Biomedical subjects

D Needham

Publications and source records attributed to D Needham.

At least 19 recordsLinked to original sources

PubMed2006

Metabolism and excretion of piperonyl butoxide in the rat.

[14C]-piperonyl butoxide (PBO) was administered to male and female rats by gavage at a dose rate of 50 or 500 mg kg-1 body weight. In all cases, the radioactivity was rapidly excreted with 87-99% being found in the 0-48-h excreta and the majority of the dose (64.1-85.0%) being eliminated in faeces. The metabolism of PBO was complex with over 25 peaks of radioactivity being seen by radio-high-performance liquid chromatography (HPLC). Using HPLC/tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR), 12 urine metabolites were assigned structures together with four plus PBO in faeces. Metabolism occurred at two sites: the methylenedioxy ring, which opened to form a catechol that could then undergo methylation, and the 2-(2-butoxyethoxy)ethoxymethyl side-chain, which underwent sequential oxidation to a series of alcohols and acids. The identified metabolites accounted for approximately 60% of the administered dose.

Administration, Oral↗

PubMed2003

Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog.

1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5 mg kg(-1) day(-1) and in dog is 1 mg kg(-1) day(-1). The maximum tolerated dose (MTD) in rat is 150 and 75 kg(-1) day(-1) for male and females, respectively. The MTD in dog is 7.5 mg kg(-1) day(-1) for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50 mg kg(-1) 14C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t(1/2) were 1.3-3.4 h for rat and 99-134 h for dog following a 5 or 50 mg kg(-1) dose, respectively. This led to large differences in the calculated AUC(0-infinity) 21-57 microg eq. h g(-1) for rat and 4889-5298 microg eq. h g(-1) for dog at 5 mg kg(-1), and 122-2358 microg eq. h g(-1) for rat and 34,110-44,296 microg eq. h g(-1) for dog at 50 mg kg(-1)). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24 h for the low dose and after 48 h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120 h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.

2,4-Dichlorophenoxyacetic Acid↗

PubMed2001

The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors.

Our laboratories have been working together in close collaboration for over 10 years concerning the design and performance of lipid-based drug delivery systems. Over the past 3 years we have conceived of, developed, and tested pre-clinically, a new liposome-based temperature-sensitive drug delivery system for the treatment of solid tumors. This work is reported in a series of four publications: "J. Liposome Res. 9 (1999) 491; Cancer Res. Adv. Brief 60(5) (2000) 1197; Cancer Res. 6(9) (2000) 748; and Cancer Res. 60 (2000) 6950". Following a brief introduction concerning the motivations behind the work, this article will review these studies, including some of our earlier work that led to these ideas, and will present the rational design of the new liposome formulation from a materials engineering perspective.

Animals↗

PubMed2001

Toronto Critical Care Medicine Symposium, 18-20 October 2001, Canada: research breakthroughs are not enough.

At the 2001 Toronto Critical Care Medicine Symposium, exciting new research results were presented, including a randomized trial of peri-operative pulmonary-artery catheter use and evidence-based guidelines for the prevention of ventilator-acquired pneumonia. Presenters reviewed other important recent critical care developments such as (1) activated protein C and low-dose steroids in sepsis, (2) prone positioning and long-term outcomes in patients with adult respiratory distress syndrome, and (3) medical errors in the critical care unit. Along with these new findings, another theme emerged during the symposium. This theme emphasized that research breakthroughs are not sufficient in themselves: outcome studies are needed to learn how new research is applied on a large-scale basis within actual clinical practice. Furthermore, additional study is needed for an understanding of how physicians implement new research findings. Successful methods of enhancing the widespread adoption of new research require further study.

Adult↗

PubMed2001

Interaction of synthetic HA2 influenza fusion peptide analog with model membranes.

The interaction of the synthetic 21 amino acid peptide (AcE4K) with 1-oleoyl-2-[caproyl-7-NBD]-sn-glycero-3-phosphocholine membranes is used as a model system for the pH-sensitive binding of fusion peptides to membranes. The sequence of AcE4K (Ac-GLFEAIAGFIENGWEGMIDGK) is based on the sequence of the hemagglutinin HA2 fusion peptide and has similar partitioning into phosphatidylcholine membranes as the viral peptide. pH-dependent partitioning in the membrane, circular dichroism, tryptophan fluorescence, change of membrane area, and membrane strength, are measured to characterize various key aspects of the peptide-membrane interaction. The experimental results show that the partitioning of AcE4K in the membrane is pH dependent. The bound peptide inserts in the membrane, which increases the overall membrane area in a pH-dependent manner, however the depth of insertion of the peptide in the membrane is independent of pH. This result suggests that the binding of the peptide to the membrane is driven by the protonation of its three glutamatic acids and the aspartic acid, which results in an increase of the number of bound molecules as the pH decreases from pH 7 to 4.5. The transition between the bound state and the free state is characterized by the Gibbs energy for peptide binding. This Gibbs energy for pH 5 is equal to -30.2 kJ/mol (-7.2 kcal/mol). Most of the change of the Gibbs energy during the binding of AcE4K is due to the enthalpy of binding -27.3 kJ/mol (-6.5 kcal/mol), while the entropy change is relatively small and is on the order of 6.4 J/mol.K (2.3 cal/mol.K). The energy barrier separating the bound and the free state, is characterized by the Gibbs energy of the transition state for peptide adsorption. This Gibbs energy is equal to 51.3 kJ/mol (12.3 kcal/mol). The insertion of the peptide into the membrane is coupled with work for creation of a vacancy for the peptide in the membrane. This work is calculated from the measured area occupied by a single peptide molecule (220 A(2)) and the membrane elasticity (190 mN/m), and is equal to 15.5 kJ/mol (3.7 kcal/mol). The comparison of the work for creating a vacancy and the Gibbs energy of the transition state shows that the work for creating a vacancy may have significant effect on the rate of peptide insertion and therefore plays an important role in peptide binding. Because the work for creating a vacancy depends on membrane elasticity and the elasticity of the membrane is dependent on membrane composition, this provides a tool for modulating the pH for membrane instability by changing membrane composition. The insertion of the peptide in the membrane does not affect the membrane permeability for water, which shows that the peptide does not perturb substantially the packing of the hydrocarbon region. However, the ability of the membrane to retain solutes in the presence of peptide is compromised, suggesting that the inserted peptide promotes formation of short living pores. The integrity of the membrane is substantially compromised below pH 4.8 (threshold pH), when large pores are formed and the membrane breaks down. The binding of the peptide in the pore region is reversible, and the pore size varies on the experimental conditions, which suggests that the peptide in the pore region does not form oligomers.

Amino Acid Sequence↗

PubMed2001

Factors affecting time delay to treatment in a tuberculosis control programme in a sub-Saharan African country: the experience of The Gambia.

SETTING: Rural and urban health centres in The Gambia, West Africa. OBJECTIVES: To estimate the time delay between onset of symptoms and initiation of treatment and identify the risk factors influencing the delay in patients with tuberculosis (TB). DESIGN: Structured interviews with newly diagnosed TB patients aged over 15 years presenting to TB control staff in four health centres. RESULTS: A total of 152 TB patients were interviewed. The median delay from onset of symptoms to commencement of treatment was 8.6 weeks (range 5-17). Delay to treatment was independent of sex, but was shorter in young TB patients. The median delay was longer in rural than in urban areas (12 weeks [range 8.5-17] vs. 8 [4-12], P < 0.01) and in those who did not attend school, but this effect disappeared after adjusting for age and area of residence. Patients who reported haemoptysis as one of their initial symptoms had shorter delays to treatment. There was no relation between duration of delay to treatment and cure rate, but longer delay did increase the risk of death. CONCLUSION: Starting TB patients on treatment as early as possible plays a major role in reducing disease transmission in the community. Key to this is increasing awareness of the signs and symptoms of TB and ensuring easy access to diagnostic facilities and treatment.

Adolescent↗

PubMed2000

Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release.

The tumor drug concentrations, drug distributions, and therapeutic efficacies achieved by three fundamentally different liposomes, nonthermosensitive liposome (NTSL), traditional thermosensitive liposome (TTSL), and low temperature sensitive liposome (LTSL); free doxorubicin (DOX); and saline in combination with hyperthermia (HT) were directly compared in a human tumor xenograft model. NTSL is a nonthermosensitive liposome in the physiological temperature range, TTSL is a traditional thermosensitive liposome that triggers in the range of approximately 42-45 degrees C and releases drug over approximately 30 min, and LTSL is a new low temperature sensitive liposome that triggers in the range of approximately 39-40 degrees C and releases drug in a matter of seconds. Because of the different attributes of the liposomes, it was possible to delineate the relative importance of liposome drug encapsulation, HT cytotoxicity, HT-drug interaction, HT-induced liposomal delivery, and HT-triggered liposomal drug release in achieving antitumor activity. Athymic nude mice bearing the FaDu human tumor xenograft were given a single i.v. dose of 5 mg/kg of DOX (free drug or liposome encapsulated), and the tumors were then heated to either 34 degrees C or 42 degrees C for 1 h at 34 degrees C. All treatment groups were similar, achieving low concentrations of DOX (0-4.5 ng/mg). At 42 degrees C, the LTSL (25.6 ng/mg) achieved the highest DOX concentration (P < 0.04), but all three liposomal formulations (7.3-25.6 ng/mg) were higher than saline or DOX (0-0.7 ng/mg; P < 0.02). LTSL + HT was also the only group that resulted in significant amounts of DNA-bound DOX (silver nitrate-extractable fraction; P < 0.02). Tumor tissue sections were visualized for DOX fluorescence to investigate the local distribution of the drug in the tumor and confirm the relative drug concentrations based on fluorescence intensity. There was relatively little fluorescence seen with treatment groups at 34 degrees C. At 42 degrees C, the LTSL showed the most DOX fluorescence (P < 0.01), and the fluorescence, although not homogeneous, was pervasive throughout the tumor sections. Therapeutic efficacy of treatments was determined from tumor growth time. At 34 degrees C, the only treatment group significantly better than the saline group (9.8 days) was the NTSL group, with a growth time of 20.9 days (P < 0.02). At 42 degrees C, all three liposomal formulations were more efficacious than DOX. LTSL + HT had the longest growth time (51.4 days) and the most number of local controls at 60 days (six of nine tumors). With HT, the DOX concentrations and fluorescence were tightly correlated with tumor growth delay, indicating that adequate (increased) drug delivery can be predictive of therapeutic effect. Overall, the LTSL + HT group showed the largest DOX concentration, the highest and most pervasive DOX fluorescence, and the most antitumor effect. Thus, HT-triggered liposomal drug release may account for the largest differential therapeutic effect and demonstrates the importance of rapid drug release from the drug carriers at the tumor site.

Animals↗

PubMed2000

PEG-covered lipid surfaces: bilayers and monolayers.

In this review paper we survey the ways in which various micropipet techniques have been used to study the mechanochemical and interactive features of lipid bilayer vesicles and monolayer-coated gas bubbles. Special emphasis will be made on characterizing the barrier properties of grafted PEG layers and how a hierarchical approach that uses a short barrier and extended ligand allows us to start to mimic nature's own solution to the problem of ubiquitous repulsion and specific attraction. The information gained from such studies not only characterizes the membrane and other lipid surfaces and their intersurface interactions from a fundamental materials science perspective, but also provides essential materials property data that are required for the successful design and deployment of lipid-based carriers and other capsules in applications involving this so-called 'stealthy' surface.

Journal Article↗

PubMed2000

Lipid-coated microgels for the triggered release of doxorubicin.

We have systematically engineered a polymeric, multi-component drug delivery system composed of a lipid-coated hydrogel microparticle (microgel). The design of this delivery system was motivated by the recent elucidation of the mechanism of regulated secretion from the secretory granule and the compositional and structural features that underlie its ability to store and release endogenous drug-like compounds. The present work describes the assembly and response of a prototype construct which displays several important features of the secretory granule, including its high drug loading capacity, and triggered microgel swelling, resulting in the burst release of drug. To achieve this, ionic microgels were synthesized, and loaded with doxorubicin via ion exchange. These microgels were then coated with a lipid bilayer, and the release of doxorubicin was triggered from the gels using either lipid-solubilizing surfactants or electroporation. The use of a microanalytical technique is featured utilizing micropipette manipulation that allows the study of the behavior of individual microparticles. The lipid-coated microgels were electroporated in saline solution; they swelled and disrupted their bilayer coating over a period of several seconds and exchanged doxorubicin with the external plasma saline over a period of several minutes. It is envisioned that this system will ultimately find utility in drug delivery systems that are designed to release chemotherapeutic agents and peptides by the application of a triggering signal.

Antineoplastic Agents↗

PubMed2000

A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model.

The single biggest challenge now facing drug delivery (for liposomes and indeed other carriers) is to initiate and produce release of the encapsulated drug only at the diseased site and at controllable rates. Our efforts have focused on developing a new thermal-sensitive drug delivery system, specifically for the local control of solid tumors. We describe here a new lipid formulation containing doxorubicin that has been optimized for both mild hyperthermic temperatures (39 degrees C to 40 degrees C) that are readily achievable in the clinic and rapid release times of drug (tens of seconds). This new liposome, in combination with mild hyperthermia, was found to be significantly more effective than free drug or current liposome formulations at reducing tumor growth in a human squamous cell carcinoma xenograft line (FaDu), producing 11 of 11 complete regressions lasting up to 60 days posttreatment.

Animals↗

PubMed2000

Water permeability and mechanical strength of polyunsaturated lipid bilayers.

Micropipette aspiration was used to test mechanical strength and water permeability of giant-fluid bilayer vesicles composed of polyunsaturated phosphatidylcholine PC lipids. Eight synthetic-diacyl PCs were chosen with 18 carbon chains and degrees of unsaturation that ranged from one double bond (C18:0/1, C18:1/0) to six double bonds per PC molecule (diC18:3). Produced by increasing pipette pressurization, membrane tensions for lysis of single vesicles at 21 degrees C ranged from approximately 9 to 10 mN/m for mono- and dimono-unsaturated PCs (18:0/1, 18:1/0, and diC18:1) but dropped abruptly to approximately 5 mN/m when one or both PC chains contained two cis-double bonds (C18:0/2 and diC18:2) and even lower approximately 3 mN/m for diC18:3. Driven by osmotic filtration following transfer of individual vesicles to a hypertonic environment, the apparent coefficient for water permeability at 21 degrees C varied modestly in a range from approximately 30 to 40 microm/s for mono- and dimono-unsaturated PCs. However, with two or more cis-double bonds in a chain, the apparent permeability rose to approximately 50 microm/s for C18:0/2, then strikingly to approximately 90 microm/s for diC18:2 and approximately 150 microm/s for diC18:3. The measurements of water permeability were found to scale exponentially with the reduced temperatures reported for these lipids in the literature. The correlation supports the concept that increase in free volume acquired in thermal expansion above the main gel-liquid crystal transition of a bilayer is a major factor in water transport. Taken together, the prominent changes in lysis tension and water permeability indicate that major changes occur in chain packing and cohesive interactions when two or more cis-double bonds alternate with saturated bonds along a chain.

Kinetics↗

PubMed2000

Effect of chain length and unsaturation on elasticity of lipid bilayers.

Micropipette pressurization of giant bilayer vesicles was used to measure both elastic bending k(c) and area stretch K(A) moduli of fluid-phase phosphatidylcholine (PC) membranes. Twelve diacyl PCs were chosen: eight with two 18 carbon chains and degrees of unsaturation from one double bond (C18:1/0, C18:0/1) to six double bonds per lipid (diC18:3), two with short saturated carbon chains (diC13:0, diC14:0), and two with long unsaturated carbon chains (diC20:4, diC22:1). Bending moduli were derived from measurements of apparent expansion in vesicle surface area under very low tensions (0.001-0.5 mN/m), which is dominated by smoothing of thermal bending undulations. Area stretch moduli were obtained from measurements of vesicle surface expansion under high tensions (>0.5 mN/m), which involve an increase in area per molecule and a small-but important-contribution from smoothing of residual thermal undulations. The direct stretch moduli varied little (< +/-10%) with either chain unsaturation or length about a mean of 243 mN/m. On the other hand, the bending moduli of saturated/monounsaturated chain PCs increased progressively with chain length from 0.56 x 10(-19) J for diC13:0 to 1.2 x 10(-19) J for diC22:1. However, quite unexpectedly for longer chains, the bending moduli dropped precipitously to approximately 0.4 x 10(-19) J when two or more cis double bonds were present in a chain (C18:0/2, diC18:2, diC18:3, diC20:4). Given nearly constant area stretch moduli, the variations in bending rigidity with chain length and polyunsaturation implied significant variations in thickness. To test this hypothesis, peak-to-peak headgroup thicknesses h(pp) of bilayers were obtained from x-ray diffraction of multibilayer arrays at controlled relative humidities. For saturated/monounsaturated chain bilayers, the distances h(pp) increased smoothly from diC13:0 to diC22:1 as expected. Moreover, the distances and elastic properties correlated well with a polymer brush model of the bilayer that specifies that the elastic ratio (k(c)/K(A))(1/2) = (h(pp) - h(o))/24, where h(o) approximately 1 nm accounts for separation of the headgroup peaks from the deformable hydrocarbon region. However, the elastic ratios and thicknesses for diC18:2, diC18:3, and diC20:4 fell into a distinct group below the correlation, which showed that poly-cis unsaturated chain bilayers are thinner and more flexible than saturated/monounsaturated chain bilayers.

Biophysical Phenomena↗

PubMed2000

AnkB, a periplasmic ankyrin-like protein in Pseudomonas aeruginosa, is required for optimal catalase B (KatB) activity and resistance to hydrogen peroxide.

In this study, we have cloned the ankB gene, encoding an ankyrin-like protein in Pseudomonas aeruginosa. The ankB gene is composed of 549 bp encoding a protein of 183 amino acids that possesses four 33-amino-acid ankyrin repeats that are a hallmark of erythrocyte and brain ankyrins. The location of ankB is 57 bp downstream of katB, encoding a hydrogen peroxide-inducible catalase, KatB. Monomeric AnkB is a 19.4-kDa protein with a pI of 5.5 that possesses 22 primarily hydrophobic amino acids at residues 3 to 25, predicting an inner-membrane-spanning motif with the N terminus in the cytoplasm and the C terminus in the periplasm. Such an orientation in the cytoplasmic membrane and, ultimately, periplasmic space was confirmed using AnkB-BlaM and AnkB-PhoA protein fusions. Circular dichroism analysis of recombinant AnkB minus its signal peptide revealed a secondary structure that is approximately 65% alpha-helical. RNase protection and KatB- and AnkB-LacZ translational fusion analyses indicated that katB and ankB are part of a small operon whose transcription is induced dramatically by H(2)O(2), and controlled by the global transactivator OxyR. Interestingly, unlike the spherical nature of ankyrin-deficient erythrocytes, the cellular morphology of an ankB mutant was identical to that of wild-type bacteria, yet the mutant produced more membrane vesicles. The mutant also exhibited a fourfold reduction in KatB activity and increased sensitivity to H(2)O(2), phenotypes that could be complemented in trans by a plasmid constitutively expressing ankB. Our results suggest that AnkB may form an antioxidant scaffolding with KatB in the periplasm at the cytoplasmic membrane, thus providing a protective lattice work for optimal H(2)O(2) detoxification.

Amino Acid Sequence↗

PubMed2000

Premature closure of foramen ovale and renal vein thrombosis in a stillborn twin homozygous for methylene tetrahydrofolate reductase gene polymorphism: a clinicopathologic case study.

Premature closure of the foramen ovale, 4-chamber cardiac hypertrophy, and renal vein/vena cava thrombosis were found at autopsy of a stillborn dizygotic twin at 36 weeks gestational age. Review of the original prenatal sonograms showed features suggestive of early closure of the foramen ovale. Homozygosity for the 5, 10 methylene tetrahydrofolate reductase mutation was shown only in the affected twin after the parents were found to be heterozygous for the mutation. The difference in outcome of the twins following prenatal treatment with beta mimetics and corticosteroids for preterm labor may be related to the added susceptibility factor for thromboembolism associated with presumed hyperhomocysteinemia in the proband which was not shared by the surviving healthy twin. The role of premature closure of the foramen ovale and prenatal treatment are discussed but remain uncertain.

Cardiomegaly↗

PubMed2000

Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas.

The effect of hyperthermia on the accumulation of technetium-99m-labeled liposomes was studied in feline sarcomas. Each cat received two separate injections of liposomes. The first was used to quantify the amount of technetium-99m-labeled liposomes within the tumor under normothermic conditions. The second injection was made at the beginning of a 60-min hyperthermia procedure. Planar scintigraphy was used to measure the activity of technetium-99m-labeled liposomes within the tumor at predetermined times up to 18 h after injection. Regions of interest were drawn for the tumor, lungs, liver, kidney, and aorta. Counts in the regions of interest were decay corrected. Counts/pixel in the tumor under normothermic and hyperthermic conditions were normalized to aorta counts/pixel. A total of 16 cats were eligible for the study. In two of the 16 cats, incomplete count data precluded analysis. In the remaining 14 cats, hyperthermia resulted in a significant increase in liposome accumulation in the tumor (P = 0.001). Tumor volume ranged from 1.2 to 236.2 cm3, and thermal dose ranged from 2.0 to 243.3 CEM43CT90 (equivalent time that the 10th percentile temperature was equal to 43 degrees C). There was not a relationship between either tumor volume or hyperthermia dose on the magnitude of increased liposome accumulation, suggesting that this method has application across a range of tumor volumes and degrees of heatibility.

Animals↗

PubMed1998

A synthetic mimic of the secretory granule for drug delivery.

Secretory cells contain submicroscopic granules composed of a polyanionic polymer network that is collapsed owing to the presence of hydronium ions and weak base cations. The network is encapsulated within a lipid membrane, and functions as a vehicle for the osmotically inert storage of a variety of granule-bound endogenous mediator species, such as histamine, serotonin and proteases. These species are excreted from the granule and thence from the cell in response to external biochemical signals. Hydrogels that swell and shrink in response to external stimuli might serve as synthetic analogues of secretory granules. Here we describe the systematic engineering of multi-component, environmentally responsive hydrogel microspheres, coated with a lipid bilayer to mimic more closely the natural secretory granule. These microspheres exhibit pH- and ion-dependent volume phase transitions and ion-sensitive exchange of bound cations when the encapsulating lipid membrane is porated. We stimulated poration electrically in individual microgel particles immobilized and manipulated with a micropipette. This system could find use for the triggered release of encapsulated drugs in the body.

Acrylamides↗

PubMed1998

pH and Ion-Triggered Volume Response of Anionic Hydrogel Microspheres.

Micrometer-sized (4-7 µm diameter) poly(methacrylic acid) (PMAA) hydrogel microspheres were synthesized by precipitation polymerization. Individual microspheres were held in a micropipet and visualized by interference contrast microscopy. They were characterized with regard to their mass, density, water content, electrophoretic mobility, and apparent pKa. Equilibrium changes in volume were measured as functions of the pH and NaCl concentration of the suspending solution. The maximum reduction in the microsphere equilibrium volume (Vrmax) at pH 3.0 was 0.28, where Vr was the ratio of the microsphere volume at the test pH to its volume at pH 6.6. A Donnan-based thermodynamic model, modified to include counterion binding because of the high fixed charge density in the microspheres (3.0 M), was applied to determine the difference in the ion concentration between the interior and exterior of the gel. The ion concentration differences (which were related to the osmotic pressure) predicted by the model were proportional to the microsphere equilibrium volume with changing pH and salt concentration. This supported the hypothesis that the equilibrium volume of the microspheres was set by a force balance between the osmotic pressure and the elasticity of the hydrogel matrix. Microspheres changed from their maximum equilibrium volume at pH 6.6 to their minimum equilibrium volume at pH 3.0 in 300 ms. This indicated that diffusion of the polymer matrix and not diffusion of ions into and out of the microsphere was the rate-limiting factor in determining a microsphere's swelling rate.

Journal Article↗

PubMed1998

Interactions between poly(2-ethylacrylic acid) and lipid bilayer membranes: effects of cholesterol and grafted poly(ethylene glycol).

The exchange of the protonatable polymer, poly(2-ethylacrylic acid) (PEAA), has been studied with vesicle membranes containing cholesterol from 0 to 60 mol% or PEG2000-lipid (5 mol%). The release of an entrapped dye from 100 nm extruded liposomes was used as an assay for membrane perturbation by the polymer as a function of pH. The inclusion of cholesterol was found to reduce the pH at which the polymer caused release of the dye from the lipid vesicles, and the degree of polymer protonation (i.e., degree of hydrophobicity) correlated well with the increase in elastic expansion modulus of the vesicle bilayer. The results are discussed in terms of a balance between polymer solubility and membrane expansion. With respect to the PEG barrier, the presence of 5 mol% PEG2000, which represents full surface coverage, did not prevent PEAA from inducing contents release, demonstrating that highly hydrated polymeric layers are not effective barriers for other water soluble polymers, and may point to some association between the two polymers.

Acrylates↗