial pore diffusion was affected by the M(w) of PVAL backbone. Release profiles from 2 to 12 weeks could be attained by modification of composition and molecular weight of PVAL-g-PLGA and merit further investigations under in vivo conditions. The in vitro cytotoxicity of PVAL-g-PLGA is comparable to PLGA and therefore, this new class of biodegradable polyesters has considerable potential for parenteral drug delivery systems.

Animals↗

PubMed2003

Structure and dosimetric analysis of biodegradable glasses for prostate cancer treatment.

This work analyzes SiO2 and SiO2-CaO glasses incorporated with samarium atoms produced by sol-gel synthesis. The goal is to provide biocompatible and biodegradable radioactive seeds as an alternative to be used in brachytherapy for the treatment of prostate cancer. The chemical and physical characteristics of the obtained glasses were analyzed by energy dispersive x-ray spectroscopy, x-ray diffraction, He picnometry, and nitrogen adsorption analysis. A theoretical analysis of the process of neutron activation of the samples was also conducted through the calculation of the activity of the seeds and the beta- and gamma-ray doses emitted by the seeds. The results demonstrate the incorporation of samarium atoms in the glass matrix. The experimental data coupled with the theoretical studies in neutron activation suggest that it is possible to obtain radioactive seeds with activities equivalent to 125I seeds used in prostatic brachytherapy.

Biocompatible Materials↗

PubMed1985

Evaluation of subdermal biodegradable implants incorporating rifampicin as a method of drug delivery in experimental tuberculosis of guinea pigs.

Conventional chemotherapy of tuberculosis and leprosy requires rifampicin to be administered orally. The long period of treatment and adverse side effects of the drug lead to poor compliance. To overcome this, subdermal implants incorporating rifampicin in pure and micro-encapsulated forms with biodegradable material were used as a new drug delivery system in experimental tuberculosis of guinea pigs. Two experiments were performed with 45-mg and 100-mg drug implants. Progress of infection was followed at intervals by studying necropsy scores and weights of the organs of predilection and levels of the drug in the blood were determined. There was a constant and sustained release of the drug in therapeutic concentrations for 30 and 50 days until the implants were completely assimilated without causing any damage to the implant site. The importance of multiple implants at long intervals is discussed.

Animals↗

PubMed1998

Induction of secretory and serum antibody responses following oral administration of antigen with bioadhesive degradable starch microparticles.

Bioadhesive degradable starch microparticles were used to deliver antigen and immunoglobulin A (IgA)-enhancing cytokines to the oral mucosa. Degradable starch microparticle immunization groups consisted of rats dosed topically at the sublingual epithelium of the oral cavity, by subcutaneous injection in the vicinity of the major salivary glands or by oral intubation with degradable starch microparticles containing dinitrophenyl-bovine serum albumin +/- IL-5/IL-6 +/- penetration enhancer (alpha-lysophosphatidylcholine). Dinitrophenyl-bovine serum albumin was also adsorbed onto alum for salivary gland vicinity injection and administered to the oral cavity in soluble form. Animals were subjected to 3 immunization cycles, and sequential samples were assayed by radioimmunoassay for salivary IgA, tear IgA and serum IgG anti-dinitrophenyl antibodies after secondary and tertiary immunization. Salivary IgA responses were highest in degradable starch microparticle groups receiving penetration enhancer at 71 days post-secondary immunization and continued in one degradable starch microparticle((oral cavity) and two injected (salivary gland vicinity) groups for up to 88 days post-tertiary immunization. Long-term tear responses were also observed in degradable starch microparticle groups receiving penetration enhancer, but they dissipated before the salivary gland-alum responses following tertiary immunization. Serum IgG responses were most pronounced in salivary gland groups, but long-term low level responses were detectable in oral cavity groups receiving degradable starch microparticle formulations with penetration enhancer. Inclusion of IL-5 and IL-6 in oral cavity-delivered degradable starch microparticle formulations consistently enhanced tear IgA while only upregulating salivary IgA antibody responses at early time points post immunization. IL-5 and IL-6 did not enhance serum IgG antibodies in any group. These data indicate that bioadhesive degradable starch microparticles can be used as a vehicle to deliver antigen and cytokine signals to the oral cavity and, when delivered in combination with a penetration enhancer, can potentiate long-term salivary IgA responses.

Administration, Oral↗

PubMed2001

Structured drug-loaded bioresorbable films for support structures.

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable PLLA films containing dexamethasone were developed through solution processing. The effect of processing parameters on the film morphology and the resulting mechanical properties was studied. A model describing the structuring of these films is suggested. Generally, the solvent evaporation rate determines the kinetics of drug and polymer crystallization and thus, both the mode of drug dispersion in the polymer and the resulting mechanical properties. Two types of structured films were studied: (1) a polymer film with drug located on its surface, obtained due to drug skin formation accompanied by a later polymer core formation; and (2) a polymer film with small drug particles and crystals distributed within the bulk, obtained by parallel solidification of the two components. A prototypical application of these films is an expandable biodegradable support structure (stent). which we have developed. This stent demonstrated good initial mechanical properties. The film structure has only a minor effect on the stent radial compression strength, but more significantly affects the tensile mechanical properties.

Biocompatible Materials↗

PubMed1998

Preparation techniques and mechanisms of formation of biodegradable nanoparticles from preformed polymers.

The techniques available to prepare biodegradable nanoparticles (nanospheres and nanocapsules) from preformed polymers are reviewed. Although there is abundant literature on this topic, only a few focus on the thorough analysis of preparative procedures. In particular, four techniques are discussed in terms of their technological advantages and drawbacks: emulsification evaporation, solvent displacement, salting-out, and emulsification diffusion. The proposed mechanism of nanoparticle formation for each technique is described from a physicochemical perspective. The effects of preparative variables on nanoparticle size and drug-entrapment efficiency are also discussed.

Biodegradation, Environmental↗

PubMed2005

Intravitreous injection of PLGA microspheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse.

PURPOSE: To evaluate the potential delay of the retinal degeneration in rd1/rd1 mice using recombinant human glial cell line-derived neurotrophic factor (rhGDNF) encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) microspheres. METHODS: rhGDNF-loaded PLGA microspheres were prepared using a water in oil in water (w/o/w) emulsion solvent extraction-evaporation process. In vitro, the rhGDNF release profile was assessed using radiolabeled factor. In vivo, rhGDNF microspheres, blank microspheres, or microspheres loaded with inactivated rhGDNF were injected into the vitreous of rd1/rd1 mice at postnatal day 11 (PN11). The extent of retinal degeneration was examined at PN28 using rhodopsin immunohistochemistry on whole flat-mount retinas, outer nuclear layer (ONL) cell counting on histology sections, and electroretinogram tracings. Immunohistochemical reactions for glial fibrillary acidic protein (GFAP), F4/80, and rhodopsin were performed on cryosections. RESULTS: Significant delay of rod photoreceptors degeneration was observed in mice receiving the rhGDNF-loaded microspheres compared to either untreated mice or to mice receiving blank or inactivated rhGDNF microspheres. The degeneration delay in the eyes receiving the rhGDNF microspheres was illustrated by the increased rhodopsin positive signals, the preservation of significantly higher number of cell nuclei within the ONL, and significant b-wave increase. A reduction of the subretinal glial proliferation was also observed in these treated eyes. No significant intraocular inflammatory reaction was observed after the intravitreous injection of the various microspheres. CONCLUSIONS: A single intravitreous injection of rhGDNF-loaded microspheres slows the retinal degeneration processes in rd1/rd1 mice. The use of injectable, biodegradable polymeric systems in the vitreous enables the efficient delivery of therapeutic proteins for the treatment of retinal diseases.

Animals↗

PubMed1993

New advances in vaccine delivery systems.

Successful application of the next generation of vaccines will require that protection be induced with a minimal number of administrations, and that a practical approach to inducing immunity at mucosal surfaces be developed. For these reasons, vaccine-containing microspheres were formulated from the biodegradable and biocompatible copolymer poly(DL-lactide-co-glycolide) [DL-PLG]. Subcutaneous immunization of mice with 1- to 10-microns microspheres containing a toxoid vaccine of staphylococcal enterotoxin B (SEB) induced a 500-fold potentiation of the circulating antitoxin response. Strong adjuvant activity was dependent on the microspheres being no more than 10 microns in diameter and required that the antigen was within the particles. The rate of DL-PLG biodegradation is a function of the ratio of lactide to glycolide, and the co-injection of SEB toxoid microspheres formulated with two different DL-PLG ratios stimulated both a primary and an anamnestic secondary antitoxin response. When it was administered by the oral or intratracheal (IT) route, microencapsulated SEB toxoid was found to be effective in the induction of concurrent circulating and disseminated mucosal antibody responses. Female rhesus macaques immunized with a microencapsulated simian immunodeficiency virus (SIV) vaccine produced high levels of circulating anti-SIV antibodies, and following oral or IT boosting, specific antibodies were found in vaginal wash fluids. Vaginal challenge with viable homologous SIV resulted in the infection of three out of four nonimmunized but only one out of seven microsphere-immunized macaques. Thus, DL-PLG microspheres are a promising approach to the delivery of vaccines, combining adjuvant activity with controlled release and effective presentation to mucosally associated lymphoid tissues (MALT).

Adjuvants, Immunologic↗

PubMed1998

Implantable Slow-Release Chemotherapeutic Polymers for the Treatment of Malignant Brain Tumors.

BACKGROUND: Despite significant advances in neurosurgery, radiation therapy, and chemotherapy, the prognosis for patients with malignant brain tumors remains dismal. In an effort to improve control of local disease, we have developed a biodegradable, controlled-release polymer that is implanted directly at the tumor site. METHODS: The preclinical and clinical development of the polymeric delivery of chemotherapeutic agents for treatment of patients with malignant gliomas is reviewed. RESULTS: Carmustine (BCNU)-impregnated biodegradable polymer is the first new therapy approved by the FDA for patients with gliomas in 23 years. This delivery system provides high local concentration of drug with minimal systemic toxicity and obviates the need for drug to cross the blood-brain barrier. Randomized, multi-institutional, double-blinded, placebo-controlled studies have shown improved survival in patients treated for gliomas both at initial presentation and at recurrence. Several clinical principles have emerged from the use of this polymer system, and further applications are currently being investigated. CONCLUSIONS: Local delivery of therapeutic agents via biodegradable polymers may play an increasing role in patients with brain tumors.

Journal Article↗

PubMed2002

Design of biodegradable particles for protein delivery.

Major research issues in protein delivery include the stabilization of proteins in delivery devices and the design of appropriate protein carriers in order to overcome mucosal barriers. We have attempted to combine both issues through the conception of new biodegradable polymer nanoparticles: (i) poly(ethylene glycol) (PEG)-coated poly(lactic acid) (PLA) nanoparticles, chitosan (CS)-coated poly(lactic acid-glycolic acid (PLGA) nanoparticles and chitosan (CS) nanoparticles. These nanoparticles have been tested for their ability to load proteins, to deliver them in an active form, and to transport them across the nasal and intestinal mucosae. Additionally, the stability of some of these nanoparticles in simulated physiological fluids has been studied. Results showed that the PEG coating improves the stability of PLA nanoparticles in the gastrointestinal fluids and helps the transport of the encapsulated protein, tetanus toxoid, across the intestinal and nasal mucosae. Furthermore, intranasal administration of these nanoparticles provided high and long-lasting immune responses. On the other hand, the coating of PLGA nanoparticles with the mucoadhesive polymer CS improved the stability of the particles in the presence of lysozyme and enhanced the nasal transport of the encapsulated tetanus toxoid. Finally, nanoparticles made solely of CS were also stable upon incubation with lysozyme. Moreover, these particles were very efficient in improving the nasal absorption of insulin as well as the local and systemic immune responses to tetanus toxoid, following intranasal administration. In summary, these results show that a rational modification in the composition and structure of the nanoparticles, using safe materials, increases the prospects of their usefulness for mucosal protein delivery and transport.

Animals↗

PubMed2001

[Long-term immunogenicity and immunologic priming of animals to pulsed controlled-release system for tetanus toxoid vaccine delivery].

AIM: To evaluate the immunogenicity of tetanus toxoid (TT) encapsulated in biodegradable polymer microspheres composed of polylactide (PLA). METHODS: The antibody levels elicited by microsphere formulations in mice for 1 year were examined, the anamnestic responses to a low dose booster 1 year after priming were also examined. RESULTS: Microsphere formulations made from PLA were characterized by pulse controlled-release models, differing in polymer molecular weight, protein loading and particle size of the microspheres. Microsphere formulations elicited significantly higher IgG antibody levels than a single injection of soluble TT. The antibody levels elicited by microsphere formulations were similar to those elicited by three doses of soluble TT. CONCLUSION: A single-dose tetanus toxoid based on pulsed release from biodegradable and biocompatible polymer microspheres has been developed. The formulations showed great benefits and pharmaceutical application.

Animals↗

PubMed2002

Biodegradable microspheres of curcumin for treatment of inflammation.

Curcumin, a natural constituent of Curcuma longa (turmeric, CAS 458-37-7) was formulated as prolonged release biodegradable microspheres for treatment of inflammation. Natural biodegradable polymers, namely, bovine serum albumin and chitosan were used to encapsulate curcumin to form a depot forming drug delivery system. Microspheres were prepared by emulsion-solvent evaporation method coupled with chemical cross-linking of the natural polymers. Curcumin could be encapsulated into the biodegradable carriers upto an extent of 79.49 and 39.66% respectively with albumin and chitosan. Different drug:polymer ratios did not affect the mean particle size or particle size distribution significantly. However, the concentration of the crosslinking agent had remarkable influence on the drug release. In-vitro release studies indicated a biphasic drug release pattern, characterized by a typical burst-effect followed by a slow release which continued for several days. Evaluation of antinflammatory activity using Freund's adjuvant induced arthritic model in Wistar rats revealed significant difference between both the formulations, albumin microspheres and chitosan micropheres as well as against control. It was evident from the present study that the curcumin biodegradable microspheres could be successfully employed as prolonged release drug delivery system for better therapeutic management of inflammation as compared to oral or subcutaneous route.

Absorbable Implants↗

PubMed2005

Delivery of neurotrophin-3 to the cochlea using alginate beads.

OBJECTIVE: The aim of this study was to design a novel cochlear neurotrophin (NT) delivery system for the rescue of auditory neurons after ototoxicity-induced deafening. BACKGROUND: NT-3 is a trophic growth factor that promotes the survival of the auditory nerve and may have a potential therapeutic role in slowing neuron loss in progressive deafness, especially as an adjunct to the current cochlear implant. Beads made from alginate are biodegradable, slow release substances that can be placed at the round window or inside the cochlea. This study investigated the loading properties, release kinetics, and implantation potential of alginate beads loaded with NT-3. METHODS: Alginate beads were prepared using an ionic gelation technique and postloaded with NT-3. Release of NT-3 was measured using enzyme-linked immunosorbent assay over 5 days. Alginate beads were implanted into deafened guinea pigs for 28 days, after which survival of auditory neurons was assessed. RESULTS: Enzyme-linked immunosorbent assay studies demonstrated a 98% to 99% loading of NT-3 with a slow, partial release over 5 days in Ringer's solution. Furthermore, the addition of heparin to the delivery system modulated NT-3 release to a steadier pattern. Implantation of alginate-heparin beads in guinea pig cochleae produced minimal local tissue reaction. NT-3 loaded beads implanted at both the round window and within the scala tympani of the basal turn provided auditory neurons significant protection from degradation and apoptosis compared with unloaded beads or untreated cochleae. CONCLUSIONS: This study demonstrates alginate beads to be a safe, biodegradable and effective delivery system for NT-3 to the cochlea.

Alginates↗