Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone morphogenetic proteins (BMPs) that have the potential to elicit new bone in vivo have been used in a tissue-engineering approach for the repair of bone injuries and bone defects. Although it is now possible to generate large amounts of recombinant human (rh) BMPs for medical use, the major challenge remains in the development of optimal local delivery systems for these proteins. Here we describe the development of a synthetic biodegradable polymer, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block copolymer (PLA-DX-PEG). This polymer exhibits promising degradation characteristics for BMP delivery systems and good biocompatibility under test conditions. PLA-DX-PEG/rhBMP-2 composite implants induced ectopic new bone formation effectively when tested in vivo, and can repair large bone defects orthotopically. This polymeric delivery system represents an advance in the technology for the enhancement of bone repair.
 ...
PMID:A biodegradable polymer as a cytokine delivery system for inducing bone formation. 1128 90

Gelatin microparticles were prepared by co-lyophilization with poly(ethylene glycol) (PEG) as a protein micronization adjuvant. Aqueous solutions containing gelatin and PEG at various mixing ratios were freeze-dried. The lyophilizates were dispersed in methylene chloride and subjected to particle size analysis. The particle size decreased as the PEG/gelatin ratio increased. The microparticles isolated from the suspension had spherical microdomains with sizes ranging from 1 to 10 microm, which indicated that phase separation between PEG and gelatin during freezing was involved in the formation mechanism of gelatin microparticles. By using this technology, gelatin microparticles with an average size of less than 10 microm, with high purity of more than 90% and with good dispersibility could be obtained with high yield. The gelatin microparticles with average sizes from 5 to 20 microm were applied to encapsulation into biodegradable PLGA/PLA microspheres via a solid-in-oil-in-water emulsion process. The entrapment efficiency was highly dependent on the particle size and the size distribution, signifying that solid microparticles with an average diameter of less than 5 m and an maximal diameter of less than 10 microm would be required for effective encapsulation. These gelatin microparticles would be useful for studying and developing various drug delivery systems.
 ...
PMID:Preparation of gelatin microparticles by co-lyophilization with poly(ethylene glycol): characterization and application to entrapment into biodegradable microspheres. 1133 73

The development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, taxol, in poly(ethylene glycol) (PEG)-coated biodegradable poly(lactic acid) (PLA) microspheres with a mean diameter of 2-6 microm. A solution of taxol and PLA dissolved in an acetone/dichloromethane mixture was poured into an aqueous solution of PEG [or poly(vinyl alcohol) (PVA] with stirring with a high-speed homogenizer for the formation of microspheres. Taxol recovery in PLA-PEG microspheres was higher (61.2 +/- 2.3%) than with PVA-based (41.6 +/- 1.8%) preparations. An analysis by diffuse reflectance infrared Fourier transform spectroscopy revealed that PEG was incorporated well on the PLA microsphere surface. Scanning electron microscopy revealed that the PEG-coated PLA microspheres were spherical in shape and had a smooth surface texture like those of PVA-based preparations. The amount of drug release was much higher initially (25-30%); this was followed by a constant slow-release profile for a 30-day period of study. This PEG-coated PLA microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.
 ...
PMID:Controlled delivery of taxol from poly(ethylene glycol)-coated poly(lactic acid) microspheres. 1142 3

The purpose of the present work was to produce and characterize poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) nanoparticles (size lower than 300 nm) containing a high loading of plasmid DNA in a free form or co-encapsulated with either poly(vinyl alcohol) (PVA) or poly(vinylpyrrolidone) (PVP). The plasmid alone or with PVA or PVP was encapsulated by two different techniques: an optimized w/o/w emulsion-solvent evaporation technique as well as by a new w/o emulsion-solvent diffusion technique. Particle size, zeta potential, plasmid DNA loading and in vitro release were determined for the three plasmid-loaded formulations. The influence of the initial plasmid loadings (5, 10, 20 microg plasmid DNA/mg PLA-PEG) on those parameters was also investigated. The plasmid loaded into the nanoparticles and released in vitro was quantified by fluorimetry and the different molecular forms were identified by gel electrophoresis. PLA-PEG nanoparticles containing plasmid DNA in a free form or co-encapsulated with PVA or PVP were obtained in the range size of 150-300 nm and with a negative zeta potential, both parameters being affected by the preparation technique. Encapsulation efficiencies were high irrespective of the presence of PVA or PVP (60-90%) and were slightly affected by the preparation technique and by the initial loading. The final plasmid DNA loading in the nanoparticles was up to 10-12 microg plasmid DNA/mg polymer. Plasmid DNA release kinetics varied depending on the plasmid incorporation technique: nanoparticles prepared by the w/o diffusion technique released their content rapidly whereas those obtained by the w/o/w showed an initial burst followed by a slow release for at least 28 days. No significant influence of the plasmid DNA loading and of the co-encapsulation of PVP or PVA on the in vitro release rate was observed. In all cases the conversion of the supercoiled form to the open circular and linear forms was detected. In conclusion, plasmid DNA can be very efficiently encapsulated, either in a free form or in combination with PVP and PVA, into PLA-PEG nanoparticles. Additionally, depending on the processing conditions, these nanoparticles release plasmid DNA either very rapidly or in a controlled manner.
 ...
PMID:Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA. 1145 11

The aim of our work was to examine the relationship between modifications of the surface of nanocapsules (NC) by adsorption or covalent grafting of poly(ethylene oxide) (PEG), and changes in their phospholipid (PL) content on complement activation (C3 cleavage) and on uptake by macrophages. The physicochemical characterization of the NC included an investigation of their properties, such as surface charge, size, hydrophilicity, morphology and homogeneity. This is the first time that such properties have been correlated with biological interactions for NC, a novel carrier system with a structure more complex than nanospheres. C3 crossed immunoelectrophoresis revealed the reduced activation for NC with longer PEG chain and higher density, although all formulations induced C3 cleavage to a lesser or greater extent. NC bearing PEG covalently bound to the surface were weaker activators of complement than plain PLA [poly(D,L-lactide)] NC or nanospheres (NS). Furthermore, the fluorescent/confocal microscopy of J774A1 cells in contact with NC reveal a dramatically reduced interaction with PEG-bearing NC. However, the way in which PEG was attached (covalent or adsorbed) seemed to affect the mechanism of uptake. Taken together, these results suggest that the low level of protein binding to NC covered with a high density of 20kDa PEG chains is likely to be due to the steric barriers surrounding these particles, which prevents protein adsorption and reduces their interaction with macrophages.
 ...
PMID:Relationship between complement activation, cellular uptake and surface physicochemical aspects of novel PEG-modified nanocapsules. 1157 71

A formaldehyde-mediated aggregation pathway (FMAP) has been shown to be primarily responsible for the solid-state aggregation of lyophilized formalinized protein antigens [e.g., tetanus toxoid (TT) and formalinized bovine serum albumin (f-BSA)] in the presence of moisture and physiological temperature. Coincorporation of the formaldehyde-interacting amino acid, histidine, strongly inhibits the FMAP. The purpose of this study was to test whether previous solid-state data are applicable toward the stabilization of formalinized antigens encapsulated in poly(lactide-co-glycolide) (PLGA)-based microspheres. Formaldehyde-treated bovine serum albumin (f-BSA) and BSA were selected as a model formalinized protein antigen and a nonformalinized control, respectively. As in the solid state, we found that the FMAP was dominant in the aggregation of f-BSA encapsulated in PLGA 50/50 microspheres, whereas the aggregation mechanism of encapsulated BSA was mostly converted from thiol-disulfide interchange to an acid-catalyzed noncovalent pathway. The lack of noncovalent aggregation in encapsulated f-BSA could be explained by its higher thermodynamic stability after formalinization, which inhibits protein unfolding. Targeting the FMAP, coencapsulation of histidine and trehalose successfully inhibited the aggregation of f-BSA in microspheres. By combining the use of an optimized oil-in-oil (o/o) encapsulation method, coencapsulation of histidine and trehalose, and use of low-acid-content poly(D,L-lactide) (PLA) and poly(ethylene glycol) (PEG) blends, a 2-month continuous release of f-BSA was achieved with the absence of aggregation.
 ...
PMID:Stabilization of a model formalinized protein antigen encapsulated in poly(lactide-co-glycolide)-based microspheres. 1174 14

Insulin and insulin/poly(ethylene glycol) (PEG)-loaded poly(l-lactide) (PLA) nanoparticles were produced by gas antisolvent (GAS) CO(2) precipitation starting from homogeneous polymer/protein organic solvent solutions. Different amounts of PEG 6000 (0, 10, 30, 50, 100, and 200% PEG/PLA w/w) or concentration of 30% PEG/PLA with PEGs with different molecular weight (MW; 350, 750, 1900, 6000, 10,000, and 20,000) were used in the preparations. The process resulted in high product yield, extensive organic solvent elimination, and maintenance of > 80% of the insulin hypoglycemic activity. Nanospheres with smooth surface and compact internal structure were observed by scanning electron microscopy. The nanospheres presented a mean particle diameter in the range 400-600 nm and narrow distribution profiles. More than 90% of drug and PEG were trapped in the PLA nanoparticles when low MW PEGs were used in the formulation, whereas the addition of high MW PEGs significantly reduced the loading yield. In all cases, in vitro release studies showed that only a little amount of drug was released from the preparations. However, formulations containing low MW PEGs allowed for a slow but constant drug release throughout 1500 h, whereas a burst was obtained by increasing the PEG MW. In conclusion, the GAS process offers a mean to produce protein-loaded nanoparticles possessing the prerequisites for pharmaceutical applications. The PEG added to the formulation was found to play a key role in the simultaneous solute precipitation phenomena and in determining the release behavior and the chemical-physical properties of the formulation.
 ...
PMID:Production of insulin-loaded poly(ethylene glycol)/poly(l-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques. 1174 21

Poly(lactic acid)-poly(ethylene glycol)-biotin (PLA-PEG-biotin) is a degradable polymer with protein resistant properties that can undergo rapid surface engineering in aqueous media to create biomimetic surfaces. Surface engineering of this polymer is dependent on biomolecular interactions between the biotin end group and the protein avidin. Given the vigorous conditions of synthesis, it is essential that the manufacture of the polymer does not alter the biotin structure or its molecular recognition. Equally, it is important that the incorporation of biotin does not adversely affect the physicochemical properties of the polymer. (1)H NMR provides evidence of biotin attachment and structural integrity. (1)H NMR, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC) analysis shows there is no significant effect on bulk properties induced by the biotin end group. Surface plasmon resonance (SPR) and fluorescent spectroscopy studies using the 2-(4'-hydroxyazobenzene) benzoic acid (HABA)/avidin complex show that the biotin moieties binding capabilities are not impaired by the synthesis.
 ...
PMID:Synthesis and characterisation of a degradable poly(lactic acid)-poly(ethylene glycol) copolymer with biotinylated end groups. 1174 23

The micellar-like particle systems produced from poly-D,L-lactide-poly(ethylene glycol) (PLA-PEG) copolymers have been assessed using a range of physicochemical characterisation methods, followed by in vivo studies of their biodistribution after intravenous administration to the rat. The size of the PEG chain was kept constant at 5 or 2 kDa, while the PLA size increased within a series from 2 to 25 kDa. The results obtained reveal, that in an aqueous medium the copolymers assembled into micellar-like structures, with the PLA segments forming the core and the PEG segments the surrounding corona. The size of the PLA segments dominated the process of assembly of the molecules and the characteristics of the resultant micellar-like particles. The PLA-PEG micellar particles were found to be less dynamic than those obtained from conventional surfactants. Particles formed from the lower molecular weight PLA polymers allowed a level of chain mobility while the cores of the micellar particles formed from higher molecular weight PLA appeared to be solid-like in nature. The size of the micellar particles was dependent on the copolymer molecular weight and the z-average diameter increased from 25 to 76 nm as the molecular weight of the PLA moiety increased. This provides an ability to control the particle size by adjusting the molecular weight of the PLA moiety. Following intravenous administration to the rat model, micellar-like particles smaller than approximately 70 nm accumulated in the liver, despite the fact that the PEG corona provided an effective steric stabilization effect. Micellar-like particles with a diameter of more than approximately 70 nm exhibited prolonged systemic circulation and reduced liver uptake, although the steric stabilisation of these particles was shown to be less effective. These findings agree with recent observations from other research groups; that indicate a possibility that very small particulates can pass through the sinusoidal fenestrations in the liver and gain access to the parenchymal cells of the liver.
 ...
PMID:Polylactide-poly(ethylene glycol) micellar-like particles as potential drug carriers: production, colloidal properties and biological performance. 1177 Jul 6

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.
 ...
PMID:Design of biodegradable particles for protein delivery. 1177 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>