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

We have prepared a semi-interpenetrating network (IPN) of poly(ethylene glycol) dimethacrylate (PEGDMA) with entrapped poly(D,L-lactide) (PLA) using photochemical techniques. These IPNs were developed for the controlled delivery of protein drugs such as growth factors. The PEG component draws water into the network, forming a hydrogel within the PLA matrix, controlling and facilitating release of the protein drug, while the PLA component both strengthens the PEG hydrogel and enhances the degradation and elimination of the network after the protein drug is released. The rate and extent of swelling and the resultant protein release kinetics could be controlled by varying the PEG/PLA ratio and total PLA content. These IPNs were prepared using a biocompatible benzyl benzoate/benzyl alcohol solvent system that yields a uniform, fine dispersion of the protein throughout the PEG/PLA IPN matrix. IPNs composed of high molecular mass PLA and lower PEG/PLA ratios exhibited lower equilibrium swelling ratios. The release of bovine serum albumin (BSA), a model protein, from these IPNs was characterized by a large initial burst, regardless of the PEG/PLA ratio, due to the entrapment of residual solvent within the network. Microparticles of the PEG/PLA IPNs were also prepared using a modified Prolease strategy. Residual solvent removal was significantly enhanced using this process. The microparticles also exhibited a significant reduction in the initial burst release of protein. Mixtures of different compositions of PEG/PLA microparticles should be useful for the delivery of a variety of protein drugs with different release kinetics from any tissue-engineering matrix.
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PMID:Semi-interpenetrating network of poly(ethylene glycol) and poly(D,L-lactide) for the controlled delivery of protein drugs. 1579 85

A novel poly(DL-lactic acid) (PLA) derivative with a diethoxy propanol ester at the end, named PLA-acetal, was synthesized by ring opening polymerization using DL-lactide and 3,3-diethoxy propanol. PLA-acetal was hydrolyzed to a PLA derivative with a formyl group, named PLA-aldehyde, by acid treatment. Reductive amination between PLA-aldehyde and methoxypolyethylene glycol amine (MeO-PEG(N)) gave the block copolymer (PLA-(MeO-PEG(N))). Nanoparticles were prepared by emulsification-solvent evaporation or solvent diffusion using PLA-(MeO-PEG(N)) or a conventional methoxypolyethylene glycol-PLA block copolymer, PLA-(MeO-PEG(O)). PLA-(MeO-PEG(N)) nanoparticles had a particle size of 60-340 nm, dependent on the preparative procedure, while PLA-(MeO-PEG(O)) nanoparticles prepared by solvent diffusion showed a particle size of 60 nm. The PLA-(MeO-PEG) nanoparticles with a smaller PEG introduction degree exhibited a more negative zeta potential. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD) could be incorporated efficiently in PLA-(MeO-PEG(N)) nanoparticles. It is suggested that PLA-aldehyde should be useful as a functional intermediate for derivatization of PLA, and PLA-(MeO-PEG(N)) can be used for the preparation of PEG-coated PLA nanoparticles.
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PMID:Preparation of a PLA-PEG block copolymer using a PLA derivative with a formyl terminal group and its application to nanoparticulate formulation. 1581 47

The objective of this research is to develop injectable polymers solution based controlled release delivery systems for testosterone (TSN), using phase sensitive and thermosensitive polymers. A combination of poly(lactide) (PLA) and solvents mixture of benzyl benzoate (BB) and benzyl alcohol (BA) was used in the phase sensitive polymer delivery system. The effects of solvents system and drug loading on the in vitro TSN release were evaluated. In the case of thermosensitive polymer delivery systems, a series of low-molecular-weight poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with varying ratio of lactide/glycolide (LA/GA, 2.0-3.5) were studied to control the release of TSN. The effects of varying block length of copolymers 1-4 on the in vitro TSN release were evaluated. Phosphate buffer saline (pH 7.4) containing 0.5% (w/v) Tween-80 was used as in vitro release medium. The amount of the released TSN was determined by an HPLC method. A controlled (zero-order) in vitro release of TSN was observed from both the phase sensitive and thermosensitive polymer delivery systems. Addition of BA (15%, v/v) in solvents system significantly (p<0.05) increased the release rate of TSN (0.33+/-0.01 mg/ml) from phase sensitive delivery system in comparison to solvent without BA (0.27+/-0.00 mg/day). Increasing drug loading also increased release rate. In the case of thermosensitive polymer delivery system, increasing the hydrophobic PLGA block length of copolymers significantly (p<0.05) decreased the release rate of TSN. It is evident from this study that the phase sensitive and thermosensitive polymers are suitable for developing prolong-release injectable implant delivery systems for TSN.
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PMID:Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation. 1584 3

Our newly developed drug delivery carrier, cationic bovine serum albumin (CBSA) conjugated with poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was designed for brain drug delivery. CBSA, as a brain specific targetor, was covalently conjugated with the maleimide function group at the distal of poly(ethyleneglycol) (PEG) surrounding the nanoparticles. To evaluate its blood-brain barrier (BBB) transcytosis and toxicity against the BBB endothelial tight junction, we have explored a method of coculture with brain capillary endothelial cells (BCECs) on the top of micro-porous membrane of cell culture insert and astrocytes on the bottom side. The permeability of 14C-labeled sucrose was determined. For the CBSA-NP transcytosis study, a lipophilic fluorescent probe, 6-coumarin, was incorporated into nanoparticles. The BBB permeability of CBSA-NP in vitro was calculated and compared with native bovine serum albumin (BSA) conjugated pegylated nanoparticles (BSA-NP). As the coculture model, the transendothelial electrical resistance reached up to 313+/-23 ohms cm2. The tight junction between BCECs in the coculture could be visualized by scanning electron microscopy and transmission electron microscopy. The unchanged permeability of 14C-labeled sucrose comparing to that in the appearance of 200 microg/ml of CBSA-NP proved that CBSA-NP did not impact the integrity of BBB endothelial tight junctions. CBSA-NP also showed little toxicity against BCECs. The permeability of CBSA-NP was about 7.76 times higher than that of BSA-NP, while the transcytosis was inhibited in the excess of free CBSA. It was concluded that CBSA-NP preferentially transported across BBB with little toxicity, which offered the possibility to deliver therapeutic agents to CNS.
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PMID:Cationic albumin conjugated pegylated nanoparticle with its transcytosis ability and little toxicity against blood-brain barrier. 1584 9

Bone morphogenetic proteins (BMP) induce bone formation in vivo, and clinical application in repair of bone fractures and defects is expected. However, appropriate systems to deliver BMP for clinical use need to be developed. We synthesized a new synthetic biodegradable polymer, poly-D,L-lactic acid-para-dioxanone-polyethylene glycol block copolymer (PLA-DX-PEG), to serve as a biocompatible, biodegradable polymer for recombinant human (rh) BMP-2 delivery systems. In animal experiments, new bone was efficiently formed and a large bone defect was repaired using PLA-DX-PEG/rhBMP-2 composites. In addition, this new polymer could be used as an injectable delivery system for rhBMP-2. The rhBMP-2/PLA-DX-PEG composites also could be combined with other materials such as hydroxyapatite or titanium. This new synthetic polymer might be used for rhBMP-2 delivery in various clinical situations involving repair of bone, leading to great changes in orthopedic treatment.
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PMID:Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins. 1587 2

The objective of this research is to develop injectable controlled delivery systems for the contraceptive hormone, levonorgestrel (LNG), using phase sensitive and thermosensitive polymers. A combination of poly (lactide) (PLA) and a solvent mixture of benzyl benzoate (BB) and benzyl alcohol (BA) was used in the phase-sensitive polymer delivery systems. The effects of solvent systems and polymer concentrations on the in vitro LNG release were evaluated. In the case of thermosensitive polymer delivery systems, a series of low-molecular-weight poly (lactide-co-glycolide)-poly (ethylene glycol)-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with varying ratios of lactide/glycolide (LA/GA, 2.0-3.5) were used. The effects of varying block length of copolymers 1, 2, 3, and 4 on the in vitro LNG release were evaluated. Phosphate buffer saline (pH 7.4) containing 0.5% w/v Tween-80 was used as in vitro release medium. The amount of the released LNG was determined by an high pressure liquid chromatography (HPLC) method. A controlled (zero-order) in vitro release of LNG was observed from both phase-sensitive and thermosensitive-polymer delivery systems. Increasing the concentration of the phase-sensitive polymer from 5% to 30% significantly (p < 0.05) decreased the release rate of LNG from 38.32 microg/day to 31.45 microg/day; and increasing the hydrophilic fraction of the solvents mixture (i.e., BA) significantly (p < 0.05) increased the release rate of LNG. In the case of the thermosensitive polymer delivery system, increasing the hydrophobic PLGA block length of copolymers significantly (p < 0.05) decreased the release rate of LNG (98.65 microg/day to 67.60 microg/day). It is evident from this study that both the phase sensitive and thermosensitive polymers are suitable for developing prolonged-release injectable delivery systems for the contraceptive hormone.
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PMID:In vitro release of levonorgestrel from phase sensitive and thermosensitive smart polymer delivery systems. 1592 81

Triblock copolymer PLA-PEG-PLA were synthesized using ring opening polymerization with different LA/EG ratio. Micellar aggregates were prepared from these block copolymers and characterized. The degradation characteristics of selected copolymers were assessed in both micellar and film forms. Surface segregation of PEG was also quantified as a function of copolymer composition. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanospheres with good efficiency. The drug release profile showed good control over the release of paclitaxel from these polymers.
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PMID:Micelle-like nanoparticles of PLA-PEG-PLA triblock copolymer as chemotherapeutic carrier. 1594 11

This paper focuses on the dependence of the rheological properties of PLA-PEG and PLGA dispersions and films on the polymer structural properties, in order to obtain useful information to predict and explain the performance of polyester films as drug-delivery systems. In this study, one PLA-PEG and three PLGA polymers of different molecular mass were synthesized and characterized by NMR, GPC, DSC and TGA-FT-IR. To characterize the viscoelastic behaviour of concentrated solutions in dichloromethane and of the films obtained by a solvent-casting technique, oscillatory shear rheometry was used. The polymer dispersions showed a characteristic Newtonian viscous behaviour, but with different consistency index depending on the nature of the polymer. Freshly prepared, PLGA and PLA-PEG films had elastic modulus (G') greater than viscous modulus (G"). The decrease in both moduli caused by an increase in temperature from 25 to 37 degrees C was especially marked for the polymers with T(g) below or around 25 degrees C (PLGA 27 kDa and PLA-PEG 27 kDa). After being immersed in pH 7.4 aqueous solution for one week, PLGA films showed a significant increase in both G' and G", due to the promotion of polymer-polymer interactions in a non-solvent medium. In contrast, the PLA-PEG film became softer and more hydrated, due to the amphiphilic character of the polymer. The water taken up by the film acted as a plasticizer and induced the softening of the system. These results suggest that the presence of PEG chains exerts a strong influence on the mechanical properties of polyesters films and, possibly, the performance as coating or matrices of drug-delivery systems.
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PMID:Structural properties of biodegradable polyesters and rheological behaviour of their dispersions and films. 1600 21

A novel biodegradable amphiphilic triblock copolymer bearing pendant carboxyl groups PLGG-PEG-PLGG was successfully prepared by ring-opening copolymerization of l-lactide (LA) with (3s)-benzoxylcarbonylethyl-morpholine-2, 5-dione (BEMD) in the presence of dihydroxyl poly(ethylene glycol) (PEG) as a macroinitiator in bulk at 130 degrees C using SnOct(2) as catalyst and by subsequent catalytic hydrogenation. The copolymer could form micelles in aqueous solution with the cmc dependent on the composition of the copolymer. The micelles exhibited a homogeneous spherical morphology and a unimodal size distribution. Their degradation rate in the presence of proteinase K was faster than that of PLA, and they showed a low degree of cytotoxicity to the articular cartilage cells. This biodegradable amphiphilic block copolymer with pendant carboxyl groups is capable of further modification and is expected to facilitate a variety of potential biomedical applications, such as drug carriers, tissue engineering, etc.
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PMID:Synthesis and characterization of biodegradable amphiphilic triblock copolymers containing L-glutamic acid units. 1600 33

Recombinant human bone morphogenetic protein (rhBMP) is viewed as a therapeutic cytokine because of its ability to induce bone. However, the high doses of rhBMP required for bone induction in humans remain a major hurdle for the therapeutic application of this protein. The development of a methodology that would effectively overcome the weak responsiveness to human BMP is highly desired. In the present study, we investigate the ability of a prostaglandin E EP4 receptor selective agonist (EP4A) to augment the bone-inducing ability of BMP in a biodegradable delivery system. A block copolymer composed of poly-D,L-lactic acid with random insertion of p-dioxanone and polyethylene glycol (PLA-DX-PEG, polymer) was used as the delivery system. Polymer discs containing rhBMP-2 and EP4A were implanted into the left dorsal muscle pouch of mice to examine the dose-dependent effects of EP4A. Fifty mice were divided into 5 groups based on the contents of rhBMP and EP4 in the polymer (group 1; BMP 5 microg EP4A 0 microg, group 2; BMP 5 microg EP4 3 microg, group 3; BMP 5 microg EP4 30 microg, group 4; BMP 5 microg EP4 300 microg, group 5; BMP 0 microg EP4 30 microg, n=10 each). All implants were harvested, examined radiologically, and processed for histological analysis 3 weeks after surgery. On dual-energy X-ray absorptiometry (DXA) analysis, the bone mineral content (BMC) of the ossicles was 6.52+/-0.80 (mg), 9.36+/-1.89, 14.21+/-1.27, and 18.75+/-2.31 in groups 1, 2, 3, and 4 respectively. In terms of BMC, the values of groups 3 and 4 were significantly higher than those of group 1. The mean BMC value of group 4 was approximately 3 times higher than that of group 1. No significant difference in body weight was noted among the groups during the experimental period. In summary, the presence of a prostaglandin E EP4 receptor selective agonist in the carrier polymer enhanced the bone-inducing capacity of rhBMP-2 with no apparent systemic adverse effects.
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PMID:Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist. 1602 58


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