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PubMed1998

Characterization of soluble, salt-loaded, degradable PLGA films and their release of tetracycline.

A local drug delivery system has been designed to release tetracycline over a period of 30 days from poly (lactide-co-glycolide) films. Incorporation of either soluble salt excipients or low molecular weight polymeric species has been found to modulate the release kinetics of the system. The following research describes the fabrication of the delivery system, monitors tetracycline release from the system, and fully characterizes the degradation of the polymer films via scanning electron microscopy, gel permeation chromatography, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and X-ray diffraction techniques. Results show that the modulation via use of salts occurs without changing the inherent degradation rate of the system. We suggest that this phenomenon may be due to the increased amount of swelling and uptake of buffer by the films loaded with soluble salt. Uptake, therefore, may be creating microscopic pores that permit further diffusion of tetracycline from the polymer matrix as well as allow the free monomers to leave the system, thereby preventing autocatalysis within the system.

Biodegradation, Environmental↗
PubMedDate not supplied

Bioerodible polymeric nanoparticles for targeted delivery of proteic drugs.

Significant efforts are being devoted to develop nanotechnology for drug delivery, mainly because of the distinct advantages offered by nanometer-size polymeric systems. Moreover, targeted drug delivery can be obtained by polymer conjugation to biospecific ligands. The present investigation was aimed mainly at determining the targeting ability of hybrid nanoparticles based on synthetic polymer/protein hybrid matrices. These nanoparticles were designed for liver targeted release of proteic drugs with antiviral activity, such as alpha-interferon. Human serum albumin and the monoesters of alternating copolymers of maleic anhydride/alkyl vinyl ethers of oligo(ethylene glycol) were selected as proteic and synthetic components, respectively. Digalactosyl diacyl glycerol, a natural glycolipid selectively recognized by the asialofetuin receptor present on liver hepatocytes was used as active targeting agent. Nanoparticles of 100-300 nm average size were obtained by controlled coprecipitation method. Investigation of nanoparticle surface properties by spectroscopic analysis and by biological tests indicated that the synthesized nanoparticles do expose on their surface targeting moieties that selectively interact with liver hepatocytes receptors.

Animals↗
PubMed1992

Enhanced secretory IgA and systemic IgG antibody responses after oral immunization with biodegradable microparticles containing antigen.

Intragastric immunization may lead to the induction of antibodies in the secretory immune system including saliva. The antibody response is usually short-lived. The objectives of this study were to see whether oral immunization with biodegradable microparticles containing antigen might lead to enhanced mucosal responses. Ovalbumin (OVA) was entrapped in a novel antigen delivery system comprising poly (D,L-lactide-co-glycolide) (PLGA) microparticles. Salivary IgA and serum IgG responses after three daily oral immunizations in BALB/c mice were assayed by ELISA at weekly intervals and compared with those to soluble antigen. Low levels of salivary IgA antibodies were detected at Weeks 2 and 3 in both groups and no significant differences were found. After a secondary series of intragastric immunizations at Week 4, marked differences were apparent between the groups. The mean salivary IgA titre at Week 6 was 959 +/- 494 U compared with 30 +/- 5 in the soluble OVA group (P less than 0.0001). Significant differences were still apparent at Weeks 7-8 through the value was falling. Serum IgG antibodies were detectable and were significantly greater in the particle group (at Weeks 4 and 8) than in controls (P less than 0.001). These results suggest that microparticles are taken up by antigen-presenting cells in Peyer's patches, then slowly degrade in vivo and release entrapped antigens, and thus can function as potent antigen delivery systems giving rise to both mucosal and systemic responses. Microparticles have considerable potential as a controlled released antigen delivery system for the induction of longer-term immune responses at mucosal surfaces.

Administration, Oral↗
PubMed2005

Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies.

PURPOSE: To develop safe and effective systemically administered nonviral gene therapy vectors for solid tumors, DNA-containing poly(ethylene glycol)-modified (PEGylated) gelatin nanoparticles were fabricated and evaluated in vitro and in vivo. METHODS: Reporter plasmid DNA encoding for beta-galactosidase (pCMV-beta) was encapsulated in gelatin and PEGylated gelatin nanoparticles using a water-ethanol solvent displacement method under controlled pH and temperature. Lewis lung carcinoma (LLC) cells in culture were transfected with the pCMV-beta in the control and nanoparticle formulations. Periodically, the expression of beta-galactosidase in the cells was measured quantitatively using an enzymatic assay for the conversion of o-nitrophenyl-beta-D: -galactopyranoside (ONPG) to o-nitrophenol (ONP). Qualitative expression of beta-galactosidase in LLC cells was observed by staining with 5-bromo-4-chloro-3-indolyl-beta-D: -galactopyranoside (X-gal). Additionally, the plasmid DNA-encapsulated gelatin and PEGylated gelatin nanoparticles were administered intravenously (i.v.) and intratumorally (i.t.) to LLC-bearing female C57BL/6J mice. At various time points postadministration, the animals were sacrificed and transgene expression in the tumor and liver was determined quantitatively by the ONPG to ONP enzymatic conversion assay and qualitatively by X-gal staining. RESULTS: Almost 100% of the pCMV-beta was encapsulated in gelatin and PEGylated gelatin nanoparticles (mean diameter 200 nm) at 0.5% (w/w) concentration. PEGylated gelatin nanoparticles efficiently transfected the LLC cells and the beta-galactosidase expression, as measured by the ONPG to ONP enzymatic conversion assay at 420 nm absorbance, increased starting from 12 h until 96 h post-transfection. The efficient expression of LLC cells was also evident by the X-gal staining method that shows blue color formation. The in vivo studies showed significant expression of beta-galactosidase in the tumor following administration of DNA-containing PEGylated gelatin nanoparticles to LLC-bearing mice by both i.v. and i.t. routes. Following i.v. administration of pCMV-beta in PEGylated gelatin nanoparticles, for instance, the absorbance at 420 nm per gram of tumor increased from 0.60 after 12 h to 0.85 after 96 h of transfection. After i.t. administration, the absorbance values increased from 0.90 after 12 h to almost 1.4 after 96 h. CONCLUSIONS: The in vitro and in vivo results of this study clearly show that a long-circulating, biocompatible and biodegradable, DNA-encapsulating nanoparticulate system would be highly desirable for systemic delivery of genetic constructs to solid tumors.

Animals↗
PubMed2000

Evaluation of the regenerative effect of a 25% doxycycline-loaded biodegradable membrane for guided tissue regeneration.

BACKGROUND: Biodegradable materials have been successfully utilized for guided tissue regeneration (GTR) and local delivery systems (LDS) because they are biocompatible, less cytotoxic, and do not require removal. Several studies have demonstrated that tetracyclines (TCs), when applied topically, stimulated osteogenesis in experimental bone defects. The purpose of this study was to evaluate the regenerative effect of a 25% doxycycline-loaded biodegradable GTR membrane (Doxy-M) in dogs. METHODS: Doxy-M was made by coating the inner surface of a biodegradable membrane (BD-M) with 25% doxycycline. Five male mongrel dogs with 20 created osseous defects were enrolled. The plain BD-M was used as the control membrane. Either Doxy-M or BD-M was applied in 20 randomly selected defects (10 Doxy-M, 10 BD-M) for 12 weeks with the GTR technique. The histometric analysis was evaluated with the following parameters: defect height (DH), apical extension of junctional epithelium (AEJP), new cementum height (NCH), new bone height (NBH), and new bone area (NBA). RESULTS: The Doxy-M-treated defects showed more pronounced new bone formation and less crestal bone resorption than the BD-M-treated defects. There were no statistically significant differences between the two groups in DH, AEJP, and NCH. Statistically significantly larger NBH (P <0.05) and NBA (P<0.005) were seen in the Doxy-M-treated defects. CONCLUSIONS: The results strongly suggest that Doxy-M may have a beneficial effect on osteogenesis to favor periodontal regeneration.

Absorbable Implants↗
PubMed2004

A new bone-inducing biodegradable porous beta-tricalcium phosphate.

A new type of degradable biomaterial with bone-inducing capacity was made by combining porous beta-tricalcium phosphate (beta-TCP) with a delivery system for recombinant human bone morphogenetic protein-2 (rhBMP-2). The BMP delivery system consisted of a block copolymer composed of poly-D,L-lactic acid with random insertion of p-dioxanone and polyethylene glycol (PLA-DX-PEG), a known biocompatible and biodegradable material. The efficacy of this biomaterial in terms of its bone-inducing capacity was examined by ectopic bone formation in the dorsal muscles of the mouse. In the beta-TCP implants coated with the PLA-DX-PEG polymer containing more than 0.0025% (w/w) of rhBMP-2, new ectopic bone tissues with marrow were consistently found on the surface of implants. The radiographic density of beta-TCP was diminished in a time-dependent manner. On histological examination, numerous multinucleated osteoclasts with positive tartrate-resistant acid-phosphatase (TRAP) staining were noted on the surface of the beta-TCP. These experimental results indicate that beta-TCP implants coated with synthetic rhBMP-2 delivery system might provide effective artificial bone-graft substitutes with osteoinductive capacity and biodegradable properties. In addition, this type of biomaterial may require less rhBMP-2 to induce significant new bone mass.

Absorbable Implants↗
PubMed1985

In vitro and in vivo studies of drug-releasing poly(amino acids).

Preliminary efforts directed toward the synthesis and characterization of steroid-polyamino acid conjugates indicate that the preparation of these systems is feasible. Studies have indicated that the steroids may be released from the macromolecule resulting in long-term controlled release systems. Table 4 lists several of the variables that are important in controlling biocompatibility, biodegradation, and drug release characteristics. The biocompatibility, biodegradation, and drug release characteristics are all important in the design and preparation of a drug-polyamino acid delivery system. The variables listed in Table 4 may interact and interrelate to varying degrees when considering each of these factors independently. Although perhaps preliminary, efforts to date indicate that steroids bound to polyglutamic acid or polyglutamic acid derivatives are biocompatible, capable of undergoing biodegradation, and can release drugs at appropriate rates for extended periods of time.

Animals↗
PubMed2003

Poly-D,L-lactide-co-poly(ethylene glycol) microspheres as potential vaccine delivery systems.

Adjuvants aimed at increasing the immunogenicity of recombinant antigens remain a focus in vaccine development. Worldwide, there is currently considerable care for the development of biodegradable microspheres as controlled release of vaccines, since the major disadvantage of several currently available vaccines is the need for repeated administration. Microspheres prepared from the biodegradable and biocompatible polymers, the polylactide (PLA) or polylactide-co-glycolide (PLGA), have been shown to be effective adjuvants for a number of antigens. This review mainly focuses on polylactide-co-poly(ethylene glycol) (PELA) microspheres adjuvant as vaccine delivery systems by summarizing our and other research groups' investigation on properties of the microspheres formulation encapsulating several kinds of antigens. The results indicate that compared with the commonly used PLA and PLGA, PELA showed several potentials in vaccine delivery systems, which may be due to the block copolymer have its capability to provide a biomaterial having a broad range of amphiphilic structure. PELA microspheres can control the rate of release of entrapped antigens and therefore, offer potential for the development of single-dose vaccines. The PELA microspheres have shown great potential as a next generation adjuvant to replace or complement existing aluminum salts for vaccine potential. The review mainly aims to promote the investigation of PELA microspheres adjuvant for antigens for worldwide researcher.

Animals↗
PubMed1995

In vitro and in vivo evaluation of progesterone implants based on new biodegradable poly(glutamic and glutamate esters) copolymers.

New biodegradable polypeptidic copolymers of glutamic acid and tert-butyloxycarbonylmethyl glutamate were evaluated as implantable drug delivery systems. Three copolymers varying in degrees of esterification, which is inversely proportional to the number of glutamic residues, were selected for their range of hydrophilicity and biodegradation rates. Progesterone-containing implants were then prepared by means of an extrusion process and both in vitro and in vivo evaluations were performed. The effects of drug loading, nature, and pH of release medium were investigated. In vitro/in vivo correlations were established for some types of implants. Finally, mathematical fitting of the data, using published models, helped to better understand the mechanisms governing release.

Animals↗
PubMed2005

Simulation of gentamicin delivery for the local treatment of osteomyelitis.

In order to understand the effect of antibiotics delivery to bone tissue, by biodegradable polymeric drug disc, for the treatment of osteomyelitis, a three-dimensional simulation model is developed. The simulation investigates the effect of pressure-induced convection on drug distribution, by taking into account the pressure gradient that exists between capillaries and interstitial space, and also as a result of the surgical opening. The clotting process at the surgical opening is incorporated into the simulation, and the effect of clotting duration is investigated. The clotting duration for the baseline simulation is 2 days and it is observed that increasing this duration depresses the mean drug concentration in the marrow and cortical bone. The effect of double burst release profile is also studied and it is observed that drug concentration drops too rapidly after the first burst to provide any therapeutic effect. However, it is shown that the drug concentration after the second burst stays above the minimum inhibitory concentration of the bacteria for a longer period of time, than would have been observed for a mono-burst release. Inserting non-biodegradable polymethylmethacrylate (PMMA) beads into bone seems to cause a higher average concentration of drug in the marrow. However, this could be brought about by the difference in the geometry between the disc and the bead, and the amount of drug packed in each bead. Further simulations on the management of dead space shows the ineffectiveness of having the void filled up with surgical gel as it becomes an additional barrier to drug delivery to the infected tissues.

Animals↗
PubMed2005

MR imaging of biodegradable polymeric microparticles: a potential method of monitoring local drug delivery.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) was encapsulated into biodegradable, bioadhesive polymeric microparticles to enable noninvasive monitoring of their local intravesical delivery with MRI. The microparticles were characterized by contrast agent encapsulation and release kinetics, T(1) relaxation rates, and contrast enhancement in vivo. The level of Gd-DTPA loading into microparticles was 14.3 +/- 0.6 mug/mg polymer. The measured T(1) relaxation rates of the microparticles showed a direct dependence on Gd-DPTA content. Both 1.5T and 4.7T MR scanners were used to image murine bladders instilled intravesically with Gd-DTPA-loaded particles in vivo. MR images showed ring-shaped regions of enhancement inscribing the bladder wall, which were attributed to the microparticles that were preferentially adherent to the mucosa lining the urothelium. The images of controls exhibited no such enhancement. The normalized signal intensities measured from post-instillation images were significantly greater (P < 0.05) than those in the pre-instillation images. Contrast enhancement was observed for at least 5 days after the initial instillation, although the enhancement decreased due to microparticle degradation or mucosa renewal. The localized distribution of biodegradable, bioadhesive microparticles encapsulating Gd-DTPA was successfully visualized with MRI in vivo, allowing particle-mediated delivery to be temporally and spatially monitored noninvasively.

Animals↗
PubMedDate not supplied

Catecholamine-containing biodegradable microsphere implants as a novel approach in the treatment of CNS neurodegenerative disease. A review of experimental studies in DA-lesioned rats.

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly(DL-lactide-co-glycolide) constitute an exciting new technology for drug delivery to the central nervous system (CNS). Implantable controlled-release microspheres containing dopamine (DA) or norepinephrine (NE) provide a novel means to compare DA- or NE -induced restitution of function in unilateral 6-hydroxydopamine lesioned rats. A suspension of 3 microL of DA- or NE-containing microspheres or empty microspheres was implanted in 2 sites of the DA denervated striatum of rats previously unilaterally lesioned with 6-hydroxydopamine. Contralateral-rotational behavior induced by apomorphine was used as an index of lesion success and, following implantation of the microspheres, also as an index of functional recovery. Interestingly, both DA- and NE-microsphere-implanted rats displayed a 30-50% reduction in the number of apomorphine-induced rotations up to 8 wk postimplantation. Rats implanted with empty microspheres did not demonstrate significant changes in contralateral rotational behavior. Behavioral studies following implantation of a mixture of DA and NE microspheres revealed an 80% decrease in the number of apomorphine induced rotations up to 4 wk. On conclusion of the studies, immunocytochemical examination revealed growth of DA and tyrosine hydroxylase immunoreactive fibers in the striatum of DA and NE microsphere-implanted rats. Functional behavior appeared to correlate with the degree of fiber growth. Preliminary electron microscopic studies showed signs of axonal sprouting in the vicinity of the implanted microspheres. No growth was noted in rats implanted with empty microspheres. This report reviews the abilities of both microencapsulated NE and DA to assure functional recovery and to promote DA fiber (re)growth in parkinsonian rats. This novel means to deliver these substances to the central nervous system could be of therapeutic usefulness in Parkinson's disease.

Animals↗
PubMedDate not supplied

Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: contribution of microencapsulation to improved biodistribution.

We have developed a new method of synthetizing superparamagnetic iron oxide nanoparticles, consisting in the modifications of Molday's method, which ensures high relaxivity (2.4 10(5) s-1.M-1.L), good chemical stability, singular biodistribution and a considerable safety margin. The ED (Efficace Dose) to LD50 ratio is 1/2400 instead of 1/50 for Gd-DTPA. In order to develop a magnetite-delivery system to the liver we have incorporated the nanoparticles into biodegradable synthetic microcapsules. Encapsulated 59Fe oxide nanoparticles are injected into rats; in these conditions the sequestration is 9-fold greater in liver and 6 and 5 times lower in blood and carcase, respectively. This modification of the biodistribution enables the use of magnetite containing microcapsules at only 0.3 mg/kg iron to obtain an improved contrast in liver.

Animals↗
PubMed2001

Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection.

Biodegradable polymer nanocapsules containing the lipophilic sunscreen, Parsol MCX (OMC), as the oil core were prepared by solvent displacement. We investigated the influence of polysorbate 85 (P-85) and poloxamer 188 (P-188) as stabilizing agents, the OMC loading capacity and the photoprotective potential of the formulations. The formation of nanocapsules is probably due to an interfacial instability arising from rapid diffusion of the solvent across the interface. The effectiveness of the stabilizing agents was attributed to their ability to inhibit coalescence during solvent diffusion. P-85 was a better stabilizer of poly(epsilon-Caprolactone)-nanocapsules than P-188. The OMC loading capacity was high (99+/-1% of OMC initial concentration). The in vitro release of OMC-nanocapsules is governed by hydrophobicity and crystallinity of the polymer and by the high lipophilicity of the drug. The OMC-nanocapsules provided partial protection against UV-induced erythema, in a manner significantly better than a conventional gel.

Animals↗
PubMed1998

Influence of processing on the stability and release properties of biodegradable microspheres containing thioridazine hydrochloride.

Biodegradable microspheres of poly(DL-lactic-co-glycolic acid) (PLGA) containing thioridazine HCl were produced by four emulsion-solvent evaporation methods including an O/W emulsion method, an O/O emulsion method, a W/O/W multiple emulsion method, and a W/O/O/O multiple emulsion method. Gel permeation chromatography was used to determine the molecular weight of the polymer before and after processing. Resultant microspheres were either incubated in an oven at 40 degrees C, or stored in a desiccated chamber at 20 degrees C. Change in the molecular weight of the polymer was monitored as a function of time. Premature degradation of the polymer was evident in microspheres produced by the O/W conventional solvent evaporation method. Thioridazine HCl catalyzed hydrolysis of PLGA was evident in normalized molecular weight distribution plots of the O/W microspheres. The in vitro release of thioridazine HCl from multiphase microspheres produced by potentiometric dispersion was compared with the release of drug from conventional microspheres prepared from the same polymer. Release of thioridazine HCl from multiphase microspheres of the W/O/O/O type occurred by diffusion during initial stages of drug release.

Biocompatible Materials↗
PubMedDate not supplied

Novel polymer-DNA hybrid polymeric micelles composed of hydrophobic poly(D,L-lactic-co-glycolic acid) and hydrophilic oligonucleotides.

Biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) was chemically conjugated to oligonucleotide (ODN) to form an amphiphatic structure which is similar to an A-B type block copolymer. A terminal end of PLGA was activated and reacted with primary amine-terminated ODN. The ODN/PLGA conjugates self-assembled in aqueous solution to form a micellar structure by serving PLGA segments as a hydrophobic core and ODN segments as a surrounding hydrophilic corona. Critical micelle concentration was determined by a spectroflurometric method. Atomic force microscopic observation revealed that the micelle size was around 80 nm. These micelles could release ODN in a sustained manner by controlled degradation of hydrophobic PLGA chains. Compared to unconjugated ODN, the ODN/PLGA micelles could be more efficiently transported within cells, presumably by endocytosis. This study proposes a potential delivery method of ODN into cells by forming hybrid ODN/PLGA micelles.

3T3 Cells↗
PubMed2006

Effect of side group chemistry on the properties of biodegradable L-alanine cosubstituted polyphosphazenes.

Biodegradable polyphosphazenes have been investigated for a variety of applications, such as controlled drug delivery matrixes, tissue-engineering scaffolds, membranes, and bone-type composites. In this study we have evaluated the effect of side group chemistry on the properties of biodegradable phosphazene polymers that contain ethyl alanato side groups together with ethyl glycinato, p-methylphenoxy, or p-phenylphenoxy side groups. The polymers were synthesized by a macromolecular substitution route. The molecular weights of aryloxy/amino acid ester cosubstituted polymers were much higher than the amino acid ester substituted polyphosphazenes described earlier. Polymer properties, such as glass transition temperature, hydrolytic degradation, surface wettability, tensile strength, and modulus of elasticity varied over a wide range following changes to the type of co-substituents on the polymer backbone. The glass transition temperatures varied from -10 to 35 degrees C and increased with the bulkiness of the side groups. Polymer films in phosphate buffer saline solution showed molecular weight declines ranging from 58% to >80% and mass loss ranging from 4% to 90% over a period of 7 weeks. Water contact angles for polymer films varied from 63 degrees to 107 degrees , with the highest angles for the alanine ethyl ester and p-phenylphenoxy cosubstituted polyphosphazene. The tensile strengths were in the range of 2.4-7.6 MPa and the modulus of elasticity was in the range of 31.4-455.9 MPa. Thus, in this study we have demonstrated the tunability of biodegradable polyphosphazenes to suit a range of biomedical applications.

Alanine↗