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Solid-state mechanochemical ?-functionalization of poly(ethylene glycol).

ABSTRACT: Poly(ethylene glycol) (PEG) is a linear polymer with a wide range of applications in chemical manufacturing, drug development and nanotechnology. PEG derivatives are being increasingly used to covalently modify small molecule and peptide drugs, as well as bioactive nanomaterials in order to improve solubility in biological serum, reduce immunogenicity, and enhance pharmacokinetic profiles. Herein we present the development of mechanochemical procedures for PEG functionalization without the need for bulk solvents, offering a cleaner and more sustainable alternative to existing solution-based PEG procedures. The herein presented mechanochemical procedures enable rapid and solvent-free derivatization of PEG with tosyl, bromide, thiol, carboxylic acid or amine functionalities in good to quantitative yields and with no polymer chain oligomerization, proving the versatility of the method.

SUBMITTER: Malca MY

PROVIDER: S-EPMC5629410 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Solid-state mechanochemical ω-functionalization of poly(ethylene glycol).

Malca Michael Y MY Ferko Pierre-Olivier PO Friščić Tomislav T Moores Audrey A

Beilstein journal of organic chemistry 20170918

Poly(ethylene glycol) (PEG) is a linear polymer with a wide range of applications in chemical manufacturing, drug development and nanotechnology. PEG derivatives are being increasingly used to covalently modify small molecule and peptide drugs, as well as bioactive nanomaterials in order to improve solubility in biological serum, reduce immunogenicity, and enhance pharmacokinetic profiles. Herein we present the development of mechanochemical procedures for PEG functionalization without the need ...[more]

PMID: 29062415

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Project description:Valve interstitial cells (VIC) are the primary cell type residing within heart valve tissues. In many valve pathologies, VICs become activated and will subsequently profoundly remodel the valve tissue extracellular matrix (ECM). A primary indicator of VIC activation is the upregulation of ?-smooth muscle actin (?SMA) stress fibers, which in turn increase VIC contractility. Thus, contractile state reflects VIC activation and ECM biosynthesis levels. In general, cell contraction studies have largely utilized two-dimensional substrates, which are a vastly different micro mechanical environment than 3D native leaflet tissue. To address this limitation, hydrogels have been a popular choice for studying cells in a three-dimensional environment due to their tunable properties and optical transparency, which allows for direct cell visualization. In the present study, we extended the use of hydrogels to study the active contractile behavior of VICs. Aortic VICs (AVIC) were encapsulated within poly(ethylene glycol) (PEG) hydrogels and were subjected to flexural-deformation tests to assess the state of AVIC contraction. Using a finite element model of the experimental setup, we determined the effective shear modulus ? of the constructs. An increase in ? resulting from AVIC active contraction was observed. Results further indicated that AVIC contraction had a more pronounced effect on ? in softer gels (72?±?21% increase in ? within 2.5?kPa gels) and was dependent upon the availability of adhesion sites (0.5-1?mM CRGDS). The transparency of the gel allowed us to image AVICs directly within the hydrogel, where we observed a time-dependent decrease in volume (time constant ?=3.04 min) when the AVICs were induced into a hypertensive state. Our results indicated that AVIC contraction was regulated by both the intrinsic (unseeded) gel stiffness and the CRGDS peptide concentrations. This finding suggests that AVIC contractile state can be profoundly modulated through their local micro environment using modifiable PEG gels in a 3D micromechanical-emulating environment. Moving forward, this approach has the potential to be used towards delineating normal and diseased VIC biomechanical properties using highly tunable PEG biomaterials. STATEMENT OF SIGNIFICANCE.

Project description:Growth factors have been shown to be potent mediators of osteogenesis. However, their use in tissue-engineered scaffolds not only can be costly but also can induce undesired responses in surrounding tissues. Thus, the ability to specifically induce osteogenic differentiation in the absence of exogenous growth factors through manipulation of scaffold material properties would be desirable for bone regeneration. Previous research indicates that addition of inorganic or hydrophobic components to organic, hydrophilic scaffolds can enhance multipotent stem cell (MSC) osteogenesis. However, the combined impact of scaffold inorganic content and hydrophobicity on MSC behavior has not been systematically explored, particularly in three-dimensional (3D) culture systems. The aim of the present study was therefore to examine the effects of simultaneous increases in scaffold hydrophobicity and inorganic content on MSC osteogenic fate decisions in a 3D culture environment toward the development of intrinsically osteoinductive scaffolds. Mouse 10T½ MSCs were encapsulated in a series of novel scaffolds composed of varying levels of hydrophobic, inorganic poly(dimethylsiloxane) (PDMS) and hydrophilic, organic poly(ethylene glycol) (PEG). After 21 days of culture, increased levels of osteoblast markers, runx2 and osteocalcin, were observed in scaffolds with increased PDMS content. Bone extracellular matrix (ECM) molecules, collagen I and calcium phosphate, were also elevated in formulations with higher PDMS:PEG ratios. Importantly, this osteogenic response appeared to be specific in that markers for chondrocytic, smooth muscle cell, and adipocytic lineages were not similarly affected by variations in scaffold PDMS content. As anticipated, the increase in scaffold hydrophobicity accompanying increasing PDMS levels was associated with elevated scaffold serum protein adsorption. Thus, scaffold inorganic content combined with alterations in adsorbed serum proteins may underlie the observed cell behavior.

Dataset Information

Solid-state mechanochemical ?-functionalization of poly(ethylene glycol).

Publications

Solid-state mechanochemical ω-functionalization of poly(ethylene glycol).

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