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Results for “Biodegradable Delivery Systems”

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PubMed2002

Suppression of collagen-induced arthritis by single administration of poly(lactic-co-glycolic acid) nanoparticles entrapping type II collagen: a novel treatment strategy for induction of oral tolerance.

OBJECTIVE: Poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer, is a carrier for drug delivery systems. This study was undertaken to investigate the tolerogenic effect of single administration of PLGA entrapping type II collagen (CII) on the development of collagen-induced arthritis (CIA). METHODS: The biophysical properties of PLGA nanoparticles entrapping CII (PLGA-CII) were investigated by in vitro release testing of CII, immunohistochemistry analysis, and electron microscopy. PLGA-CII was fed singly to animals 14 days before immunization, and the effect on joint inflammation was assessed. Circulating IgG anti-CII antibodies and T cell responses to CII in draining lymph nodes were assayed by enzyme-linked immunosorbent assay and (3)H-thymidine incorporation assay, respectively. The expression of messenger RNA (mRNA) for transforming growth factor beta (TGFbeta) and tumor necrosis factor alpha (TNFalpha) was determined by reverse transcriptase-polymerase chain reaction. RESULTS: The in vitro release test showed that CII was slowly discharged from PLGA-CII over a period of a month. After single administration of PLGA-CII, numerous particles approximately 300 nm in size were detectable in Peyer's patches, by electron microscopy and immunohistochemical staining for CII, 14 days after the original feeding. Mice fed a single dose of PLGA containing 40 microg of CII had significantly reduced values for incidence and severity of arthritis, serum IgG anti-CII antibodies, and CII-specific T cell proliferation as compared with mice fed solvent alone, those fed 6 doses of 20 microg CII alone, and those fed a single dose of PLGA alone. PLGA-CII was also able to suppress CIA after disease onset. Moreover, PLGA-CII-fed mice showed a higher level of TGFbeta mRNA expression in Peyer's patches, but a lower level of TNFalpha mRNA expression in draining lymph nodes, compared with the other groups of mice. CONCLUSION: Our data show that PLGA may serve as a powerful vehicle to promote the tolerance effect of oral CII and that single administration of PLGA-CII may hold promise as a new treatment strategy in rheumatoid arthritis.

Animals↗

PubMed2002

Release mechanisms from gentamicin loaded poly(lactic-co-glycolic acid) (PLGA) microparticles.

To provide local gentamicin delivery for 1 week based on a biodegradable system, poly(lactic-co-glycolic acid) (PLGA) microparticles were developed utilizing a 50/50 blend of Resomer RG 502H, an uncapped variety of 13.5 kD, and Resomer RG 503, an endcapped polymer of 36.2 kD. The liberation mechanism was investigated by analysis of morphological changes and thermal analysis focusing on the polymer glass transition temperature (T(g)) and the mechanical properties. The release of gentamicin was related to a structural breakdown of the particles reaching a critical molecular weight. A T(g) of < 37 degrees C in the hydrated state was not indicative of collapse and agglomeration of the particles because the mechanical strength of the polymer structures in the rubbery state may still render sufficient support. As the gap between incubation temperature and T(g) widened, the mechanical stability of the PLGA microparticles decreased and became decisive. Particles prepared with RG 502H show a lower ability to bear mechanical stress than RG 503 and 50/50 RG 502H/RG 503 microparticles.

Anti-Bacterial Agents↗

PubMed1996

Mucosal immunization with a measles virus CTL epitope encapsulated in biodegradable PLG microparticles.

The immunogenicity of a cytotoxic T cell epitope (CTL) representing residues 52-60 from measles virus (MV) nucleoprotein, encapsulated in poly(lactide-co-glycolide) (PLG) microparticles was evaluated after mucosal immunization. After intranasal administration of the encapsulated CTL epitope linked at the carboxyl terminus of two copies of a T-helper epitope (TT-NP6), peptide-specific and MV-specific CTL responses were detected in splenocytes. However, these responses were lower than the responses observed when the TT-NP6 peptide was administered intranasally in saline or using CTB as an adjuvant. Intranasal coadministration of the encapsulated TT-NP6 peptide with CTB did not result in any significant potentiation of the CTL responses. The effectiveness of biodegradable PLG microparticles for mucosal delivery of CTL epitopes, combined with their excellent tissue compatibility and biodegradability suggests that they represent a valuable delivery system for synthetic immunogens. However, further work is needed to define the requirements for effective absorption by the nasal epithelium.

Animals↗

PubMed2004

Poly(D,L lactic-co-glycolic acid) microspheres as biodegradable microcarriers for pluripotent stem cells.

The pluripotent nature and proliferative capacity of embryonic stem cells makes them an attractive cell source for tissue engineering and regeneration. In our study we investigated the use of poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres as biodegradable microcarriers of pluripotent cells and as delivery systems of bioactive factors, which influence cell differentiation. The pluripotent P19 embryonal carcinoma cell line was used as a model to study cell attachment, growth and differentiation of pluripotent stem cells on PLGA microspheres. Retinoic acid (RA) was encapsulated in the PLGA microcarriers to influence cell differentiation-more specifically, to induce P19 cell differentiation into neurons. The results revealed that P19 cells attach and grow on the surface of the RA loaded PLGA microspheres. Moreover, the RA loaded PLGA microspheres were shown to be as effective as soluble RA at inducing P19 cell differentiation into neurons. Hence, the results of these ex vivo studies clearly demonstrate the capacity of PLGA microspheres to serve a dual role as both delivery systems of bioactive factors and as scaffolds for pluripotent cells. More importantly, our study demonstrates the potential use of PLGA microspheres as transplantation matrices of pluripotent stem cells for tissue engineering and regeneration.

Absorbable Implants↗

PubMed2001

Aquaculture pharmaceuticals and biologicals: current perspectives and future possibilities.

With the continued expansion of cultured fin and shellfish species, aquaculture has become a key component of the animal health industry. The ever-increasing demand for quality pharmaceutical and biological products, to combat bacterial and viral infections, calls for the development of modern formulations and novel drug delivery systems. The purpose of this paper is to provide a general overview of important fish pathogens, manifested fish diseases, and control methods. Currently available pharmaceutical and biological products are tabulated. Emphasis is placed on the extension of formulation and process technologies, commonly encountered in human pharmaceuticals, to the aquaculture arena. New research efforts in the area of novel vaccine delivery systems, i.e. enteric-coated beads and biodegradable microspheres, are also summarized.

Anesthetics↗

PubMed2002

Enhanced gene expression in mouse muscle by sustained release of plasmid DNA using PPE-EA as a carrier.

Delivery of plasmid DNA by nanoparticles improves the DNA bioavailability, for instance in intramuscular administration, by localizing the DNA in the muscle tissue. Extracellular sustained release of the DNA may lead to more prolonged transgene expression. The present study describes a novel controlled gene delivery system based on a water soluble and biodegradable polyphosphoester, poly(2-aminoethyl propylene phosphate) (PPE-EA). The polymer degraded in PBS at 37 degrees C through the cleavage of the backbone phosphate bonds, and it was synthesized with a relative high molecular weight to ensure a suitable hydrolytic stability as a gene carrier. The tissue response and cytotoxicity study demonstrated a better tissue compatibility of PPE-EA in mouse muscle compared with commonly used polyethylenimine and poly-L-lysine. PPE-EA condensed DNA efficiently and protected DNA from nuclease and serum degradation. Sustained release of plasmid was achieved from PPE-EA/DNA complexes as a result of PPE-EA degradation. The DNA release profiles appear to be predominantly controlled by carrier degradation and the release rate of plasmid could be adjusted by varying the charge ratio of PPE-EA to DNA. At an N/P (amino to phosphate groups) ratio of 1, a 46% burst was observed for the first day, followed by about 4% release per day (24 microg DNA/day/mg of complex) for 12 days. Higher charge ratios reduced both the DNA release rate and the burst effect. The released DNA retained its structural and functional integrity. Intramuscular injection of PPE-EA-p43-LacZ complexes at N/P ratios of 0.5 and 1 resulted in enhanced beta-galactosidase expression in anterior tibialis muscle in Balb/c mice, as compared with naked DNA injections. Similarly, PPE-EA/IFN(alpha)2b DNA complexes generated an increased systemic level of interferon-alpha2b in mouse serum following intramuscular injection, as compared with naked DNA injection.

Absorbable Implants↗

PubMedDate not supplied

Effect of co-solvents on the controlled release of calcitonin polypeptide from in situ biodegradable polymer implants.

The objective of this study was to design an in situ biodegradable polymer implant controlled-release drug delivery system, using novel combinations of co-solvents and a model polypeptide, calcitonin (CT), and to assess the release of drug as a function of these co-solvents. Formulations were prepared by dissolving/ suspending CT polypeptide in poly-(lactic acid) (PLA) polymer solutions/suspensions containing combinations of a hydrophobic (benzyl benzoate, BB) and a hydrophilic (benzyl alcohol, BA) solvent. The CT-PLA mixtures were each injected into test tubes containing phosphate buffered saline solution to form the in situ implant and sampling was conducted over a 28-day period. The samples were analyzed for drug content using a modified Lowry protein assay procedure. Cumulative drug release demonstrated a rank-order correlation depending on the amount of the hydrophobic (BB) and hydrophilic (BA) solvents within each system. Increasing the amounts of the hydrophobic solvent, BB, in formulations demonstrated a 1.2-4.4-fold increase in CT release. Stability studies of all formulations over a 4-month period showed progressive increase in degradation of the CT polypeptide, especially at 37 degrees C, but a slower degradation pattern prevailed at 4 degrees and 20 degrees C. Differential scanning calorimetric studies revealed a homogenous mixture of drug in the polymer matrix. Overall, these studies demonstrated the feasibility of designing controlled release systems capable of releasing a polypeptide drug as a function of influence of different co-solvent combinations.

Absorbable Implants↗

PubMed1997

A novel biodegradable system based on gelatin nanoparticles and poly(lactic-co-glycolic acid) microspheres for protein and peptide drug delivery.

Gelatin nanoparticle-poly(lactic-co-glycolic acid) (PLGA) microsphere composites were prepared by encapsulating protein-loaded gelatin nanoparticles in PLGA microspheres. This encapsulation was conducted by using a phase separation method and a solvent extraction method. The average diameter of the gelatin nanoparticle-PLGA microsphere composites is between 160 and 175 microm. Protein loading efficiency is 93.2% for the nanoparticle-microsphere composite prepared by the phase separation method, while it is 31.31% for the composite prepared by the solvent extraction method. Protein release experiments indicate that this new composite system possesses sustained release characteristics. This system also demonstrates the capability of preventing the denaturation of protein drugs.

Biotransformation↗

PubMedDate not supplied

Biodegradable polymers for protein and peptide drug delivery.

We have reviewed a large cross-section of degradable polymeric delivery systems for protein and peptide pharmaceuticals. These systems include monolithic type devices in which the drug is dispersed throughout the polymer and protein-polymer conjugates where the drug is covalently bound to the polymer. These delivery systems have unique challenges associated with their development that are related to both protein stability and protein release kinetics. Despite numerous reports in the scientific literature which include many encouraging results in preclinical models, very few of these systems have been developed into viable products. The products that have made it to market, however, have proven to be very successful and demonstrate the significant advantages that these systems can provide. The continuous advances in biotechnology will produce more proteins and peptides that will be difficult to administer by conventional means, and an increased demand for controlled or site-specific delivery systems is anticipated.

Alginates↗

PubMed2004

Long-circulating DNA-complexed biodegradable multiblock copolymers for gene delivery: degradation profiles and evidence of dysopsonization.

Biodegradable cationic polymers have become promising alternatives to traditional polycationic gene delivery systems in which the high charge densities of high molecular weight polymers contribute significantly to cellular toxicities. Previous research has shown that biodegradable, multiblock copolymers (MBC), PEG-PLL-g-16% His, are efficient gene carriers with negligible cellular toxicities. The present research was designed to characterize the polymer degradation as well as to determine the biodistribution of the MBC after systemic administration. Polymer degradation was performed in buffer as a function of pH, in serum and within polymer/pDNA complexes. The MBC exhibited exponential decay with a half-life (t1/2) of approximately 14 min at pH 9.0, approximately 5 h at pH 7.4 and approximately 2 h in serum. However, there was little or no degradation observed at pH 4.0 and the MBC within the complexes degraded between 4 and 8 h in serum. Biodistribution data performed with fluorescently labeled polymer and pDNA revealed that intact complexes remained in the blood up to 3 days, which was also reflected in the organs as a function of time. Therefore, the cumulative data suggest that PEG may be sterically stabilizing complexes in vivo via dysopsonization in which serum proteins mask the complexes from elements of the reticuloendothelial system (RES).

Animals↗

PubMed1994

Depot drug delivery system for 5-fluorouracil after filtration surgery in the rabbit.

We investigated the potential value of 50:50 poly (DL glycolic acid-lactic acid) (PGLA) copolymer as a degradable depot delivery system for 5-fluorouracil (5-FU) after filtration surgery. Analysis of retrieved discs after implantation in 22 eyes of 22 pigmented rabbits showed a dual drug release profile and polymer mass loss characteristics. In a second group of pigmented rabbits implantation of PGLA discs impregnated with 5-FU (22 eyes) significantly lengthened the survival time of filtration fistulae compared with discs without 5-FU (18 eyes) or no disc (10 eyes) (p < 0.0001). Use of PGLA copolymer impregnated with 5-FU could prove valuable for patients undergoing glaucoma filtering surgery.

Animals↗

PubMed2003

Multi-pulse drug delivery from a resorbable polymeric microchip device.

Controlled-release drug delivery systems have many applications, including treatments for hormone deficiencies and chronic pain. A biodegradable device that could provide multi-dose drug delivery would be advantageous for long-term treatment of conditions requiring pulsatile drug release. In this work, biodegradable polymeric microchips were fabricated that released four pulses of radiolabelled dextran, human growth hormone or heparin in vitro. Heparin that was released over 142 days retained on average 96 +/- 12% of its bioactivity. The microchips were 1.2 cm in diameter, 480-560 microm thick and had 36 reservoirs that could each be filled with a different chemical. The devices were fabricated from poly(L-lactic acid) and had poly(D,L-lactic-co-glycolic acid) membranes of different molecular masses covering the reservoirs. A drug delivery system can be designed with the potential to release pulses of different drugs at intervals after implantation in a patient by using different molecular masses or materials for the membrane.

Absorbable Implants↗

PubMed2004

A new gene delivery system based on controlled release technology.

The recent rapid development of molecular biology together with the steady progress of genome projects has given us some essential and revolutionary informations of gene to elucidate all the biological phenomena at the molecular level. Under these circumstances, gene transfection has become a fundamental technology indispensable to the basic research of medicine and biology. On the other hand, the technology of gene transfection is also important for gene therapy of several diseases. Some human gene therapies have been performed with a plasmid DNA alone or virus vectors but are clinically limited by the poor gene expression of plasmid DNA and the adverse effects of virus itself, such as immunogenicity and toxicity or the possible mutagenesis of cells transfected. Therefore, several non-viral vectors of synthetic materials have been explored to enhance the transfection efficiency of gene into mammalian cells both in vitro and in vivo. In this paper, the researches about non-viral vectors and recent research trials about the controlled release of plasmid DNA are briefly reviewed to emphasize the significance of gene delivery technology in basic biology and medicine as well as clinical medicine. A new system of gene release based on biodegradable hydrogel is introduced.

Animals↗

PubMed2005

Sustained interferon-gamma delivery from a photocrosslinked biodegradable elastomer.

The application of protein therapeutics for long-term, localized delivery has been hindered by a lack of a delivery device that releases active protein at a concentration within their therapeutic window. A protein delivery system that uses an osmotic pressure delivery mechanism and a photocrosslinked biodegradable elastomer has been designed in an attempt to overcome this limitation. The elastomer is prepared through the UV initiated crosslinking of end terminal acrylated star-poly(epsilon-caprolactone-co-D,L-lactide). Interferon-gamma (IFN-gamma) was released from the optimum formulation at a constant rate of 23 ng/day over 21 days. A cell-based assay showed that over 83% of released IFN-gamma was bioactive. Furthermore, it was demonstrated that bovine serum albumin co-lyophilized with IFN-gamma was released at the same rate as IFN-gamma. This delivery formulation may be clinically useful for sustained, local protein drug delivery applications.

Animals↗

PubMed2005

Covalent conjugation of polyethyleneimine on biodegradable microparticles for delivery of plasmid DNA vaccines.

Microparticle-based delivery of nucleic acids has gained particular attention in recent years in view of improving the potency of DNA vaccination. Such improvement has been reported by encapsulation of pDNA within biodegradable microparticles or through surface adsorption on cationic microparticles. However, the intrinsic intracellular barriers for gene delivery to antigen presenting cells (APCs) have not been adequately addressed in the rational design of delivery systems for DNA vaccines. Here we report synthesis and characterization of biodegradable microparticles that (a) can passively target phagocytic APCs, (b) have intrinsic buffering ability that might allow for enhanced phagosomal escape, (c) are not cytotoxic and (d) have improved APC transfection efficiency. Branched polyethyleneimine (b-PEI) was covalently conjugated using carbodiimide chemistry to the surface of poly(lactide-coglycolide) (PLGA) microparticles to create cationic microparticles capable of simultaneously delivering both DNA vaccines as well as other immunomodulatory agents (cytokines or nucleic acids) within a single injectable delivery vehicle. Our results indicate that covalent conjugation of b-PEI allows efficient surface loading of nucleic acids, introduces intrinsic buffering properties to PLGA particles and enhances transfection of phagocytic cells without affecting the cytocompatibility of PLGA carriers.

Absorbable Implants↗

PubMed1997

Routes of immunization and antigen delivery systems for optimal mucosal immune responses in humans.

Numerous experiments performed in humans and animals have revealed that stimulation of mucosal lymphoid inductive sites such as intestinal Peyer's patches results in parallel immune responses manifested by the appearance of S-IgA antibodies in the external secretions of remote glands. However, recent experiments suggest that inductive sites associated with the upper respiratory tract, rectum, and perhaps genital tract may also function as sources of lymphoid cells that populate, with some selectivity, certain remote mucosal effector sites. Furthermore, antigen-specific IgA antibodies can be induced in certain secretions (e.g., female genital tract) not only by immunization in the vicinity of corresponding mucosal tissues (e.g., vagina and rectum) but also by oral and especially intranasal immunization. The ineffectiveness of simple delivery of soluble antigens to mucosal membranes for immunization has stimulated extensive studies of strategies for effective delivery systems that would (a) increase the antigen absorption, (b) prevent its degradation, and (c) skew the outcome of immunization to a desired goal (protective response to infectious diseases vs. tolerance; B vs. T cell responses; mucosal vs. systemic). The induction of immune responses at a desired mucosal site can be accentuated with the use of a suitable antigen-delivery system including relevant bacterial or viral vectors, edible transgenic plants expressing microbial antigens, incorporation of antigens in biodegradable microspheres or liposomes, and linkage or coadministration of antigens with cholera toxin B subunit. However, only a few antigen-delivery systems extensively used in animal experimentation have been evaluated for their efficacy in humans. The combination of various immunization routes and the use of suitable antigen-delivery systems may accomplish an important task-the induction of mucosal immune responses at a location relevant to the site of entry of a given pathogen.

Animals↗

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↗

PubMed2004

Potential applications of chitosan in veterinary medicine.

Chitosan is a partially deacetylated polymer obtained from the alkaline deacetylation of chitin which is a glucose-based unbranched polysaccharide widely distributed in nature as the principal component of exoskeletons of crustaceans and insects as well as of cell walls of some bacteria and fungi. Chitosan exhibits a variety of physicochemical and biological properties resulting in numerous applications in fields such as waste and water treatment, agriculture, fabric and textiles, cosmetics, nutritional enhancement, and food processing. In addition to its lack of toxicity and allergenicity, and its biocompatibility, biodegradability and bioactivity make it a very attractive substance for diverse applications as a biomaterial in pharmaceutical and medical fields, where it has been used for systemic and local delivery of drugs and vaccines. It also has bioactive properties in its own right. This paper reviews current veterinary applications for chitosan including wound healing, bone regeneration, analgesic and antimicrobial effects. It also discusses the potential application of chitosan to drug and vaccine delivery in veterinary species. Given the restrictions imposed by financial and animal restraint considerations, especially in farming applications, the veterinary drug delivery areas most likely to benefit from chitosan are the delivery of chemotherapeutics such as antibiotics, antiparasitics, anaesthetics, painkillers and growth promotants to mucosal epithelium for absorption for local or systemic activity, and the delivery of immunomodulatory agents to the mucosal associated lymphoid tissue for induction or modulation of local immune responses. The properties of chitosan expected to enhance these functions are discussed, and the future research directions in this field are indicated.

Analgesia↗