Bioorthogonal catalysis in complex media:Consequences of using polymeric scaffold materials on catalyst stability and activity

Bioorthogonal catalysis using transition-metal-based complexes (TMCs) is a promising approach for converting substrates to desired products in complex cellular media. Notably, the in situ activation of prodrugs or synthesis of active drugs with the aim to complement existing treatments in diseases such as cancer has received significant attention. Whereas the focus has initially been on optimizing ligands to enhance the activity and stability of the metal complexes, more recently the benign effects of compartmentalization of the catalyst into homogeneous or heterogeneous scaffolds have been unveiled. Such tailor-made carrier materials not only afford active catalysts but also permit to guide the catalyst to the site of interest in in vivo applications. This review will emphasize the potential of synthetic amphiphilic polymers that form compartmentalized nanostructures for TMCs. The use of amphiphilic polymers is well established in the field of nanomedicine for i.e. drug delivery purposes, but their application as homogeneous carrier materials for TMCs has been less well explored. Since synthetic polymers are readily functionalized with ligands and targeting moieties, they can act as versatile catalysts carriers. After a short overview of the state-of-the-art in bioorthogonal catalysis using ligand-based TMCs, we summarize the advances in using homogeneous natural polymers as scaffolds and synthetic heterogeneous carrier materials for bioorthogonal catalysis. We end this review by highlighting the recent advances of catalysis in complex media using TMCs embedded in nanostructures formed by amphiphilic synthetic polymers. The combination of polymer science and homogeneous catalysis with the field of nanomedicine may open up new opportunities for advancing the exciting field of bioorthogonal catalysis for therapeutic applications.</p

How to Determine the Role of an Additive on the Length of Supramolecular Polymers?

In polymer chemistry, modulation of sequence and control over chain length are routinely applied to alter and fine-tune the properties of covalent (co)polymers. For supramolecular polymers, the same principles underlying this control have not been fully elucidated up to this date. Particularly, rational control over molecular weight in dynamic supramolecular polymers is not trivial, especially when a cooperative mechanism is operative. We start this review by summarizing how molecular-weight control has been achieved in seminal examples in the field of supramolecular polymerizations. Following this, we propose to classify the avenues taken to control molecular weights in supramolecular polymerizations. We focus on dynamic cooperative supramolecular polymerization as this is the most challenging in terms of molecular weight control. We use a mass-balance equilibrium model to predict how the nature of the interaction of an additive B with the monomers and supramolecular polymers of component A affects the degree of aggregation and the degree of polymerization. We put forward a classification system that distinguishes between B acting as a chain capper, a sequestrator, a comonomer, or an intercalator. We also highlight the experimental methods applied to probe supramolecular polymerization processes, the type of information they provide in relation to molecular weight and degree of aggregation, and how this can be used to classify the role of B. The guidelines and classification delineated in this review to assess and control molecular weights in supramolecular polymers can serve to reevaluate exciting systems present in current literature and contribute to broaden the understanding of multicomponent systems.</p

Helical bias in supramolecular polymers accounts for different stabilities of kinetically trapped states

The idea to synthesize and self-assemble nano-graphenes with structural precision into supramolecular polymers is just one of Klaus Müllen's many pioneering contributions to the chemical sciences. To honor his impact in the field of polymer science, we here describe a study that combines experimental and computational methods in studying the stability of kinetically trapped states of supramolecular polymers. We show that the introduction of stereocenters in the sidechains allow helical supramolecular polymers based on chiral triphenylene-2,6,10-tricarboxamide monomers to escape a kinetic trap more efficiently than polymers based on their achiral analogs. Partial depolymerization of the kinetically trapped state by increasing the temperature followed by polymerization by lowering the temperature shows that monomers either polymerize on existing stacks or self-nucleate to form the thermodynamically more stable state. Chiral monomers prefer the latter more than achiral monomers.</p

Developing Pd(II) based amphiphilic polymeric nanoparticles for pro-drug activation in complex media

Novel approaches to targeted cancer therapy that combine improved efficacy of current chemotherapies while minimising side effects are highly sought after. The development of single-chain polymeric nanoparticles (SCPNs) as bio-orthogonal catalysts for targeted site-specific pro-drug activation is a promising avenue to achieve this. Currently, the application of SCPNs as bio-orthogonal catalysts is in its early stages due to reduced performance when increasing the medium's complexity. Herein, we present a systematic approach to identify the various aspects of SCPN-based catalytic systems, to improve their efficiency in future in vitro/in vivo studies. We developed amphiphilic polymers with a polyacrylamide backbone and functionalised with the Pd(ii)-binding ligands triphenylphosphine and bipyridine. The resulting polymers collapse into small-sized nanoparticles (5-6 nm) with an inner hydrophobic domain that comprises the Pd(ii) catalyst. We systematically evaluated the effect of polymer microstructure, ligand-metal complex, and substrate hydrophobicity on the catalytic activity of the nanoparticles for depropargylation reactions in water, PBS or DMEM. The results show that the catalytic activity of nanoparticles is primarily impacted by the ligand-metal complex while polymer microstructure has a minor influence. Moreover, the rate of reaction is increased for hydrophobic substrates. In addition, Pd(ii) leaching studies confirmed little to no loss of Pd(ii) from the hydrophobic interior which can reduce off-target toxicities in future applications. Careful deconstruction of the catalytic system revealed that covalent attachment of the ligand to the polymer backbone is necessary to retain its catalytic activity in cell culture medium while not in water. Finally, we activated anti-cancer pro-drugs based on 5-FU, paclitaxel, and doxorubicin using the best-performing catalytic SCPNs. We found that the rate of pro-drug activation in water was accelerated efficiently by catalytic SCPNs, whereas in cell culture medium the results depended on the type of protecting group and hydrophobicity of the prodrug. We believe our findings will aid in the development of suitable catalytic systems and pro-drugs for future in vivo applications

Dynamic covalent networks with tunable dynamicity by mixing acylsemicarbazides and thioacylsemicarbazides

Dynamic covalent networks (DCNs) use chemical bonds that break and reform at appropriate processing conditions to allow reconfiguration of the networks. Recently, the acylsemicarbazide (ASC) motif has been added to the repertoire of such dynamic covalent bonds, which is capable of hydrogen bonding as well as dynamic bond exchange. In this study, we show that its sulfur congener, thioacylsemicarbazide (TASC), also acts as a dynamic covalent bond, but exchanges at a slower rate than the ASC moiety. In addition, siloxane-based DCNs comprising either ASC or TASC motifs or a varying composition of both show tunable relaxation dynamics, which slow down with an increasing amount of TASC motifs. The reduction in stress relaxation goes hand in hand with a reduction of creep in the network and can be tuned by the ASC/TASC ratio. All networks are readily processed using compression molding and dissolve when treated with excess hydrazide in solution. The ability to control network properties and creep in dynamic covalent polymeric networks by small changes in the molecular structure of the dynamic bond allows a generalized synthetic approach while accommodating a wide temperature window for application.</p

Bisurea-Based Supramolecular Polymers for Tunable Biomaterials

Water-soluble supramolecular polymers show great potential to develop dynamic biomaterials with tailored properties. Here, we elucidate the morphology, stability and dynamicity of supramolecular polymers derived from bisurea-based monomers. An accessible synthetic approach from 2,4-toluene diisocyanate (TDI) as the starting material is developed. TDI has two isocyanates that differ in intrinsic reactivity, which allows to obtain functional, desymmetrized monomers in a one-step procedure. We explore how the hydrophobic/hydrophilic ratio affects the properties of the formed supramolecular polymers by increasing the number of methylene units from 10 to 12 keeping the hydrophilic hexa(ethylene glycol) constant. All bisurea-based monomers form long, fibrous structures with 3-5 monomers in the cross-section in water, indicating a proper hydrophobic\hydrophilic balance. The stability of the supramolecular polymers increases with an increasing amount of methylene units, whereas the dynamic nature of the monomers decreases. The introduction of one Cy3 dye affords modified supramolecular monomers, which co-assemble with the unmodified monomers into fibrous structures. All systems show excellent water-compatibility and no toxicity for different cell-lines. Importantly, in cell culture media, the fibrous structures remain present, highlighting the stability of these supramolecular polymers in physiological conditions. The results obtained here motivate further investigation of these bisurea-based building blocks as dynamic biomaterial.</p

Better together: enhanced phosphorescence and co-assembly of Pt-Pd complexes

In this issue of Chem, Che and coworkers show the sequential assembly of phosphorescent, multiblock supramolecular aggregates in one or more dimensions by a living supramolecular polymerization approach. Doping small amounts of PtII into PdII assemblies significantly improves emission properties, demonstrating a new strategy for preparing luminescent metal-organic supramolecular materials