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PubMed1999

The stability and immunogenicity of a protein antigen encapsulated in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol.

Protein-loaded microparticles were produced from blends of poly(ethylene glycol) (PEG) with poly(L-lactide) (PLA) homopolymer or poly(DL-lactide co-glycolide) copolymers (PLG) using a water-in oil-in oil method. The stability of ovalbumin (OVA) associated with microparticles prepared using PEG and 50:50 PLG, 75:25 PLG and PLA, respectively, was analysed by SDS-PAGE and quantified by scanning densitometry following incubation in PBS at 37 degrees C for up to 1 month. Fragmentation and aggregation of OVA was detected with all 3 formulations. The extent of both processes correlated with the degradation rate of the lactide polymer used and decreased in the order PLA < 75:25 PLG < 50:50 PLG. Extensive degradation of the PLG/PEG microparticles also occurred over 4 weeks whereas the use of PLA/PEG blends resulted in a stable microparticle morphology and much reduced fragmentation and aggregation of the associated protein. Following a single sub-cutaneous immunisation, high levels of specific serum IgG antibody were elicited by OVA associated with the PLA/PEG particles. Injection of OVA associated with the 75:25 PLG/PEG microparticles resulted in very low levels of specific antibody. A higher response was induced by the 50:50 PLG/PEG formulation but there was very large inter-animal variation in this group. Antibody levels elicited by all 3 formulations were significantly higher than those elicited by a single injection of soluble OVA. Analysis of antigen specific IgG1 and IgG2a antibody subtype levels also revealed the greater efficacy of the PLA/PEG microparticles as an adjuvant system. The use of PLA/PEG microparticles shows improved protein loading and delivery capacity while maintaining a high level of stability of the associated protein. These results indicate a strong correlation between the stability of microencapsulated antigen and the magnitude of the immune response following sub-cutaneous immunisation.

Animals↗
PubMed1999

New biodegradable networks of poly(N-vinylpyrrolidinone) designed for controlled nonburst degradation in the vitreous body.

Polymers of N-vinylpyrrolidinone (NVP) are known to have excellent biocompatibility when implanted in the vitreous body or used as a vitreous substitute. Although poly(NVP) is capable of absorbing relatively large amounts of water, it is not prone to hydrolysis. Yet intraocular degradation of several crosslinked poly(NVP) hydrogels has been reported recently, but some ambiguity remains about the exact mechanism of degradation of these materials. To date there is no biomaterial that combines the excellent intraocular biocompatibility on the one hand and controlled kinetics of degradation on the other hand. We attempted to design and prepare such materials through the chemical synthesis of a novel dimethacrylate crosslinker molecule. The essential feature of this molecule is that its core contains two carbonate groups, which are evidently susceptible to hydrolytic scission. We studied a series of 3-dimensional networks of poly(NVP), which were crosslinked by this molecule. This approach offers several advantages: the hydrolysis of the carbonate groups in the crosslinks leads to liberation of poly(NVP) and/or oligo(NVP) chains that can probably be cleared from the eye via phagocytosis; hydrolysis generates two alcohols and CO(2) (i.e., there is no catalytic burst effect); when these materials are implanted in dry form, swelling and degradation will progress from the exterior of the material toward its interior. Therefore, these materials can be designed such that surface degradation rather than bulk degradation occurs; the hydrolysis rate can be controlled via the crosslink density or through synthesis of other crosslink molecules with either more (>2) or less (1) carbonate groups or alternatively with one or more other labile groups. We report on the chemical synthesis of the crosslinker molecule, as well as the preparation and degradation of a series of poly(NVP)-based hydrogels in vitro and in vivo (rabbit eyes). We found that these materials indeed displayed excellent biocompatibility in the rabbit eye. Further, the experiments confirmed that degradation occurs without the burst effect. The results are in line with the idea that the rate of intraocular swelling and degradation depends on the crosslink density, but this is only a preliminary conclusion that must be strengthened by much more experimental work. Nonetheless, we foresee several applications of these or related materials in ophthalmology, for example, as biodegradable matrix materials for controlled drug delivery of ganciclovir in the vitreous body.

Animals↗
PubMed2005

Postfabrication encapsulation of model protein drugs in a negatively thermosensitive hydrogel.

A postfabrication encapsulation technique was developed for loading model protein drugs into an intelligent and biodegradable hydrogel film, which exhibits negative thermosensitivity with a desirable phase transition temperature between refrigerator temperature and body temperature. The hydrogel comprises mainly poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer, and oligo(lactide). The model proteins Hemoglobin and Bovine Serum Albumin were loaded into the hydrogel films by soaking the gels at 4 degrees C, at which the hydrogel film was swollen. The loaded drug was released gradually in PBS at 37 degrees C, where the hydrogel film was shrunken. Because the hydrogel is biodegradable, the loaded drug could be released completely. It is confirmed that proteins can, in their native structures, be included in the hydrogel via the present technique, as characterized by FTIR, Raman spectrum, UV/VIS spectrum, and circular dichroism spectrum. The highlight of our approach is avoidance of high temperatures and organic solvents in encapsulation, making it ideal for protein drug delivery systems.

Body Temperature↗
PubMed2006

Effect of WOW process parameters on morphology and burst release of FITC-dextran loaded PLGA microspheres.

Using fluorescein isothiocyanate labeled dextran (FITC-dextran 40, FD40) as a hydrophilic model compound, microspheres were prepared by a WOW double emulsion technique. Influence of process parameters on microsphere morphology and burst release of FD40 from PLGA microspheres was studied. Internal morphology of microspheres was investigated by stereological method via cryo-cutting technique and scanning electron microscopy (SEM). Drug distribution in microspheres was observed with confocal laser scanning microscopy (CLSM). Polymer nature (RG503 and RG503H) had significant influence on the micro-morphology of microspheres. Increase in continuous water phase volume (W2) led to increased surface porosity but decreased internal porosity. By increasing PVA concentration in the continuous phase from 0.1 to 1%, particle size changed marginally but burst release decreased from 12.2 to 5.9%. Internal porosity of microspheres decreased considerably with increasing polymer concentration. Increase in homogenization speed during the primary emulsion preparation led to decreased internal porosity. Burst release decreased with increasing drug loading but increased with drug molecular weight. Drug distribution in microspheres depended on preparation method. The porosity of microspheres decreased with time in the diffusion stage, but internal morphology had no influence on the release behavior in the bioerosion stage. In summary, surface porosity and internal morphology play a significant role in the release of hydrophilic macromolecules from biodegradable microspheres in the initial release phase characterized by pore diffusion.

Calorimetry, Differential Scanning↗
PubMed1999

Concomitant and controlled release of dexamethasone and 5-fluorouracil from poly(ortho ester).

A viscous bioerodible and hydrophobic poly(ortho ester) has been developed as a biocompatible, sustained drug release system for an ophthalmic application in intraocular proliferative disorders. The combination of wound healing modulators such as 5-fluorouracil and dexamethasone is a major advantage since these drugs act at different stages of these diseases. Since 5-fluorouracil is an acidic, water-soluble compound and dexamethasone exists in three chemical forms, i.e. the water-insoluble base, the highly hydrophobic acetate ester or the basic phosphate salt, it was of interest to investigate whether the physicochemical properties of the drugs have an influence on their release rates, and whether a concomitant and sustained release of both 5-fluorouracil and dexamethasone could be achieved. It has been found that lipophilicity and acidobasicity play a major role in controlling drug release rates and polymer degradation. The combination of 5-fluorouracil and dexamethasone phosphate allows a sustained and concomitant release of both drugs, due to the basic characteristics of the corticosteroid which stabilize the polymer. This system appears to be promising for concomitant and controlled drug delivery aimed at the pharmacological treatment of intraocular proliferative disorders.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

In vitro effects of brain derived neurotrophic factor released from microspheres.

The principal objective of these studies was to microencapsulate brain derived neurotrophic factor (BDNF) and to test its biological effects in vitro. Two types of microspheres with BDNF were prepared using biodegradable polymers: chitosan and poly-(L-lactic acid):poly-(L-glycolic acid). Depending on the procedure, sizes ranged from 1 micron to 1 mm as determined by an image analysis system. The biological assays confirmed that the released BDNF remains biologically active in vitro. Microencapsulation of BDNF and other trophic factors may represent a viable alternative to currently employed delivery systems in vivo and holds potential for eventual therapy of neurodegenerative disorders, in particular for peripheral neuropathies and CNS disorders where supplementation of neurotrophins retards or even prevents neural degeneration.

Animals↗
PubMed2005

[Influence of water-soluble additives on drug release kinetics from biodegradable poly(lactic-co-glycolic acid) matrix].

AIM: To evaluate the effects of an array of additives on drug release from double-layered poly(lactic-co-glycolic acid) (PLGA) matrices. METHODS: Additives differing in molecular size, hydrophilicity and steric configuration were selected for this study. An anti-proliferative 2-aminochromone, U-86983 (U-86, Pharmacia and Upjohn), was used as a model agent because of our interest in investigating local drug delivery systems for the inhibition of restenosis. RESULTS: In vitro release of U-86 PLGA matrices without additive showed a typical biphasic release kinetics, i.e. a slow diffusion release (Phase I) followed by a fast erosion-mediated release (Phase II). The water-soluble additives in PLGA matrices changed the biphasic release pattern to a near monophasic profile by increasing the release of the Phase I. Increasing the ratio of additives to PLGA in matrices caused a significant increase in U-86 release rates. A high molecular weight water-soluble additive, Pluronic F127, resulted in a matrix showing perfect zero-order release kinetics. The morphologic evaluation of matrices using scanning electron microscopy indicated that the water-soluble additives were leachable and thus generated a highly porous structure in the matrices. Conclusion Water-solubility, molecular size and steric configuration of additives are the important determinants in generating various types of pore structures in polymer matrix which in turn affect the release mechanism and release kinetics.

Biocompatible Materials↗
PubMed1996

Electro-encapsulating drugs within blood platelets: local delivery to injured arteries during angioplasty.

Prostacyclins (PGl2) inhibit platelet-platelet interactions at concentrations that do not affect platelet adhesion to collagen and other arterial subendothelial structures exposed during injury. Such compounds can be encapsulated within platelets by reversible electroporation and, using the platelet's natural haemostatic propensity, they can be targeted to injured vessels in vivo. In rat (aorta), rabbit (ileofemoral) and pig (carotid) angioplasty models, autologous platelets, electro-loaded with the stable prostacyclin iloprost and given intravenously after balloon overstretch injury, substantially reduced platelet deposition at the lesion site as compared with control platelets. In the pig model, when the drug-loaded platelets were delivered directly to the injury site during angioplasty via a double balloon delivery catheter, platelet deposition was restricted to monolayer coverage (> 80% reduction compared with controls). Candidate antiproliferative drugs (for co-encapsulating with iloprost) are being investigated in order to develop a combined antithrombotic/antirestenosis strategy for use during angioplasty and thrombolysis procedures. Autologous platelets as drug-targeting vehicles should obviate many of the immunological, toxicological and biodegradability concerns inherent in the use of other drug transport vectors such as antibodies, viruses, liposomes and synthetic polymer microcapsules.

Angioplasty, Balloon↗
PubMed1990

Hepatic tissue distribution of doxorubicin-loaded nanoparticles after i.v. administration in reticulosarcoma M 5076 metastasis-bearing mice.

In our previous studies, doxorubicin-loaded polyisohexylcyanoacrylate nanoparticles have been proven to increase dramatically the antitumoral activity of the cytotoxic agent in metastasis-bearing mice. The experimental model consisted of metastases induced by i.v. inoculation of reticulosarcoma M 5076 cell suspension to C57BL/6 mice. The improved efficacy of the drug was noted in terms of either metastasis count or survival. Therefore, tissue-distribution studies of this drug delivery system within the metastatic liver after i.v. administration were undertaken to gain more insight into the mechanism of action. Doxorubicin measurements in healthy hepatic or neoplastic tissue were carried out together with histological examinations using transmission electron microscopy. These results demonstrated the hepatic tissue to be an efficient reservoir of the drug when it was injected associated with nanoparticles. Accumulation of biodegradable nanoparticles with associated doxorubicin in Kupffer cells created a gradient of drug concentration for a massive and prolonged diffusion of the free drug towards the neoplastic tissue.

Animals↗
PubMed1985

Long-acting injectable microsphere formulation for the parenteral administration of levonorgestrel.

The pharmacokinetic and pharmacodynamic effects of a long-acting formulation of levonorgestrel microencapsulated in a biodegradable polymer poly(DL-lactide-CO-glycolide) was tested in baboons. The polymer microspheres provided continuous release of levonorgestrel for up to 6 months following a single intramuscular injection. The treatment inhibits ovarian function for 3-6 months, depending on the dose. The duration and pattern of levonorgestrel release varies according to the quality and size of the microspheres. The microsphere delivery system offers a promising new approach to developing a long-acting injectable contraceptive based on levonorgestrel.

Animals↗
PubMedDate not supplied

Polymeric nanostructures for drug delivery applications based on Pluronic copolymer systems.

The first part of this article reviewed the applications of nanostructures derived from Pluronic block copolymers that have potentials in the field of biomedical sciences. Pluronic block copolymers are used not only in drug delivery systems but also in gene and cancer therapies. In the second part, the chemical modifications of Pluronic copolymers and their applications in biomedical science were reviewed. Chemical modifications of Pluronic copolymers not only improve the properties of the polymers but they also impart more attractive properties to the block copolymers. The common systems used to modify Pluronic copolymers are polyacrylic acids, polybases, and biodegradable polyesters. Pluronics were also modified at both ends with functional groups to improve the mechanical properties of hydrogels.

Coated Materials, Biocompatible↗
PubMed2000

Tailoring new gene delivery designs for specific targets.

Advancing biotechnology spurs the development of new pharmaceutically engineered gene delivery vehicles with the capability to target specific cell types. The low density lipoprotein (LDL) element of the terplex gene carrier is shown to be efficient in delivery to smooth muscle cells as well as inducing minimal toxicity to A7R5 cells in culture. The terplex system condensed plasmid DNA into polyplex sizes ranging from 100 to 400 nm. Terplex demonstrated higher transfection efficacy than Lipofectin. Lactose was conjugated through a poly(ethyl glycol) (PEG) spacer to poly(L-lysine) (PLL) to tailor a gene carrier capable of condensing plasmid DNA. This cationic polymer targeted Hep G2 cells preferentially in culture. The inclusion of a lactose targeting moiety greatly increased the efficacy of the gene carrier over PEG-PLL and Lipofectin. A biodegradable nanoparticle gene carrier, polysaccharide-graft-PLL and poly(D,L-lactic acid), was synthesized and characterized. The nanoparticle size was controllable by changing the copolymer concentration, where the particles could be as small as 60 nm. When polysaccharide was used in the copolymer, the nanoparticle became more DNA adsorbent. The JLI mAb was linked to PLL. This gene carrier targets the antigen confined to stage II immature cortical thymocytes for leukemia therapy. A 20,000 mw PLL backbone was sufficient for compaction of DNA. Folic acid linked to PLL through a PEG spacer is currently being studied for DNA condensation and delivery to membrane associated folate binding protein positive endothelial cancer cells.

Endocytosis↗
PubMed2000

Immunization with DNA, adenovirus or both in biodegradable alginate microspheres: effect of route of inoculation on immune response.

To determine the potential for biodegradable alginate microspheres to be used as a delivery vehicle for DNA based vaccines, we constructed a plasmid, pMNe-gal-SV40, containing the bacterial beta-galactosidase (LacZ) gene under the control of the murine cytomegalovirus (MCMV) immediate-early promoter and the simian virus 40 (SV40) polyadenylation signal. The effect of the route of administration and co-administration of adenovirus on systemic and mucosal immune responses were investigated. Mice were inoculated orally, intranasally (i.n.), intramuscularly (i.m.), subcutaneously (s.c.) or intraperitoneally (i.p.) on days 0, 14 and 28 with microspheres containing plasmid DNA, bovine adenovirus type 3 (BAd3) or plasmid DNA + BAd3. Systemic routes of immunization (i.m., s.c. and i.p.) resulted in higher LacZ- or BAd3-specific IgG ELISA titers compared to those obtained by mucosal routes of inoculation (oral and i.n.). Mucosal immunization led to slightly higher titers of LacZ- or BAd3-specific IgA at mucosal sites compared to those obtained by the various systemic routes. All the routes of immunization induced LacZ-specific lymphoproliferation. Co-administration of BAd3 enhanced the LacZ-specific IgG response irrespective of the route of administration.

3T3 Cells↗
PubMed2005

Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery.

To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.

Biocompatible Materials↗
PubMed2005

Effects of EGF and bFGF on irradiated parotid glands.

Radiotherapy is common treatment for head-and-neck cancer, during which the salivary glands are often included within the radiation field. The most common side effect of this treatment is the development of oral dryness (xerostomia). This study considers the administration of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF or FGF2) at physiological concentrations before and after irradiation in order to repair radiation-induced damage in salivary gland cells. As a preliminary examination of the efficacy of this approach we have characterized the effects of EGF and bFGF on the apoptotic response of 15-Gy irradiated rat salivary glands in vitro. Also, we have developed a controlled-release delivery system to effectively administer the growth factor to the gland since local delivery is essential to avoid unwanted protection of cancer cells. In vitro administration of bFGF prior to and immediately after irradiation partially protected (44%) the rat parotid gland. EGF did not show any significant radioprotective effect on parotid glands after a single 15-Gy irradiation dose. Encapsulation, storage and release of bFGF from biodegradable 50/50 PLGA microspheres did not affect the functionality of the growth factor in vitro.

Animals↗
PubMed2006

Sulfated chitin and chitosan as novel biomaterials.

Chitin and chitosan are known to be natural polymers and they are non-toxic, biodegradable and biocompatible. Chemical modification of chitin and chitosan with sulfate to generate new bifunctional materials is of interest because the modification would not change the fundamental skeleton of chitin and chitosan, would keep the original physicochemical and biochemical properties and finally would bring new or improved properties. The sulfated chitin and chitosan have a variety of applications, such as, adsorbing metal ions, drug delivery systems, blood compatibility, and antibacterial field. The purpose of this review is to take a closer look about the different synthetic methods and potential applications of sulfated chitin and chitosan. Based on current research and existing products, some new and futuristic approaches in this context area are discussed in detail. From the studies reviewed, we concluded that sulfated chitin and chitosan are promising materials for biomedical applications.

Biocompatible Materials↗
PubMed1990

A new degradable controlled release device for treatment of periodontal disease: in vitro release study.

The substantivity of a drug in the periodontal pocket is an important factor determining its effect on the subgingival flora. Therefore, one of the predominant factors in the development of a sustained release delivery device is the ability to control the rate of release of the drug. Previous studies have demonstrated the advantages of the local sustained release of chlorhexidine from nondegradable devices in the treatment of periodontal diseases. The aim of this study was to develop a degradable sustained release device composed of a cross-linked protein containing chlorhexidine as the therapeutic agent. The in vitro release profile of chlorhexidine from the degradable films was altered by the amount of chlorhexidine incorporated into the film, by the cross-link density of the polymer, and by the chlorhexidine salt used. The chlorhexidine in the final pharmaceutical preparation did not lose its antibacterial activity as was shown in an in vitro antibacterial test. This work demonstrates that the release of chlorhexidine from a degradable delivery system and the degradation of the matrix can be controlled by variation in the formulation. This presents a new dental drug delivery system that can be used as an adjunct in the treatment of periodontal diseases in the future. These studies enable us to choose the pharmaceutical formulations for clinical trials to be conducted testing the efficacy of this treatment modality.

Biodegradation, Environmental↗