Objective: The objective of this study is to design a physical model of a magnetic filtration sys... more Objective: The objective of this study is to design a physical model of a magnetic filtration system which can separate magnetic nanoparticle (MNP)-tagged cytokines from fluid at physiologically relevant flow rates employed during cardiopulmonary bypass (CPB) procedures. Methods: The Navier-Stokes equations for the pressure driven flow in the chamber and the quasistatic stray magnetic field produced by an array of permanent magnets were solved using finite element analysis in COMSOL Multiphysics for 2D and 3D representations of the flow chamber. Parameters affecting the drag and magnetic forces including flow chamber dimensions, high gradient magnet array configurations, and particle properties, were changed and evaluated for their effect on MNP capture. Results: Flow chamber dimensions which achieve appropriate flow conditions for CPB were identified, and magnetic force within the chamber decreased with increased chamber height. A magnetic “block” array produced the highest magnetic force within the chamber. Polymeric microparticles loaded with MNPs were shown to have increased particle capture with increased hydrodynamic diameter. Conclusion: The model achieved a predicted efficiency up to 100% capture in a single-pass of fluid flowing at 1.75 L/min. Significance: This work is an important step in designing a magnetic flow chamber that can remove the magnetically tagged cytokines under high flow employed during CPB. Cytokines have been shown to stimulate the systemic inflammatory response (SIR) associated with CPB and are an established therapeutic target to mitigate the SIR. In the long term, this work aims to guide researchers in the more accurate design of magnetic separation systems.
Ophthalmic drug delivery via eye drops is inefficient because only about 1-5% of the drug permeat... more Ophthalmic drug delivery via eye drops is inefficient because only about 1-5% of the drug permeates the cornea during the short residence time of a few minutes. Contact lenses are receiving considerable attention for delivering ophthalmic drugs because of higher bioavailability and the possibility of sustained release from hour to days, and possibly longer. The drug release durations from contact lenses are typically measured in vitro and it is challenging to relate the in vitro release to in vivo release, particularly for hydrophobic drugs which may not exhibit sink release in vitro and in vivo. The in vitro release can be fitted to diffusion equation to determine the partition coefficient and diffusivity, which can then be utilized to model in vivo release. The Higuchi equation is frequently used to model the short time release from a contact lens to determine diffusivity with the implicit assumption that the release is under sink conditions and the starting concentration in the lens was uniform. Both conditions may be violated when measuring release of hydrophobic drugs from contact lenses because the diffusivity and partition coefficient, and also the time needed for equilibrium are not known a priori. Here we develop a method to use the data for both loading and release of cyclosporine, which is a common hydrophobic ophthalmic drug, to determine the partition coefficient and diffusivity. The proposed approach does not require sink conditions and also does not require the lens to be fully equilibrated during loading, which may take almost a month for lenses considered here. The model is based on solving the diffusion equation in the gel along with a mass balance in the fluid. The model equations are solved numerically by finite difference. When the value of partition coefficient is high, such as it is for cyclosporine, the dynamic data is only sensitive to a ratio of partition coefficient and diffusivity, and this ratio had to first be determined from the loading data. Then the two unknown parameters were obtained by minimizing the error between the model prediction and experimental data. The method was used to determine D and K for several silicone hydrogel formulations with varying ratio of hydrogel and silicone fractions.
Gold nanoparticles (GNPs) are commonly synthesized using the Turkevich method, but there are limi... more Gold nanoparticles (GNPs) are commonly synthesized using the Turkevich method, but there are limitations on the maximum concentration of gold nanoparticles that can be achieved using this method (often < 1 mM (=0.34 mg/mL) gold precursor loading). Here, we report an inverse Turkevich method which significantly increases the concentration of gold nanoparticles (up to 5-fold) in the aqueous phase by introducing poly (vinyl alcohol) (PVA) to the synthesis system for stabilization. The aim of this study is to understand the effect of PVA and other synthesis parameters, such as trisodium citrate and tetrachloroauric acid concentration, with the goal of maximizing concentration while maintaining gold nanoparticle morphology, stability, and narrow size distribution. The size distribution of GNPs is investigated for a range of parameters by dynamic light scattering and electron microscopy, and ultraviolet-visible (UV–vis) spectroscopy is also utilized to explore the localized surface pla...
Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple... more Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity ...
The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be i... more The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor-α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves׳ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds.
Objective: The objective of this study is to design a physical model of a magnetic filtration sys... more Objective: The objective of this study is to design a physical model of a magnetic filtration system which can separate magnetic nanoparticle (MNP)-tagged cytokines from fluid at physiologically relevant flow rates employed during cardiopulmonary bypass (CPB) procedures. Methods: The Navier-Stokes equations for the pressure driven flow in the chamber and the quasistatic stray magnetic field produced by an array of permanent magnets were solved using finite element analysis in COMSOL Multiphysics for 2D and 3D representations of the flow chamber. Parameters affecting the drag and magnetic forces including flow chamber dimensions, high gradient magnet array configurations, and particle properties, were changed and evaluated for their effect on MNP capture. Results: Flow chamber dimensions which achieve appropriate flow conditions for CPB were identified, and magnetic force within the chamber decreased with increased chamber height. A magnetic “block” array produced the highest magnetic force within the chamber. Polymeric microparticles loaded with MNPs were shown to have increased particle capture with increased hydrodynamic diameter. Conclusion: The model achieved a predicted efficiency up to 100% capture in a single-pass of fluid flowing at 1.75 L/min. Significance: This work is an important step in designing a magnetic flow chamber that can remove the magnetically tagged cytokines under high flow employed during CPB. Cytokines have been shown to stimulate the systemic inflammatory response (SIR) associated with CPB and are an established therapeutic target to mitigate the SIR. In the long term, this work aims to guide researchers in the more accurate design of magnetic separation systems.
Ophthalmic drug delivery via eye drops is inefficient because only about 1-5% of the drug permeat... more Ophthalmic drug delivery via eye drops is inefficient because only about 1-5% of the drug permeates the cornea during the short residence time of a few minutes. Contact lenses are receiving considerable attention for delivering ophthalmic drugs because of higher bioavailability and the possibility of sustained release from hour to days, and possibly longer. The drug release durations from contact lenses are typically measured in vitro and it is challenging to relate the in vitro release to in vivo release, particularly for hydrophobic drugs which may not exhibit sink release in vitro and in vivo. The in vitro release can be fitted to diffusion equation to determine the partition coefficient and diffusivity, which can then be utilized to model in vivo release. The Higuchi equation is frequently used to model the short time release from a contact lens to determine diffusivity with the implicit assumption that the release is under sink conditions and the starting concentration in the lens was uniform. Both conditions may be violated when measuring release of hydrophobic drugs from contact lenses because the diffusivity and partition coefficient, and also the time needed for equilibrium are not known a priori. Here we develop a method to use the data for both loading and release of cyclosporine, which is a common hydrophobic ophthalmic drug, to determine the partition coefficient and diffusivity. The proposed approach does not require sink conditions and also does not require the lens to be fully equilibrated during loading, which may take almost a month for lenses considered here. The model is based on solving the diffusion equation in the gel along with a mass balance in the fluid. The model equations are solved numerically by finite difference. When the value of partition coefficient is high, such as it is for cyclosporine, the dynamic data is only sensitive to a ratio of partition coefficient and diffusivity, and this ratio had to first be determined from the loading data. Then the two unknown parameters were obtained by minimizing the error between the model prediction and experimental data. The method was used to determine D and K for several silicone hydrogel formulations with varying ratio of hydrogel and silicone fractions.
Gold nanoparticles (GNPs) are commonly synthesized using the Turkevich method, but there are limi... more Gold nanoparticles (GNPs) are commonly synthesized using the Turkevich method, but there are limitations on the maximum concentration of gold nanoparticles that can be achieved using this method (often < 1 mM (=0.34 mg/mL) gold precursor loading). Here, we report an inverse Turkevich method which significantly increases the concentration of gold nanoparticles (up to 5-fold) in the aqueous phase by introducing poly (vinyl alcohol) (PVA) to the synthesis system for stabilization. The aim of this study is to understand the effect of PVA and other synthesis parameters, such as trisodium citrate and tetrachloroauric acid concentration, with the goal of maximizing concentration while maintaining gold nanoparticle morphology, stability, and narrow size distribution. The size distribution of GNPs is investigated for a range of parameters by dynamic light scattering and electron microscopy, and ultraviolet-visible (UV–vis) spectroscopy is also utilized to explore the localized surface pla...
Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple... more Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity ...
The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be i... more The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor-α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves׳ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds.
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Papers by Olivia Lanier