Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy with the p... more Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy with the potential to induce protein production to treat and prevent a range of diseases. While significant progress has been made in the design of in vitro-transcribed mRNA with high potency, low-cost manufacturing, and low innate immunogenicity, the widespread use of mRNA as a therapeutic requires safe and effective in vivo delivery technologies. Libraries of ionizable lipid nanoparticles (LNPs) have been designed to encapsulate mRNA, prevent its degradation, and
Frontiers in bioengineering and biotechnology, 2017
Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provid... more Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provide excellent lubrication to cartilage surfaces. Consequently, when joint disease or replacement leads to increased friction and surface damage in the joint, robust synthetic LUB alternatives that could be used therapeutically to improve lubrication and surface protection are needed. Here, we report the characterization of a lubricating multiblock bottlebrush polymer whose architecture was inspired by LUB, and we investigate the role of fibronectin (FN), a glycoprotein found in the superficial zone of cartilage, in mediating the tribological properties of the polymer upon shear between mica surfaces. Our surface forces apparatus (SFA) normal force measurements indicate that the lubricin-mimetic (mimLUB) could be kept anchored between mica surfaces, even under high contact pressures, when an intermediate layer of FN was present. Additional SFA friction measurements show that FN would also e...
Journal of controlled release : official journal of the Controlled Release Society, Jan 2, 2018
Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor ... more Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allo...
The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary ... more The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary lubricating abilities arise from two key structural features: i) a dense mucin-like domain consisting of hydrophilic oligosaccharides and ii) an end terminus that anchors the molecule to articulating surfaces. When bound, lubricin molecules attract and trap water near a surface, reducing friction and facilitating glide. Synthetic analogues were previously created to mimic lubricin using thiol-terminated polyacrylic acid-graft-polyethylene glycol (pAA-g-PEG) brush copolymers. The PEG moiety was designed to mimic the mucin-like domain of lubricin and the thiol-terminus was designed to anchor the molecules to cartilage surfaces, mimicking the binding domain. In this study, these synthetic lubricin-mimetics were bound to gold-coated surfaces to characterize the relationship between the polymers' molecular architecture and their lubricating capacity. A library of nine copolymer brushes was synthesized using different sizes of pAA and PEG. Larger molecular weight polymers created smoother, more densely covered surfaces (p < 0.05). Additionally, the hydrodynamic sizes of the polymers in solution were correlated with their lubricating abilities (p < 0.05). Friction coefficients of cartilage against polymer-treated gold surfaces were lower than cartilage against untreated surfaces (Δμeq = − 0.065 ± 0.050 to − 0.093 ± 0.045, p < 0.05).
Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vesse... more Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction, and attenuated heart failure. Nanoparticle-mediated RN...
The glycoprotein, lubricin, is the primary boundary lubricant of articular cartilage and has been... more The glycoprotein, lubricin, is the primary boundary lubricant of articular cartilage and has been shown to prevent cartilage damage after joint injury. In this study, a library of eight bottle-brush copolymers were synthesized to mimic the structure and function of lubricin. Polyethylene glycol (PEG) grafted onto a polyacrylic acid (pAA) core mimicked the hydrophilic mucin-like domain of lubricin, and a thiol terminus anchored the polymers to cartilage surfaces much like lubricin's C-terminus. These copolymers, abbreviated as pAA-g-PEG, rapidly bound to cartilage surfaces with binding time constants ranging from 20 to 39 min, and affected lubrication under boundary mode conditions with coefficients of friction ranging from 0.140 AE 0.024 to 0.248 AE 0.030. Binding and lubrication were highly correlated (r 2 ¼ 0.89-0.99), showing that boundary lubrication in this case strongly depends on the binding of the lubricant to the surface. Along with time-dependent and dose-dependent behavior, lubrication and binding of the lubricin-mimetics also depended on copolymer structural parameters including pAA backbone length, PEG side chain length, and PEG:AA brush density. Polymers with larger backbone sizes, brush sizes, or brush densities took longer to bind (p < 0.05). Six of the eight polymers reduced friction relative to denuded cartilage plugs (p < 0.05), suggesting their potential to lubricate and protect cartilage in vivo. In copolymers with shorter pAA backbones, increasing hydrodynamic size inhibited lubrication (p < 0.08), while the opposite was observed in copolymers with longer backbones (p < 0.05). These polymers show similar in vitro lubricating efficacy as recombinant lubricins and as such have potential for in vivo treatment of post-traumatic osteoarthritis.
Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provid... more Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provide excellent lubrication to cartilage surfaces. Consequently, when joint disease or replacement leads to increased friction and surface damage in the joint, robust synthetic LUB alternatives that could be used therapeutically to improve lubrication and surface protection are needed. Here, we report the characterization of a lubricating multiblock bottlebrush polymer whose architecture was inspired by LUB, and we investigate the role of fibronectin (FN), a glycoprotein found in the superficial zone of cartilage, in mediating the tribological properties of the polymer upon shear between mica surfaces. Our surface forces apparatus (SFA) normal force measurements indicate that the lubricin-mimetic (mimLUB) could be kept anchored between mica surfaces, even under high contact pressures, when an intermediate layer of FN was present. Additional SFA friction measurements show that FN would also e...
The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary ... more The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary lubricating abilities arise from two key structural features: i) a dense mucin-like domain consisting of hydrophilic oligosaccharides and ii) an end terminus that anchors the molecule to articulating surfaces. When bound, lubricin molecules attract and trap water near a surface, reducing friction and facilitating glide. Synthetic analogues were previously created to mimic lubricin using thiol-terminated polyacrylic acid-graft-polyethylene glycol (pAA-g-PEG) brush copolymers. The PEG moiety was designed to mimic the mucin-like domain of lubricin and the thiol-terminus was designed to anchor the molecules to cartilage surfaces, mimicking the binding domain. In this study, these synthetic lubricin-mimetics were bound to gold-coated surfaces to characterize the relationship between the polymers' molecular architecture and their lubricating capacity. A library of nine copolymer brushes was synthesized using different sizes of pAA and PEG. Larger molecular weight polymers created smoother, more densely covered surfaces (p < 0.05). Additionally, the hydrodynamic sizes of the polymers in solution were correlated with their lubricating abilities (p < 0.05). Friction coefficients of cartilage against polymer-treated gold surfaces were lower than cartilage against untreated surfaces (Δμeq = − 0.065 ± 0.050 to − 0.093 ± 0.045, p < 0.05).
Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy with the p... more Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy with the potential to induce protein production to treat and prevent a range of diseases. While significant progress has been made in the design of in vitro-transcribed mRNA with high potency, low-cost manufacturing, and low innate immunogenicity, the widespread use of mRNA as a therapeutic requires safe and effective in vivo delivery technologies. Libraries of ionizable lipid nanoparticles (LNPs) have been designed to encapsulate mRNA, prevent its degradation, and
Frontiers in bioengineering and biotechnology, 2017
Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provid... more Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provide excellent lubrication to cartilage surfaces. Consequently, when joint disease or replacement leads to increased friction and surface damage in the joint, robust synthetic LUB alternatives that could be used therapeutically to improve lubrication and surface protection are needed. Here, we report the characterization of a lubricating multiblock bottlebrush polymer whose architecture was inspired by LUB, and we investigate the role of fibronectin (FN), a glycoprotein found in the superficial zone of cartilage, in mediating the tribological properties of the polymer upon shear between mica surfaces. Our surface forces apparatus (SFA) normal force measurements indicate that the lubricin-mimetic (mimLUB) could be kept anchored between mica surfaces, even under high contact pressures, when an intermediate layer of FN was present. Additional SFA friction measurements show that FN would also e...
Journal of controlled release : official journal of the Controlled Release Society, Jan 2, 2018
Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor ... more Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allo...
The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary ... more The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary lubricating abilities arise from two key structural features: i) a dense mucin-like domain consisting of hydrophilic oligosaccharides and ii) an end terminus that anchors the molecule to articulating surfaces. When bound, lubricin molecules attract and trap water near a surface, reducing friction and facilitating glide. Synthetic analogues were previously created to mimic lubricin using thiol-terminated polyacrylic acid-graft-polyethylene glycol (pAA-g-PEG) brush copolymers. The PEG moiety was designed to mimic the mucin-like domain of lubricin and the thiol-terminus was designed to anchor the molecules to cartilage surfaces, mimicking the binding domain. In this study, these synthetic lubricin-mimetics were bound to gold-coated surfaces to characterize the relationship between the polymers' molecular architecture and their lubricating capacity. A library of nine copolymer brushes was synthesized using different sizes of pAA and PEG. Larger molecular weight polymers created smoother, more densely covered surfaces (p < 0.05). Additionally, the hydrodynamic sizes of the polymers in solution were correlated with their lubricating abilities (p < 0.05). Friction coefficients of cartilage against polymer-treated gold surfaces were lower than cartilage against untreated surfaces (Δμeq = − 0.065 ± 0.050 to − 0.093 ± 0.045, p < 0.05).
Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vesse... more Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction, and attenuated heart failure. Nanoparticle-mediated RN...
The glycoprotein, lubricin, is the primary boundary lubricant of articular cartilage and has been... more The glycoprotein, lubricin, is the primary boundary lubricant of articular cartilage and has been shown to prevent cartilage damage after joint injury. In this study, a library of eight bottle-brush copolymers were synthesized to mimic the structure and function of lubricin. Polyethylene glycol (PEG) grafted onto a polyacrylic acid (pAA) core mimicked the hydrophilic mucin-like domain of lubricin, and a thiol terminus anchored the polymers to cartilage surfaces much like lubricin's C-terminus. These copolymers, abbreviated as pAA-g-PEG, rapidly bound to cartilage surfaces with binding time constants ranging from 20 to 39 min, and affected lubrication under boundary mode conditions with coefficients of friction ranging from 0.140 AE 0.024 to 0.248 AE 0.030. Binding and lubrication were highly correlated (r 2 ¼ 0.89-0.99), showing that boundary lubrication in this case strongly depends on the binding of the lubricant to the surface. Along with time-dependent and dose-dependent behavior, lubrication and binding of the lubricin-mimetics also depended on copolymer structural parameters including pAA backbone length, PEG side chain length, and PEG:AA brush density. Polymers with larger backbone sizes, brush sizes, or brush densities took longer to bind (p < 0.05). Six of the eight polymers reduced friction relative to denuded cartilage plugs (p < 0.05), suggesting their potential to lubricate and protect cartilage in vivo. In copolymers with shorter pAA backbones, increasing hydrodynamic size inhibited lubrication (p < 0.08), while the opposite was observed in copolymers with longer backbones (p < 0.05). These polymers show similar in vitro lubricating efficacy as recombinant lubricins and as such have potential for in vivo treatment of post-traumatic osteoarthritis.
Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provid... more Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provide excellent lubrication to cartilage surfaces. Consequently, when joint disease or replacement leads to increased friction and surface damage in the joint, robust synthetic LUB alternatives that could be used therapeutically to improve lubrication and surface protection are needed. Here, we report the characterization of a lubricating multiblock bottlebrush polymer whose architecture was inspired by LUB, and we investigate the role of fibronectin (FN), a glycoprotein found in the superficial zone of cartilage, in mediating the tribological properties of the polymer upon shear between mica surfaces. Our surface forces apparatus (SFA) normal force measurements indicate that the lubricin-mimetic (mimLUB) could be kept anchored between mica surfaces, even under high contact pressures, when an intermediate layer of FN was present. Additional SFA friction measurements show that FN would also e...
The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary ... more The glycoprotein lubricin is the primary boundary lubricant of articular cartilage. Its boundary lubricating abilities arise from two key structural features: i) a dense mucin-like domain consisting of hydrophilic oligosaccharides and ii) an end terminus that anchors the molecule to articulating surfaces. When bound, lubricin molecules attract and trap water near a surface, reducing friction and facilitating glide. Synthetic analogues were previously created to mimic lubricin using thiol-terminated polyacrylic acid-graft-polyethylene glycol (pAA-g-PEG) brush copolymers. The PEG moiety was designed to mimic the mucin-like domain of lubricin and the thiol-terminus was designed to anchor the molecules to cartilage surfaces, mimicking the binding domain. In this study, these synthetic lubricin-mimetics were bound to gold-coated surfaces to characterize the relationship between the polymers' molecular architecture and their lubricating capacity. A library of nine copolymer brushes was synthesized using different sizes of pAA and PEG. Larger molecular weight polymers created smoother, more densely covered surfaces (p < 0.05). Additionally, the hydrodynamic sizes of the polymers in solution were correlated with their lubricating abilities (p < 0.05). Friction coefficients of cartilage against polymer-treated gold surfaces were lower than cartilage against untreated surfaces (Δμeq = − 0.065 ± 0.050 to − 0.093 ± 0.045, p < 0.05).
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Papers by Mingchee Tan