Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0267964 (PAA)
 2,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigate the static properties of a water-dispersed lamellar ( L) phase formed in the melt state with a nearly symmetric poly(styrene)-block-poly(acrylic acid) (PS- b-PAA) diblock copolymer. The PAA brush is considered as a model flat polyelectrolyte ( PE) brush of controlled surface density. Thanks to small-angle X-ray scattering, its behavior in water is studied as a function of (i) its ionization, through the pH of the dispersions which is increased by an addition of a known amount of a base, i.e. sodium hydroxyde NaOH, and (ii) in the presence of a monovalent salt, i.e. sodium chloride NaCl, of concentration C(S). At low pH, we find that the brush effectively behaves as a neutral brush. At high pH, the brush is in the so-called "osmotic regime", in which all sodium counterions are trapped within the brush volume and stretch the chains via an osmotic effect. The properties of such a brush in the presence of a monovalent salt, confirm this result, showing a C(S)(-1/3) dependence in the brush height L(O), in agreement with mean-field predictions. The L(O)- C(S) profiles at different ionizations give access to the actual brush internal charge fraction f. The results are found to be in very good quantitative agreement with experimental measures found in the literature, and can be completely and quantitatively described by Oosawa's approach to counterion condensation in a semi-dilute to concentrated solution of charged, rod-like chains.
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PMID:Water-dispersed lamellar phases of symmetric poly(styrene)-block-poly(acrylic acid) diblock copolymers: model systems for flat dense polyelectrolyte brushes. 1502 11

On exposure to an acidic pH, linear poly(amidoamine)s (PAAs) cause membrane perturbation and consequently have potential as endosomolytic polymers for the intracellular delivery of genes and toxins. Previous studies used PAAs in the hydrochloride form only. The aim of this study was to investigate systematically the effect of the PAA counterion on pH-dependent membrane activity, general cytotoxicity, and PAA solution properties to help guide optimization of PAA structure for further development of PAA-protein conjugates. PAAs (ISA 1, 4, 22, and 23; M(w) 10000-50000 g/mol) were synthesized to provide a library of PAAs having different counterions including the acetate, citrate, hydrochloride, lactate, phosphate, and sulfate salts. pH-Dependent membrane activity was assessed using a rat red blood cell haemolysis assay (conducted at a starting pH of 7.4, 6.5, or 5.5; 1 mg/mL; 1 h), and general cytotoxicity was investigated using a murine melanoma cell line (B16F10) and a human bladder endothelial-like cell line (ECV-304). Whereas poly(ethyleneimine) was haemolytic at the starting pH of 7.4 at 1 h [ approximately 50% haemoglobin (Hb) release], none of the PAA salts were haemolytic at a starting pH of 7.4 or 6.5. Although PAA acetate, citrate, and lactate were also non-haemolytic at the starting pH of 5.5, the sulfate and hydrochloride forms caused significant haemolysis (up to 80% Hb release) and ISA 22 and 23 phosphate were also markedly haemolytic ( approximately 70% Hb release). These counterion-specific differences were also clearly visible using scanning electron microscopy, which was used to visualize the red blood cell morphology. All PAAs were relatively nontoxic (IC(50) >or= 300-5000 microg/mL) compared to poly-l-lysine (IC(50) = 2-10 microg/mL), the PAA hydrochloride salts produced the greatest cytotoxicity, and the B16F10 cells were more sensitive than the ECV-304 cells. Small-angle neutron scattering suggested that ISA 23 hydrochloride had a larger hydrodynamic radius (5.1 +/- 0.2 nm) than the citrate salt (3.1 +/- 0.2 nm). These results provide indirect evidence for the salt- and pH-dependent changes in the conformation of the polymer coil. This study clearly demonstrates the importance of optimization of the counterion form when developing endosomolytic polymers designed to mediate pH-dependent membrane permeabilization.
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PMID:Poly(amidoamine) salt form: effect on pH-dependent membrane activity and polymer conformation in solution. 1513 5

Bioresponsive poly(amidoamine)s (PAA)s are currently under development as endosomolytic polymers for intracellular delivery of proteins and genes. Here for the first time, small-angle neutron scattering (SANS) is used to systematically investigate the pH-dependent conformational change of an endosomolytic polymer, the PAA ISA 23. The radius of gyration of the ISA23 was determined as a function of pH and counterion, the aim being to correlate changes in polymer conformation with membrane activity assessed using a rat red blood cell haemolysis assay. With decreasing pH, the ISA23 radius of gyration increased to a maximum (R(g) approximately 80 A) around pH = 3, before subsequently decreasing once more. At high pH and therefore high ionic strengths, the polymer is negatively charged and adopts a rather compact structure (R(g) approximately 20 A), presumably with the dissociated carboxylic groups on the exterior of the polymer coil. At low pH, the coil again collapses (R(g) < 20 A), presumably due to the effects of the high ionic strength. It is concluded that the nature of the salt form has no direct bearing on the size of the polymer coil, but it does indirectly determine the prevailing pH and, hence, polymer conformation. Pulsed-gradient spin-echo NMR measurements were in good agreement with the SANS estimates of the radius of gyration, although ISA23 polydispersity does complicate the data interpretation/comparison. These results support the proposed mode of action of PAAs, namely a coil expansion on passing from a neutral pH (extracellular) to an acidic pH (endosomal and lysosomal) environments. The results do, however, suggest that the charge on the polymer shows a closer correlation with the haemolysis activity rather than the polymer conformation.
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PMID:Understanding the mechanism of action of poly(amidoamine)s as endosomolytic polymers: correlation of physicochemical and biological properties. 1524 60

Oral induction of a disseminated mucosal immune response with polyplex-based DNA vaccines requires the delivery of intact polyplexes (polyelectrolyte complexes formed by self-assembly of plasmid DNA with a cationic polymer) to subepithelial lymphoid tissue (e.g. Peyer's patches) within the gastrointestinal tract. This work describes the formulation of a microparticle polyplex carrier allowing the potential of this approach to be realised. PEGylated PEI/DNA polyplexes (DNA concentration 20 microg/ml) formed at N/P 5:0 (defined as the ratio of polycation amino groups to DNA phosphates) were stable to salt-induced aggregation and could be concentrated to a final DNA concentration of 1 mg/ml without polyplex size increase. Polyplexes containing 1:1 polyethylene glycol (PEG)/polyethylenimine (PEI) ratio (mass/mass) gave similar levels of luciferase gene expression in B16F10 cells compared to non-PEG complexes. Poly-(D,L-lactide-co-glycolide) (PLGA) microparticles containing PEGylated polyplexes (approximately 17% DNA encapsulation efficiency) were formulated using a modified double emulsion solvent evaporation method. The microencapsulation and release of intact polyplexes from the microparticle carrier was demonstrated using polyanion (heparin sulfate and poly(aspartic acid) (PAA)) displacement techniques and electron microscopy. Microparticles containing PEGylated polyplexes (24 microg beta-galactosidase DNA) were given orally to Wistar rats. Significant transgene expression (compared to background) was found in peripheral tissue (spleen) 72 h after administration. This work demonstrates the potential application of microparticle carriers for mucosal polyplex-based vaccination.
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PMID:Formulation of a microparticle carrier for oral polyplex-based DNA vaccines. 1537 19

According to our "block-copolymer-free" strategy for self-assembly of polymers, noncovalently connected micelles (NCCM) with poly(epsilon-caprolactone) (PCL) as the core and poly(acrylic acid) (PAA) as the shell in aqueous solutions were attained due to specific interactions between the component polymers. The micellar structure was then locked in by the reaction of PAA with diamine. Afterward, hollow spheres based on PAA network were obtained by either core degradation with lipase or core dissolution with dimethylformamide of the cross-linked micelles. The cavitation process was monitored by dynamic light scattering, which indicated a mass decrease and size expansion. The hollow structure is confirmed by transmission electron microscopy observations. The resultant hollow spheres are pH- and salt-responsive: there is a substantial volume increase when pH changes from acid to base, and vice versa. The volume change takes place dramatically over the pH-range from 5.8 to 7.5. Furthermore, this volume-pH-dependence is found to be completely reversible provided the effect of ionic strength is excluded. The volume change can be adjusted by changing the shell thickness and the cross-linking degree of the hollow spheres. The salt effect on the hollow sphere size depends on pH: with increasing salt concentration the size shows an increase, a decrease, and a little change in acidic, basic, and neutral media, respectively.
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PMID:pH-responsive core-shell particles and hollow spheres attained by macromolecular self-assembly. 1569 4

The effect of pH on the complex formation between poly(acrylic acid) (PAA) and poly(ethylene oxide) (PEO) has been studied in aqueous solutions by turbidimetric and fluorescent methods. It was shown that the formation of insoluble interpolymer complexes is observed below a certain critical pH of complexation (pH(crit1)). The formation of hydrophilic interpolymer associates is possible above pH(crit1) and below a certain pH(crit2). The effects of polymer concentrations in solution and PEO molecular weight as well as inorganic salt addition on these critical pH values were studied. The polymeric films based on blends of PAA and PEO were prepared by casting from aqueous solutions with different pHs. These films were characterized by light transmittance measurements and differential scanning calorimetry. The existence of the pH value above which the polymers form an immiscible blend was demonstrated. The transitions between the interpolymer complex, miscible blend, and immiscible blend caused by pH changes are discussed. The recommendations for preparation of homogeneous miscible films based on compositions of poly(carboxylic acids) and various nonionic water-soluble polymers are presented.
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PMID:PH effects in the complex formation and blending of poly(acrylic acid) with poly(ethylene oxide). 1587 16

Controlled drug delivery and gene transfection involve contact of artificial polyelectrolytic systems that can interact dramatically with biopolymers and cells when they are introduced in blood. Given the complexity of body aqueous media in terms of physical chemistry, a model approach was selected in attempt to understand the behavior of artificial polyelectrolytes introduced in body fluids. Selection in terms of molecular weight was highlighted in a previous paper. In the present study the formation and the stability of fractions obtained when a polycation is added to a polyanion according to a titrating process mimicking injection into blood was considered for different polycation/polyanion couples. Poly(amino serinate) and poly(L-lysine) were used as polybases, and poly(acrylic acid), poly(L-lysine citramide) and poly(L-lysine citramide imide) as polyacids. Four fractions corresponding to different positive/negative charge ratios were formed for each couple. At low polyion concentration (13 mg/L) and given salt concentration, the stability of the complex fractions depended on molecular weight and charge density of the polyions. The NaCl concentration required to destabilize the different interpolyelectrolyte complexes was found to decrease from the first fraction to the fourth one. Upon decreasing the salt concentration, macroscopic flocculation occurred in the case of PLL/PAA complex fractions only. For the other couples, dynamic light scattering showed that several hundreds nanometer sized particles were formed that were stable in a broad range of NaCl concentration, including the physiological 0.15 ionic strength. At higher polyion concentrations, stable solid precipitate was formed regardless of the system. The absence of flocculation in the case of highly diluted poly(L-lysine citramide) and poly(L-lysine citramide imide) polyanions in salted media is assigned to the presence of non-ionic hydroxyl and amide polar groups along the complexed chains. Data show that introducing non-ionic functions along the polyelectrolyte chains is a good means to keep interpolyelectrolyte complexes dispersed in salted media, a conclusion of interest in the field of condensation of genes by polycations.
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PMID:Polyelectrolyte complex formation and stability when mixing polyanions and polycations in salted media: a model study related to the case of body fluids. 1591 Dec 24

We report the development of a solid polymer electrolyte film from hydrogen bonding layer-by-layer (LBL) assembly that outperforms previously reported LBL assembled films and approaches battery integration capability. Films were fabricated by alternating deposition of poly(ethylene oxide) (PEO) and poly(acrylic acid) (PAA) layers from aqueous solutions. Film quality benefits from increasing PEO molecular weight even into the 10(6) range due to the intrinsically low PEO/PAA cross-link density. Assembly is disrupted at pH near the PAA ionization onset, and a potential mechanism for modulating PEO:PAA ratio within assembled films by manipulating pH is discussed. Ionic conductivity of 5 x 10(-5) S/cm is achievable after short exposure to 100% relative humidity (RH) for plasticization. Adding free ions by exposing PEO/ PAA films to lithium salt solutions enhanced conductivity to greater than 10(-5) S/cm at only 52% RH and tentatively greater than 10(-4) S/cm at 100% RH. The excellent stability of PEO/PAA films even when exposed to 1.0 M salt solutions led to an exploration of LBL assembly with added electrolyte present in the adsorption step. Fortuitously, the modulation of PEO/PAA assembly by ionic strength is analogous to that of electrostatic LBL assembly and can be attributed to electrolyte interactions with PEO and PAA. Dry ionic conductivity was enhanced in films assembled in the presence of salt as compared to films that were merely exposed to salt after assembly, implying different morphologies. These results reveal clear directions for the evolution of these promising solid polymer electrolytes into elements appropriate for electrochemical power storage and generation applications.
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PMID:Highly ion conductive poly(ethylene oxide)-based solid polymer electrolytes from hydrogen bonding layer-by-layer assembly. 1598 79

The bridging mechanism of antithrombin inhibition of thrombin is a dominant mechanism contributing a massive approximately 2500-fold acceleration in the reaction rate and is also a key reason for the clinical usage of heparin. Our recent study of the antithrombin-activating properties of a carboxylic acid-based polymer, poly(acrylic acid) (PAA), demonstrated a surprisingly high acceleration in thrombin inhibition (Monien, B. H.; Desai, U. R. J. Med. Chem. 2005, 48, 1269). To better understand this interesting phenomenon, we have studied the mechanism of PAA-dependent acceleration in antithrombin inhibition of thrombin. Competitive binding studies with low-affinity heparin and a heparin tetrasaccharide suggest that PAA binds antithrombin in both the pentasaccharide- and the extended heparin-binding sites, and these results are corroborated by molecular modeling. The salt-dependence of the K(D) of the PAA-antithrombin interaction shows the formation of five ionic interactions. In contrast, the contribution of nonionic forces is miniscule, resulting in an interaction that is significantly weaker than that observed for heparins. A bell-shaped profile of the observed rate constant for antithrombin inhibition of thrombin as a function of PAA concentration was observed, suggesting that inhibition proceeds through the "bridging" mechanism. The knowledge gained in this mechanistic study highlights important rules for the rational design of orally available heparin mimics.
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PMID:Mechanism of poly(acrylic acid) acceleration of antithrombin inhibition of thrombin: implications for the design of novel heparin mimics. 1607 53

Au nanoparticles encapsulated within polystyrene-block-poly(acrylic acid) (PS-b-PAA) micelles assemble into regular, one-dimensional arrays when they are exposed to solvent conditions that relax interfacial curvature in the micellar shell. Nanoparticle chaining was induced by adding salt, acid, or cationic carbodiimide to the suspension of purified encapsulated Au nanoparticles (Au@PS-b-PAA). The resulting assemblies were characterized by scanning and transmission electron microscopies, by dark-field optical microscopy, and by visible absorption spectroscopy. The length of the chains was modulated by varying the concentration of additive. More importantly, the spacing between Au nanoparticles was dictated entirely by the shell thickness of the Au@PS-b-PAA starting material. Far-field polarization microspectroscopy demonstrated directional surface plasmon coupling in a straightened nanoparticle chain, which is a basic requirement for the use of these assemblies as plasmon waveguides.
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PMID:Plasmonic nanoparticle chains via a morphological, sphere-to-string transition. 1620 95


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