Non-activated esters are prominently featured functional groups in polymer science, as ester functional monomers display great structural diversity and excellent compatibility with a wide range of... Show moreNon-activated esters are prominently featured functional groups in polymer science, as ester functional monomers display great structural diversity and excellent compatibility with a wide range of polymerization mechanisms. Yet, their direct use as a reactive handle in post-polymerization modification has been typically avoided due to their low reactivity, which impairs the quantitative conversion typically desired in post-polymerization modification reactions. While activated ester approaches are a well-established alternative, the modification of non-activated esters remains a synthetic and economically valuable opportunity. In this review, we discuss past and recent efforts in the utilization of non-activated ester groups as a reactive handle to facilitate transesterification and aminolysis/amidation reactions, and the potential of the developed methodologies in the context of macromolecular engineering. Show less
Dammeijer, F.; Gulijk, M. van; Klaase, L.; Nimwegen, M. van; Bouzid, R.; Hoogenboom, R.; ... ; Aerts, J.G. 2022
Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the... Show moreTerminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)& ndash;STAT5 pathway signaling in medi-ating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i admin-istration inhibited antitumor T-cell effector function, low-dose chronic JAK3i significantly improved T-cell responses and decreased tumor load in mouse models of solid cancer. Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared with both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy.Superscript/Subscript Available Show less
Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show... Show moreAssociations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPAR alpha pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4 alpha signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health. Show less
Guyse, J.F.R. van; Bernhard, Y.; Hoogenboom, R. 2020
Only recently, post-polymerization modification reactions of unactivated polyacrylates have been emerging as an attractive alternative to utilizing reactive monomers, enabling the synthetic... Show moreOnly recently, post-polymerization modification reactions of unactivated polyacrylates have been emerging as an attractive alternative to utilizing reactive monomers, enabling the synthetic upcycling of these widely applied polymers. Within this contribution, the triazabicyclodecene-catalyzed transesterification of polyacrylates is reported, including the reaction kinetics and the broad scope for macromolecular design of functional copolyacrylates. More specifically, the transesterification is performed under equilibrium conditions with a set of primary alcohols whereby the reaction kinetics and the obtained conversion as a function of stoichiometric excess of alcohol are evaluated. The results show that the obtained conversion is dependent on the polarity of the solvent and of the alcohol. Through this approach, the transesterification degree can be accurately controlled by stoichiometry, enabling the precise modulation of the macromolecular structure. Finally, the utility of this approach is demonstrated to incorporate functional side chains that are incompatible with radical polymerization, to facilitate Diels-Alder and thiol-ene reactions, enabling access to a broad range of functional materials from simple polyacrylate homopolymer precursors. Show less
Conjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the... Show moreConjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the biocompatible poly(2-ethyl-2-oxazoline) (PEtOx). The drug is attached to the side chains of a polymer carrier through a hydrolytically cleavable ester linker, via a sequential postpolymerization modification. The chemical modulation of this ester, i.e., by primary or secondary alcohols, is demonstrated to greatly influence the ester hydrolysis rate. This crucial parameter allows us to tune the in vitro kinetics of the sustained drug release for periods exceeding a month in phosphate-buffered saline (PBS). The synthetic accessibility of the cleavable linker, together with the modularity of the drug release rate offered by this approach, highlights the utility of this class of polymers in the field of long-lasting drug delivery systems for persistent and chronic disease treatment. Show less
Egghe, T.; Cools, P.; Guyse, J.F.R. van; Asadian, M.; Khalenkow, D.; Nikiforov, A.; ... ; Geyter, N. de 2020
The plasma polymerization of amide-based precursors is a nearly unexplored research area, which is in contrast with the abundance of reports focusing on amide-based surface modification using wet... Show moreThe plasma polymerization of amide-based precursors is a nearly unexplored research area, which is in contrast with the abundance of reports focusing on amide-based surface modification using wet chemistry. Therefore, this study aims to profoundly investigate the near-atmospheric pressure plasma polymerization of N,N-dimethylacrylamide (DMAM) to obtain stable coatings. In contrast to the unstable coatings obtained at lower discharge powers, the stable coatings that were obtained at higher powers showed a lower hydrophilicity as assessed by water contact angle (WCA). This decrease in hydrophilicity with increasing plasma power was found to be related to a reduced preservation of the monomer structure, as observed by Fourier transform infrared (FTIR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and XPS C60 depth profiling, a rarely used but effective combination of techniques. Furthermore, the chemical composition of the coating was found to be in good agreement with the plasma active species observed by optical emission spectroscopy. Additionally, XPS C60 depth profiling indicated a difference between the top layer and bulk of the plasma polymer due to spontaneous oxidation and/or postplasma coating deposition. Finally, the stable coatings were also found to have cell-interactive behavior toward MC3T3 as studied by in vitro live/dead fluorescence imaging and (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assays. With the latter technique, a cell viability of up to 89% as compared with tissue culture plates after 1 day of cell culture was observed, indicating the potential of these coatings for tissue engineering purposes. Show less
