Browsing by Author "Edgar, Kevin J."

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    Adsorption of Biomacromolecules onto Polysaccharide Surfaces
    Zhang, Xiao (Virginia Tech, 2014-10-02)
    Plant cell wall polysaccharides are abundant natural polymers making them potential sources for sustainable and biodegradable materials. Interfacial behavior, including adsorption and enzymatic degradation, of several plant cell wall polysaccharides and their derivatives were studied with a quartz crystal microbalance with dissipation monitoring (QCM-D), surface plasmon resonance (SPR) and atomic force microscopy (AFM). Xyloglucan adsorption isotherms were obtained to probe how cellulose-hemicellulose interactions were affected by the type of cellulose substrate and molar mass of xyloglucan. Xyloglucan as small as a heptasaccharide still adsorbed irreversibly onto cellulose. Carboxymethyl cellulose (CMC) adsorption onto cellulose and viscoelastic properties and water contents of the adsorbed CMC layers were obtained from a combination of QCM-D and SPR data. The CMC samples formed hydrated and viscoelastic layers compared to the relatively rigid xyloglucan layer. Pectin model surfaces were prepared by pectin adsorption from citric phosphate buffer onto gold substrates. These pectin model surfaces were used for subsequent interaction studies with xyloglucan and enzymatic degradation behavior. There is a strong correlation between the degree of esterification (DE) and film resistance to degradation with the high DE being the most susceptible to degradation. The adsorption of two mixed linkage glucans (MLG), barley and lichen MLG, onto regenerated cellulose (RC) surfaces in the absence and presence of other matrix polysaccharides was studied. Viscoelastic properties of the resulting layer were compared as a function of the proprotion of '-(1''3) linkages with lichen MLG forming softer gel-like layers on RC. The lichen MLG layers were further used for enzymatic degradation studies with respect to enzyme concentration, temperature, pH and ionic strength. These studies show that polymer adsorption is a promising strategy to modify material surfaces and provides fundamental understanding of interactions and biodegradation of cell wall polysaccharides at solid/liquid interfaces.
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    Adsorption of Blood Proteins onto Polysaccharide Surfaces
    Tan, Xinyi (Virginia Tech, 2016-01-10)
    In this study, surface plasmon resonance (SPR) and quartz crystal microbalance with dissipation monitoring (QCM-D) were combined to investigate the adsorption behavior of two platelet adhesion-related blood proteins, human serum albumin (HSA) and human serum fibrinogen (HSF), on two polysaccharide materials used for hemodialysis membrane applications: regenerated cellulose and cellulose acetate. The study aims to provide insight into the design of novel hemocompatible polysaccharide materials. Information such as real-time adsorption curves, adsorbed amounts, and water contents of the protein layers were obtained and analyzed. The results suggested 1) monolayer adsorption of HSA on both cellulose and cellulose acetate, possibly with different HSA conformations; 2) a multilayer of HSF or some degree of end-on adsorption on both surfaces. The study of HSA adsorption onto cellulose acetate surfaces with different degrees of substitution indicated that the change in content of acetyl groups may not be the main factor governing the adsorbed HSA amount but may affect the conformation of adsorbed HSA molecules.
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    Amorphous solid dispersion effects on in vitro solution concentrations of quercetin
    Gilley, Andrew (Virginia Tech, 2016-08-31)
    Quercetin is a flavonol with potential health benefits including activities against cardiovascular disease, obesity, and oxidative stress. However, the benefits of quercetin are likely limited by poor bioavailability, primarily attributed to its poor aqueous solubility (due to its hydrophobicity and crystallinity) and extensive phase-II metabolism. Improving the apparent solubility of quercetin has the potential to improve its in vivo bioavailability. Strategies to increase solution concentrations in the small intestinal lumen have the potential to substantially increase quercetin bioavailability, and efficacy. We aimed to achieve this by incorporating quercetin into amorphous solid dispersions (ASDs) with cellulose derivatives, eliminating crystallinity, and selectively releasing amorphous quercetin under simulated intestinal conditions (pH 6.8, 37C). Amorphous quercetin was dispersed in cellulose esters including 6-carboxycellulose acetate butyrate (CCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate suberate (CASub) to achieve stability and provide pH-triggered release. In addition, polyvinylpyrrolidone (PVP) containing CASub and CCAB blends were prepared to further promote enhanced dissolution. The ASD employing 10% quercetin in 20% PVP:70% CASub was most successful at enhancing the solution concentration of quercetin, providing an 18-fold increase in the area under the concentration/time curve (AUC) compared to quercetin alone. These results warrant in vivo assessment of quercetin-loaded ASDs formulated with CASub and its blend with PVP towards improving the bioavailability of quercetin.
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    Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: Investigation of relationships between polymer structure and performance
    Wilson, Venecia R.; Lou, Xiaochun; Osterling, Donald J.; Stolarik, DeAnne F.; Jenkins, Gary J.; Nichols, Brittany L. B.; Dong, Yifan; Edgar, Kevin J.; Zhang, Geoff G. Z.; Taylor, Lynne S. (Springer Nature, 2020-10-28)
    Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.
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    Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance
    Wilson, Venecia R.; Lou, Xiaochun; Osterling, Donald J.; Stolarik, DeAnne F.; Jenkins, Gary J.; Nichols, Brittany L. B.; Dong, Yifan; Edgar, Kevin J.; Zhang, Geoff G. Z.; Taylor, Lynne S. (Nature Research, 2020-10-28)
    Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.
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    Amphiphilic hydroxyalkyl cellulose derivatives for amorphous solid dispersion prepared by olefin cross-metathesis
    Dong, Yifan; Mosquera-Giraldo, Laura I.; Troutman, Jacob; Skogstad, Brittny; Taylor, Lynne S.; Edgar, Kevin J. (Royal Society of Chemistry, 2016-07-07)
    Olefin cross-metathesis (CM) has enabled design and synthesis of diverse, amphiphilic cellulose ether derivatives (e.g. of ethyl and methyl cellulose). In this paper, hydroxyalkyl cellulose was selected as a hydrophilic starting material, with the additional advantage that it has DS (OH) 3.0 that allows targeting of a full range of DS of selected functional groups. Hydroxypropyl cellulose (HPC) was first etherified with 5-bromopent-1-ene to attach olefin “handles” for metathesis, whereby control of molar ratios of sodium hydride and 5-bromopent-1-ene permits full DS control of appended olefin. These olefin-terminated HPC ethers then were subjected to CM with acrylic acid and different acrylates, followed by diimide hydrogenation to reduce the resulting α,β-unsaturation. NMR and FT-IR spectroscopies were useful tools for following reaction progress. One of the product carboxyl-functionalized HPC derivatives, designated HPC-Pen106-AA-H, showed high promise as a crystallization inhibitor of the antiviral drug telaprevir. Its nucleation-induction inhibitory ability was compared to those of commercial controls, HPC and HPMCAS. All three polymers were very effective for inhibiting telaprevir crystallization, increasing induction time up to 8-fold. HPC did not effectively prevent amorphous particle growth, whereas the carboxyl-containing HPC-Pen106-AA-H and HPMCAS were able to prevent formation of agglomerates of amorphous drugs.
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    Bio-inspired Cellulose Nanocomposites
    Pillai, Karthik (Virginia Tech, 2011-04-26)
    Natural composites like wood are scale-integrated structures that range from molecular to the macroscopic scale. Inspired by this design, layer-by-layer (LbL) deposition technique was used to create lignocellulosic composites from isolated wood polymers namely cellulose and lignin, with a lamellar architecture. In the first phase of the study, adsorption of alkali lignin onto cationic surfaces was investigated using a quartz crystal microbalance with dissipation monitoring (QCM-D). Complete coverage of the cationic surface with alkali lignin occured at low solution concentration; large affinity coefficients were calculated for this system at differing pH levels. Adsorption studies with organosolv lignin in an organic solvent, and spectroscopic analysis of mixtures of cationic polymer with alkali lignin revealed a non-covalent interaction. The work demonstrated how noncovalent interactions could be exploited to molecular organize thin polyphenolic biopolymers on cationic surfaces. The second phase of the study examined the adsorption steps during the LbL assembly process to create novel lignocellulosic composites. LbL assembly was carried out using oxidized nanocellulose (NC) and lignin, along with a cationic polymer poly(diallyldimethylammonium chloride) (PDDA). QCM-D was used to follow the sequential adsorption process of the three different polymers. Two viscoelastic models, namely Johannsmann and Voigt, were respectively used to calculate the areal mass and thickness of the adsorbed layers. Atomic force microscopy studies showed a complete coverage of the surface with lignin in all the disposition cycles, however, surface coverage with NC was seen to increase with the number of layers. Free-standing composite films were obtained when the LbL process was carried out for 250 deposition cycles (500 bilayers) on a cellulose acetate substrate, following the dissolution of the substrate in acetone. Scanning electron microscopy of the cryo-fractured cross-sections showed a lamellar structure, and the thickness per adsorption cycle was estimated to be 17 nm. The third phase of the study investigated the effect of LbL ordering of the polymers versus a cast film composed of a blended mixture of the polymers, using dynamic mechanical analysis. A tan ï ¤ peak was observed in the 30 – 40 ºC region for both films, which was observed in the neat NC film. Heating of the samples under a compressive force produced opposite effects in the films, as the LbL films exhibited swelling, whereas the cast films showed densification. The apparent activation energy of this transition (65 – 80 kJ mol-1) in cast films, calculated based on the Arrhenius equation was found to be coincident to those reported for the ï ¢ transition of amorphous cellulose. The peak was seen to disappear in case of LbL films in the second heat, whereas it was recurring in case of cast films of the blended mixture, and neat NC films. Altogether, the together the work details a novel path to integrate an organized lignin and cellulose molecular structure, albeit modified from their native form, into a three-dimensional composite material.
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    Bioactive Cellulose Nanocrystal Reinforced 3D Printable Poly(epsilon-caprolactone) Nanocomposite for Bone Tissue Engineering
    Hong, Jung Ki (Virginia Tech, 2015-05-07)
    Polymeric bone scaffolds are a promising tissue engineering approach for the repair of critical-size bone defects. Porous three-dimensional (3D) scaffolds play an essential role as templates to guide new tissue formation. However, there are critical challenges arising from the poor mechanical properties and low bioactivity of bioresorbable polymers, such as poly(epsilon-caprolactone) (PCL) in bone tissue engineering applications. This research investigates the potential use of cellulose nanocrystals (CNCs) as multi-functional additives that enhance the mechanical properties and increase the biomineralization rate of PCL. To this end, an in vitro biomineralization study of both sulfuric acid hydrolyzed-CNCs (SH-CNCs) and surface oxidized-CNCs (SO-CNCs) has been performed in simulated body fluid in order to evaluate the bioactivity of the surface functional groups, sulfate and carboxyl groups, respectively. PCL nanocomposites were prepared with different SO-CNC contents and the chemical/physical properties of the nanocomposites were analyzed. 3D porous scaffolds with fully interconnected pores and well-controlled pore sizes were fabricated from the PCL nanocomposites with a 3D printer. The mechanical stability of the scaffolds were studied using creep test under dry and submersion conditions. Lastly, the biocompatibility of CNCs and 3D printed porous scaffolds were assessed in vitro. The carboxyl groups on the surface of SO-CNCs provided a significantly improved calcium ion binding ability which could play an important role in the biomineralization (bioactivity) by induction of mineral formation for bone tissue engineering applications. In addition, the mechanical properties of porous PCL nanocomposite scaffolds were pronouncedly reinforced by incorporation of SO-CNCs. Both the compressive modulus and creep resistance of the PCL scaffolds were enhanced either in dry or in submersion conditions at 37 degrees Celsius. Lastly, the biocompatibility study demonstrated that both the CNCs and material fabrication processes (e.g., PCL nanocomposites and 3D printing) were not toxic to the preosteoblasts (MC3T3 cells). Also, the SO-CNCs showed a positive effect on biomineralization of PCL scaffolds (i.e., accelerated calcium or mineral deposits on the surface of the scaffolds) during in vitro study. Overall, the SO-CNCs could play a critical role in the development of scaffold materials as a potential candidate for reinforcing nanofillers in bone tissue engineering applications.
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    Block and Graft Copolymers Containing Carboxylate or Phosphonate Anions
    Hu, Nan (Virginia Tech, 2014-11-06)
    This dissertation focuses on synthesis and characterization of graft and block copolymers containing carboxylate or phosphonate anions that are potential candidates for biomedical applications such as drug delivery and dental adhesives. Ammonium bisdiethylphosphonate (meth)acrylate and acrylamide phosphonate monomers were synthesized based on aza-Michael addition reactions. Free radical copolymerizations of these monomers with an acrylate-functional poly(ethylene oxide) (PEO) macromonomer produced graft copolymers. Quantitative deprotection of the alkylphosphonate groups afforded graft copolymers with zwitterionic ammonium bisphosphonate or anionic phosphonate backbones and PEO grafts. The zwitterionic copolymers spontaneously assembled into aggregates in aqueous media. The anionic copolymers formed aggregates in DMF and DMSO, while only small amounts of aggregates were present in copolymer/methanol or copolymer/water solutions. Binding capabilities of the acrylamide phosphonic acids were investigated through interactions with hydroxyapatite. Previously our group has prepared poly(ethylene oxide)-b-poly(acrylic acid) (PEO-b-PAA) copolymers and used these polymers as carriers for both MRI imaging agents and cationic drugs. To enhance the capabilities of those carriers in tracking and crosslinking, we have designed, synthesized and characterized amine functionalized PEO-b-PAA copolymers. First, heterobifunctional poly(ethylene oxide) (PEO) with three different molecular weights were synthesized. Modification on one of these afforded a PEO macroinitiator with a bromide on one end and a protected amine on the other end. ATRP polymerization of tert-butyl acrylate (tBuA) in the presence of this initiator and a copper (I) bromide (CuBr) catalyst yielded a diblock copolymer. The copolymer was deprotected by reaction with trifluoroacetic acid (TFA) and formed an amine terminated H2N-PEO-b-PAA. Recently our group has utilized the novel ammonium bisdiethylphosphonate (meth)acrylate and acrylamide phosphonate copolymers to incorporate Carboplatin. The resulting complexes exhibited excellent anticancer activity against MCF-7 breast cancer cells which might be related to ligand exchange of the dicarboxylate group of Carboplatin with the phosphonic acid moieties in the copolymer. Hence, complexation of small-molecule phosphonic acids with Carboplatin was investigated. Three compounds, vinylphosphonic acid, 3-hydroxypropyl ammonium bisphosphonic acid and 2-hydroxyethyl ammonium phosphonic acid were complexed with Carboplatin under acidic and neutral conditions. Covalent bonding of these acids to carboplatin was only observed under acidic pH. The covalently bonded percentage was 17%, 37% and 34%, respectively. More in-depth investigation was of great importance to further understand this complexation behavior.
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    Carboxymethylcellulose Acetate Butyrate Water-Dispersions as Renewable Wood Adhesives
    Paris, Jesse Loren (Virginia Tech, 2010-08-05)
    Two commercial carboxymethylcellulose acetate butyrate (CMCAB) polymers, high and low molecular weight (MW) forms, were analyzed in this study. High-solids water-borne dispersions of these polymers were studied as renewable wood adhesives. Neat polymer analyses revealed that the apart from MW, the CMCAB systems had different acid values, and that the high MW system was compromised with gel particle contaminants. Formulation of the polymer into water-dispersions was optimized for this study, and proved the "direct method", in which all formulation components were mixed at once in a sealed vessel, was the most efficient preparation technique. Applying this method, 4 high-solids water dispersions were prepared and evaluated with viscometry, differential scanning calorimetry, dynamic mechanical analysis, light and fluorescence microscopy, and mode I fracture testing. Thermal analyses showed that the polymer glass transition temperature significantly increased when bonded to wood. CMCAB dispersions produced fairly brittle adhesive-joints; however, it is believed toughness can likely be improved with further formulation optimization. Lastly, dispersion viscosity, film formation, adhesive penetration and joint-performance were all dependent on the formulation solvents, and moreover, these properties appeared to correlate with each other.
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    Cationic Glycopolymers for DNA Delivery: Cellular Internalization Mechanisms and Biological Characterization
    McLendon, Patrick Michael (Virginia Tech, 2009-10-20)
    Understanding the biological mechanisms of polymeric DNA delivery is essential to develop vehicles that perform optimally. In this work, the cellular internalization mechanisms of poly(glycoamidoamine) (PGAA) DNA delivery polymers were investigated. Polymer:DNA complexes interact with cell-surface glycosaminoglycans (GAGs) in a manner independent of electrostatic interactions. Desulfation and GAG removal leads to decreased uptake. Individual polyplexes appear to have differing affinities for specific GAGs, as polyplex dissociation occurs in a charge-independent manner, and may influence binding. Internalization occurs through close interactions with GAGs, as GAGs accumulate on polyplex surfaces, resulting in negatively-charged polyplexes and decompaction of intact polyplexes is observed upon interaction with GAG. PGAA polyplexes enter cells via a complex, multifaceted internalization route. Pharmacological inhibition of endocytosis and visualization by confocal microscopy reveal that internalization occurs primarily through an actin and dynamin-dependent mechanism. Caveolae/raft-mediated endocytosis appears to be the predominant internalization mechanism, with clathrin-mediated endocytosis also significantly involved. Internalization occurs to a smaller degree via macropinocytosis and direct membrane penetration. Caveolae-mediated, but not clathrin-mediated, internalization leads to transgene expression, suggesting a targeting opportunity based on uptake mechanisms. PEGylation of PGAA polyplexes was achieved to minimize polyplex aggregation in serum. Polyplex size increased in serum, but PEGylation prevented further polyplex growth over time compared to non-PEGylated polymers. Specific targeting of hepatocytes through end-modification of PEG with galactose was unsuccessful, likely due to inaccessibility of targeting groups. Further hepatocyte targeting efforts focused on malonate-based polymers with clickable linkages for facile linkage of targeting groups. Despite favorable surface presentation of galactose, receptor-specific internalization of polyplexes was unsuccessful, as competitive inhibition in HepG2 cells resulted in significant polyplex internalization derived from nonspecific membrane interactions. Chemical modification of vehicles allows systematic study of structure-function properties leading to efficient intracellular delivery. Increasing G4 molecular weight generally increases toxicity and decreases transgene expression in HeLa cells. Incorporating galactose into a lanthanide-chelating polymer facilitated efficient cellular internalization that was visualized by two-photon microscopy. Increased gene expression was observed that correlated to increasing galactose, suggesting that polymer degradation increases gene expression. Also studied were branched peptides targeted to HIV-1 TAR, which displayed high biocompatibility and favorable internalization profiles in mammalian cells.
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    Cellulose Esters and Cellulose Ether Esters for Oral  Drug Delivery Systems
    Arca, Hale Cigdem (Virginia Tech, 2016-11-01)
    Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release. The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted.
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    Cellulose-based amorphous solid dispersions enhance rifapentine delivery characteristics and dissolution kinetics in vitro
    Winslow, Christopher Jonathan (Virginia Tech, 2017-07-14)
    The efficacy of rifapentine, an oral antibiotic used in the treatment of tuberculosis, is reduced due to its degradation at gastric pH and low solubility at intestinal pH. We aimed to improve delivery properties in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). Most amorphous solid dispersions reduced rifapentine release at gastric pH, with the best performing polymer CASub showing >31-fold decrease in area under the curve compared to rifapentine alone. Lower solubility at gastric conditions was accompanied by a reduction in the acidic degradation product 3-formylrifamycin, as compared to rifapentine alone. Certain formulations also showed enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with the best performing polymer HPMCAS showing almost a 4-fold increase in total area under the curve compared to rifapentine alone. These in vitro results suggest that delivery of rifapentine via amorphous solid dispersion with cellulose polymers may improve bioavailability in vivo.
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    Characterization of Laser Modified Surfaces for Wood Adhesion
    Dolan, Jeffrey Alan (Virginia Tech, 2014-07-01)
    The controlled degradation of wood surfaces with infrared light from a CO2 pulsed laser facilitated adhesion without the use of additional resins. Laser modification creates a surface phenomenon that physically and chemically alters the natural biopolymer organization of lignocellulosic materials in a way that promotes adhesion when hot pressed using typical industrial equipment. Laser optimization was determined through mechanical and microscopic observation. It was determined that a mild level of laser surface modification (scale of 30 W/mm2) resulted in the highest bond-line strength. The large spot size of the laser beam resulted in evenly modified surfaces. Surface analysis revealed that laser modification changed native wood morphology, hydrolyzed and vaporized hemicellulose, and enriched the surface with cellulose II and lignin. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR FTIR) was used to analyze the bulk of the laser material. This experiment revealed a change in the hydroxyl region related to hydrogen bonding conformations between wood polymers, mainly cellulose. X-ray photoelectron spectroscopy (XPS) provided an elemental composition of the top 5 nanometers of the surface, which resulted in increased carbon-carbon/carbon-hydrogen linkages and decreased oxygen containing bonds due to laser ablation. Static acid-base contact angle analysis was conducted using three probe liquids to find the Lewis acid, Lewis base, and dispersion components of the top nanometer of surface chemistry. Contact angle analysis revealed laser modified samples had a surface free energy that remained similar to the control wood sample. In addition, the dispersion component of the surface free energy increased due to laser ablation while acid-base components were reduced. Atomic force microscopy (AFM) visually displays a reduction in surface roughness due to the laser technique. An additional set of experiments like thermal gravimetric analysis, thermal pre and post treatments, and heated ATR FTIR and XPS support findings which require more investigation into this adhesion phenomenon.
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    Characterizing Interfacial and Bulk Interactions Between Cellulose Ethers and Bile Salts: Impact on In Vitro Lipid Digestion
    Zornjak, Jennifer Anne (Virginia Tech, 2019-01-14)
    Elevated levels of lipids and LDL-cholesterol in the blood are significant risk factors associated with developing cardiovascular diseases (CVDs). A potential strategy to combat these risk factors is decreasing lipid absorption by modulating the digestibility of lipids in the human intestinal tract. Since bile salts (BS) play key roles during this process, lipid digestion could be controlled ultimately by limiting the access of BS to the lipid surface. Cellulose ethers (CEs), surface-active dietary fibers and common food additives, might be promising ingredients to control lipid digestion either by creating surface layers around lipid droplets that hinder adsorption of BS, or by sequestering BS in the aqueous phase. However, the precise mechanisms behind these interactions remain unclear. Surface analysis techniques were used to better understand the mechanisms by which CEs with diverse molecular structure and charge (commercial and novel hydroxypropyl-cellulose (HPC)) interact with BS at the solid surface and in the aqueous phase. The potential of CE-stabilized emulsions to influence lipid digestion was also investigated in vitro. Both CEs show potential in modulating lipid digestion; the potential of the commercial HPC to interfere with lipid digestion may be more related to its ability to sequester BS in solution and form mixed HPC-BS complexes that are not easily removed from the surface, whereas the novel HPC seems more effective at creating strong surface layers that resist displacement by BS. These findings can be exploited in developing strategies to design novel food matrices with improved functional properties to optimize lipid digestion and absorption.
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    Chemical Modification of Alginates in Organic Media
    Pawar, Siddhesh Nitin (Virginia Tech, 2013-07-25)
    Alginates are (1and4) linked linear copolysaccharides composed of B-D-mannuronic acid (M) and its C-5 epimer, a-L-guluronic acid (G). Several strategies to synthesize organically modified alginate derivatives have been reported, but almost all chemistries are performed in either aqueous or aqueous-organic media. The ability to react alginates homogeneously in organic solvents would open up access to a wide range of new chemistries and derivatives. However, past attempts have been restricted by the absence of methods for alginate dissolution in organic media. We therefore report a strategy to solubilize tetrabutylammonium (TBA) salts of alginic acid in polar aprotic solvents containing tetrabutylammonium fluoride (TBAF). Acylation of TBA-alginate was performed in DMSO/TBAF to get products with DSacetyl up to ~ 1.0. We further report that by using appropriate solvent conditions, placement of acyl groups can be controlled to achieve either random or M-selective substitution. Alginate acetates synthesized in an M-selective fashion were used to study the ability of these derivatives to form Ca-crosslinked hydrogels. Detailed structure-property analyses were performed to identify acetylation reaction conditions and product properties that may be ideal for hydrogel formation. Furthermore, alginate esters were synthesized via modification of carboxylate groups on the backbone. These derivatives dissolved in polar aprotic solvents without the need to add TBAF. A proof of concept study showed their utility in the solubility enhancement of the poorly water soluble flavonoid naringenin.
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    Chemical Modification of Cellulose Esters for Oral Drug Delivery
    Meng, Xiangtao (Virginia Tech, 2016-06-20)
    Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists.
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    Cross-metathesized polysaccharide derivatives and processes for preparing them
    Edgar, Kevin J.; Matson, John B.; Meng, Xiangtao (US Patent Office, 2020-08-11)
    Methods for the cross-metathesis of polysaccharides with one or more olefin-terminated side chains and cross-metathesized products are described. In an exemplary embodiment, a method for the synthesis of cellulose ω-carboxyesters via olefin cross-metathesis is described. Conditions of the reactions were relatively mild and the olefin-substituted polysaccharides and the appropriate monomeric olefin partners appear to follow Grubbs rules as summarized herein. The compounds and methods may be useful for structure-property studies, particularly those aimed at developing polymers for drug delivery, such as for controlled-release drug delivery systems, controlled-release coatings, increasing bioavailability of drugs, and maintaining drug supersaturation in the GI tract.
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    The Design and Study of Lanthanide-Chelating Macromolecular Diagnostic and Delivery Agents
    Bryson, Joshua Matthew (Virginia Tech, 2009-08-07)
    Macromolecular magnetic resonance imaging (MRI) contrast agents have unique localization and contrast enhancement properties. We have designed and studied a monodisperse paramagnetic β-cyclodextrin click cluster (Gd10) decorated with Gd-containing arms and unique contrast enhancing polymers. To synthesize Gd10, a novel alkyne-functionalized diethylenetriaminetetraacetic acid chelate was created and coupled to a per-azido-β-cyclodextrin core and chelated with Gd(III) to yield the precursor macromolecule. Luminescence measurements were carried out using an analogous structure Eu(III)-containing structure and indicated that each lanthanide has an average of 1.8 water exchange sites. Gd10 yields a high relaxivity profile (6.2 mM⁻¹ s⁻¹ per Gd(III) at 9.4 T). Gd10 shows toxicity higher than clinically used contrast agents such as Magnevist&trade in vitro in cardiomyoblast cells. No acute toxicity was observed in the rats (n = 9) and contrast enhanced image analysis indicates renal processes may be involved in clearance. The contrast enhancing polymers we developed are new macromolecular beacons that allow the delivery of nucleic acids to be visualized at different biological scales. They contain repeated oligoethyleneamines, for binding and compacting nucleic acids into nanoparticles, and Gd(III)/Eu(III) chelates. The chelated lanthanides allow the visualization of the delivery vehicle via microscopy and via magnetic resonance imaging (MRI). We demonstrate that these new delivery beacons effectively bind plasmid DNA(pDNA) and protect their cargo nucleic acids from nuclease damage. The lanthanide-chelate materials have been found to efficiently deliver pDNA into cultured cells and do not exhibit toxicity. Micrographs of cultured cells exposed to the nanoparticle complexes formed with fluorescein-labeled pDNA and the europium-chelated polymers reveal effective intracellular imaging of the delivery process. MRI of bulk cells exposed to the complexes formulated with pDNA and the gadolinium-chelated structures show bright image contrast, allowing visualization of effective intracellular delivery on the tissue-scale. Because of their versatility as imaging probes, these delivery beacons posses remarkable potential for tracking and understanding nucleic acid transfer in vitro and have promise for in vivo imaging applications. In later studies the Ln-chelating polymers were co-polymerized with dimethylgalacterate which definitively increases luciferase gene expression (up 50x enhancement) and cellular uptake (up to 2x enhancement).
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    Design and Synthesis of Cellulose Ether Derivatives for Oral Drug Delivery
    Dong, Yifan (Virginia Tech, 2017-05-31)
    Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications.