Interleukin‐4‐Clicked Surfaces Drive M2 Macrophage Polarization

Driving macrophage (M?) polarization into the M2 phenotype provides potential against inflammatory diseases. Interleukin‐4 (IL‐4) promotes polarization into the M2‐M? phenotype, but its systemic use is constrained by dose‐limiting toxicity. Consequently, we developed IL‐4‐decorated surfaces aiming at sustained and localized activity. IL‐4 muteins were generated by genetic code expansion; Lys42 was replaced by unnatural amino acids (uAAs). Both muteins showed cell‐stimulation ability and binding affinity to IL4Rα similar to those of wt‐IL‐4. Copper‐catalyzed (CuAAC) and copper‐free strain‐promoted (SPAAC) 1,3‐dipolar azide–alkyne cycloadditions were used to site‐selectively anchor IL‐4 to agarose surfaces. These surfaces had sustained IL‐4 activity, as demonstrated by TF‐1 cell proliferation and M2, but not M1, polarization of M‐CSF‐generated human M?. The approach provides a blueprint for the engineering of cytokine‐activated surfaces profiled for sustained and spatially controlled activity.     

Orthogonal ligation to spherical polymeric microparticles: Modular approaches for surface tailoring

Modular ligation strategies for the functionalization of polymeric microspheres provide new perspectives for their applications in material science. In the current trend article we highlight variable synthetic procedures for generating functional microspheres via orthogonal modular conjugation chemistries. An overview of the different surface chemistries available is provided, followed by surface-sensitive characterization techniques relevant for the microparticles. Finally, we explore future trends in modular orthogonal modification approaches on microparticles and provide an outlook on the perspectives that the field of surface-modification of polymeric microparticles holds.     

Interpolymer radical coupling: A toolbox complementary to controlled radical polymerization

The current review focuses on the relevance and practical benefit of interpolymer radical coupling methods. The latter are developing rapidly and constitute a perfectly complementary macromolecular engineering toolbox to the controlled radical polymerization techniques (CRP). Indeed, all structures formed by CRP are likely to be prone to radical coupling reactions, which multiply the available synthetic possibilities. Basically, the coupling systems can be divided in two main categories. The first one, including the atom transfer radical coupling (ATRC), silane radical atom abstraction (SRAA) and cobalt-mediated radical coupling (CMRC), relies on the recombination of macroradicals produced from a dormant species. The second one, including atom transfer nitroxide radical coupling (ATNRC), single electron transfer nitroxide radical coupling (SETNRC), enhanced spin capturing polymerization (ESCP) and nitrone/nitroso mediated radical coupling (NMRC), makes use of a radical scavenger in order to promote the conjugation of the polymer chains. More than a compilation of macromolecular engineering achievements, the present review additionally aims to emphasize the particularities, synthetic potential and present limitations of each system.     

Click-Chemistry (CuAAC) Trimerization of an αvβ6 Integrin Targeting Ga-68-Peptide: Enhanced Contrast for in-Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts

α_vβ₆ Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with α_vβ₆ integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the α_vβ₆-specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH₂) to enhance α_vβ₆ integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)₃ showed a 28-fold higher α_vβ₆ affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC₅₀ of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC₅₀-based selectivity over the related integrin α_vβ₈ (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)₃ holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.     

Styrenated urethane oil synthesis via CuAAC “click” chemistry approach

In this study, a novel route for the modification of sunflower oil-based partial triglycerides with styrene (St) was described. For this purpose, in the first step, copolymers of St and 4-chloromethyl styrene (P(St-co-CMS)) were synthesized by free radical polymerization (FRP) and controlled/living radical polymerization (nitroxide mediated radical polymerization (NMRP)) methods. In the second step, chloro groups of these samples were transformed into azido groups by using NaN₃/DMF and then azido groups were coupled with propargyl alcohol to achieve hydroxyl functional polystyrene chain (PSt-OH) via Cu(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) “click” chemistry approach. Finally, alcohol groups of PSt-OH and the partial glyceride (PG) were combined by the reaction with toluene 2,4-diisocyanate (TDI). As a result, styrenated urethane oil (PG-TDI-PSt) was obtained as an oil-based binder. The structures were determined by FT-IR, ¹H NMR and GPC analyses, and film properties of the products were examined according to the related standards. (PG-TDI-PSt) gave good film properties, and therefore could be considered as an applicable oil-based binder.     

Synthesis and functionalization of nanoengineered materials using click chemistry

The synthesis of nanoengineered materials with precise control over material composition, architecture and functionality is integral to advances in diverse fields, including biomedicine. Over the last 10 years, click chemistry has emerged as a prominent and versatile approach to engineer materials with specific properties. Herein, we highlight the application of click chemistry for the synthesis of nanoengineered materials, ranging from ultrathin films to delivery systems such as polymersomes, dendrimers and capsules. In addition, we discuss the use of click chemistry for functionalizing such materials, focusing on modifications aimed at biomedical applications.     

Highly efficient synthesis of cylindrical polymer brushes with various side chains via click grafting-onto approach

Though much attention has been paid to synthesis of cylindrical polymer brushes, it is still not easy to prepare well-defined brushes by a general approach. Herein, well-defined cylindrical polymer brushes with various side chains were synthesized via grafting-onto approach by CuAAC click chemistry. Narrowly dispersed polymer backbones functionalized with azide groups were obtained by post-modification of poly(glycidyl methacrylate) (PGMA) which was prepared by reversible addition-fragmentation chain transfer (RAFT) mediated radical polymerization. The alkyne-terminated side chains, polystyrene, polyacrylates, polymethacrylates and poly(N-alkyl acrylamide)s, were synthesized by RAFT mediated radical polymerization with alkyne-containing chain transfer agents (CTAs). The CuAAC reactions between the backbone and side chain polymers were conducted with an equivalent feed of alkyne-terminated side chains and azide groups under mild conditions. Influences of reaction conditions and chemical composition of polymer side chains on grafting efficiency and molecular weight distribution of the polymer brushes were investigated. It is demonstrated that the side chains of polystyrene, polyacrylates and poly(N-alkyl acylamide)s were grafted at a density above 85% while that of polymethacrylates decreased to ca. 50%. The polymer brushes synthesized under the optimized reaction conditions had well-defined chemical composition and narrow distribution of molecular weight, and their wormlike morphology was visualized by atomic force microscopy (AFM).     

Well‐Defined Poly(ethylene glycol) Hydrogels with Enhanced Mechanical Performance Prepared by Thermally Induced Copper‐Catalyzed Azide–Alkyne Cycloaddition

Poly(ethylene glycol) (PEG)‐based hydrogels have attracted increasing attention in recent years due to their good biocompatibility and low cost. However, the PEG‐based hydrogels prepared by traditional methods exhibit a poor machinability due to their disordered network structure. Herein, the preparation of well‐defined PEG‐based hydrogel via a facile thermally induced copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction is demonstrated. To accomplish this, thermochemically reduced Cu(I) catalyst is adopted to trigger “click” cross‐linking, resulting in a well‐defined PEG network. The as‐synthesized PEG‐based hydrogel exhibits good mechanical performance with a tensile strength of 2.51 MPa, which is higher than the traditional PEG‐based hydrogels prepared from CuSO₄/NaSac‐mediated or CuBr/ligand‐catalyzed CuAAC. Moreover, in vitro cytotoxicity and in vivo porcine subcutaneous implantation tests demonstrate that the as‐synthesized PEG‐based hydrogel has a good biocompatibility and low toxicity, making it a promising candidate for the applications in biomedical devices and tissue engineering.

     

One‐Step Derivatization of Reducing Oligosaccharides for Rapid and Live‐Cell‐Compatible Chelation‐Assisted CuAAC Conjugation

We report a new reagent for the functionalization of unprotected oligosaccharides with a picolyl azide group at the anomeric position for chelation‐assisted copper‐catalyzed alkyne–azide cycloaddition (CuAAC) glycoconjugation. We show that oligosaccharides functionalized with this moiety react with an apparent second‐order rate constant of 193 m ^?1 s^?1 and can be used to functionalize biomolecules bearing alkyne moieties introduced through metabolic labeling, including in live cells.     

N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a scaffold for the synthesis of inhibitors of Bcr-Abl

N‐[2‐Methyl‐5‐(triazol‐1‐yl)phenyl]pyrimidin‐2‐amine derivatives were synthesized and evaluated in vitro for their potential use as inhibitors of Bcr‐Abl. The design is based on the bioisosterism between the 1,2,3‐triazole ring and the amide group. The synthesis involves a copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) as the key step, with the exclusive production of anti‐(1,4)‐triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K‐562 cell line.