Oliver C. J. Andrén

‘One-pot’ sequential deprotection/functionalisation of linear-dendritic hybrid polymers using a xanthate mediated thiol/Michael addition

Thiol–Michael addition chemistry is a powerful tool for the preparation of functional materials. In this first report of xanthate-functional linear-dendritic polymer hybrids, the preparation of four generations of xanthate-functionalised dendron atom transfer radical polymerisation macroinitiators is described using an orthogonal chemical strategy. The controlled polymerisation of tertiary butyl methacrylate is demonstrated to high conversion and without interference from the xanthate surface groups. Modification of the peripheral xanthate groups of dendrons at the hybrid polymer chain-end has been studied using a one-pot deprotection/functionalisation strategy and a range of commercially available and bespoke acrylate monomers to form complex polymer architectures from feedstock polymers, differing in the number of modified end groups and the surface chemistry of the dendron chain end.

The first peripherally masked thiol dendrimers: a facile and highly efficient functionalization strategy of polyester dendrimers via one-pot xanthate deprotection/thiol–acrylate Michael addition reactions

Introducing multiple reactive functional groups at the periphery of dendrimer materials presents considerable challenges if the functionality is able to self-react. An efficient and facile approach to introducing masked thiols at the surface of polyester dendrimers is presented. One-pot, deprotection/thiol-acrylate Michael addition from the xanthate-functional dendritic substrates (generation zero to two) has been achieved for the first time, with high efficiency demonstrated using three acrylates of varying chemistry and avoiding disulfide formation.

Fluoride-Promoted Esterification (FPE) Chemistry: A Robust Route to Bis-MPA Dendrons and Their Postfunctionalization

Bifunctional dendrons based on 2,2-bis(methylol)propionic acid (bis-MPA) are highly desirable scaffolds for biomedical applications. This is due to their flawless nature and large and exact number of functional groups as well as being biodegradable and biocompatible. Herein, we describe a facile divergent growth approach to their synthesis from monobenzylated tetraethylene glycol and post functionalization utilizing fluoride-promoted esterification (FPE) chemistry protocols. The scaffolds, presenting selectively deprotectable hydroxyls in the periphery and at the focal point, were isolated on a multigram scale with excellent purity up to the fourth generation dendron with a molecular weight of 2346 Da in seven reactions with a total yield of 50%. The third generation dendron was used as a model compound to demonstrate its functionalizability. Selective deprotection of the dendron’s focal point was achieved with an outstanding yield of 94%, and biotin as well as azido functionalities were introduced to its focal point and periphery, respectively, through FPE chemistry. Bulky disperse red dyes were clicked through CuAAC to the dendron’s azido groups, giving a biotinylated dendron with multivalent dyes with a molecular weight of 6252 Da in a total yield of 37% in five reactions with an average yield of 82% starting from the third generation focally and peripherally protected dendron. FPE chemistry proved to be a superb improvement over previous protocols towards bis-MPA dendrons as high purity and yields were obtained with less toxic solvents and greatly improved monomer utilization.

Model studies of the sequential and simultaneous statistical modification of dendritic functional groups and their implications within complex polymer architecture synthesis

Post-synthesis modification of polymers is a synthetically appealing approach to generate a range of samples from a single, well-characterised starting material. When partial or mixed-functionalisation is sought, an inevitable statistical distribution of modification outcomes will lead to considerable variation of chemical structures within the final sample. Here we have comprehensively investigated the post-synthesis sequential/partial and simultaneous mixed modification of xanthate-functional ideal dendrons and used this data to consider the implications for the more complex linear-dendritic hybrids and hyperbranched-polydendron analogues. Although 1H NMR confirmed the potential to direct the reactions, it was clear from MALDI-TOF studies that very little of the actual targeted structures were generated in the statistical reactions.

Heterogeneous Rupturing Dendrimers

Utilizing macromolecular scaffolds as templates for the production of small molecules that are distinctively different from the original monomer feedstock has many potential applications. Herein, as a proof-of-concept, a family of dendrimers displaying internally queued disulfide bridges were synthesized and exploited as flawless macromolecular templates that selectively rupture into a set of monomeric mercaptans. Disassembly was accomplished in a reducing environment, using DTT as an external stimulus, and the thiol constituents were successfully isolated. Their composition was dictated by three dendritic regions, i.e., (i) the symmetrical trithiol of the core (C3), (ii) the interior-asymmetric trithiols (CD2), and (iii) the periphery-asymmetric monothiols (DB2), in which B functionality is of an orthogonal nature. Taking into account the steady state between disulfides and thiols in all living cells, the collapse of the dendrimers to a multitude of smaller thiols was intracellularly assessed as a means to disrupt the balance of reactive oxygen species (ROS) often elevated in cancer cells. Indeed, the fragmentation induced a significant increase of ROS in human lung carcinoma A549 cells. These findings can potentially alter the perception of dendrimers being limited to carriers to being prodrugs for intracellular delivery of ROS with the potential to fight cancer.

Membrane interactions of microgels as carriers of antimicrobial peptides

Microgels are interesting as potential delivery systems for antimicrobial peptides. In order to elucidate membrane interactions of such systems, we here investigate effects of microgel charge density on antimicrobial peptide loading and release, as well as consequences of this for membrane interactions and antimicrobial effects, using ellipsometry, circular dichroism spectroscopy, nanoparticle tracking analysis, dynamic light scattering and z-potential measurements. Anionic poly(ethyl acrylate-co-methacrylic acid) microgels were found to incorporate considerable amounts of the cationic antimicrobial peptides LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW) and to protect incorporated peptides from degradation by infection-related proteases at high microgel charge density. As a result of their net negative z-potential also at high peptide loading, neither empty nor peptide-loaded microgels adsorb at supported bacteria-mimicking membranes. Instead, membrane disruption is mediated almost exclusively by peptide release. Mirroring this, antimicrobial effects against several clinically relevant bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa) were found to be promoted by factors facilitating peptide release, such as decreasing peptide length and decreasing microgel charge density. Microgels were further demonstrated to display low toxicity towards erythrocytes. Taken together, the results demonstrate some interesting opportunities for the use of microgels as delivery systems for antimicrobial peptides, but also highlight several key factors which need to be controlled for their successful use.

Facile thiolation of hydroxyl functional polymers

Sulfur is an important component in many biological systems. In the hands of an organic chemist it can provide an ample handle for a myriad of robust reactions including thiol-ene click chemistry. ...

Synthesis and in Vitro Evaluation of Monodisperse Amino-Functional Polyester Dendrimers with Rapid Degradability and Antibacterial Properties

Amine functional polymers, especially cationically charged, are interesting biomacromolecules for several reasons, including easy cell membrane entrance, their ability to escape endosomes through the proton sponge effect, spontaneous complexation and delivery of drugs and siRNA, and simple functionalization in aqueous solutions. Dendrimers, a subclass of precision polymers, are monodisperse and exhibit a large and exact number of peripheral end groups in relation to their size and have shown promise in drug delivery, biomedical imaging and as antiviral agents. In this work, hydroxyl functional dendrimers of generation 1 to 5 based on 2,2-bis(methylol)propionic acid (bis-MPA) were modified to bear 6 to 96 peripheral amino groups through esterification reactions with beta-alanine. All dendrimers were isolated in high yields and with remarkable monodispersity. This was successfully accomplished utilizing the present advantages of fluoride-promoted esterification (FPE) with imidazole-activated monomers. Straightforward postfunctionalization was conducted on a second generation amino-functional dendrimer with tetraethylene glycol through NHS-amidation and carbonyl diimidazole (CDI) activation to full conversion with short reaction times. Fast biodegradation of the dendrimers through loss of peripheral beta-alanine groups was observed and generational- and dose-dependent cytotoxicity was evaluated with a set of cell lines. An increase in neurotoxicity compared to hydroxyl-functional dendrimers was shown in neuronal cells, however, the dendrimers were slightly less neurotoxic than commercially available poly(amidoamine) dendrimers (PAMAMs). Additionally, their effect on bacteria was evaluated and the second generation dendrimer was found unique inhibiting the growth of Escherichia coli at physiological conditions while being nontoxic toward human cells. Finally, these results cement a robust and sustainable synthetic route to amino-functional polyester dendrimers with interesting chemical and biological properties.

Degradable high Tg sugar-derived polycarbonates from isosorbide and dihydroxyacetone

Polycarbonates from isosorbide and dihydroxyacetone (DHA) have been synthesised using organocatalytic step-growth polymerization of their corresponding diols and bis-carbonylimidazolides monomers. ...