Urs Rauwald

Triply Triggered Doxorubicin Release From Supramolecular Nanocontainers

The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers.

Correlating solution binding and ESI-MS stabilities by incorporating solvation effects in a confined cucurbit[8]uril system.

The high-throughput characterization of solution binding equilibria is essential in biomedical research such as drug design as well as in material applications of synthetic systems in which reversible binding interactions play critical roles. Although isothermal titration calorimetry (ITC) has been widely employed for describing such binding events, factors such as speed, concentration, and sample complexity would principally favor a mass spectrometry approach. Here, we show a link between ITC and electrospray ionization mass spectrometry (ESI-MS) by incorporating solvation free energies in the study of the ternary complexes of the macrocyclic host cucurbit[8]uril (CB[8]). The binding affinities of 32 aromatic reference complexes were studied by ITC and ESI-MS and combined with solvation data of the guests from an implicit solvation model (SM8) to obtain a correlation between aqueous and gas-phase measurements. The data illustrates the critical importance of solvation on the binding strength in CB[8]s ternary complexes. Finally, this treatment enabled us to predict association constants that were in excellent agreement with measured values, including several highly insoluble guest compounds.

A supramolecular route for reversible protein-polymer conjugation

The supramolecular formation of a PEGylated bovine serum albumin (BSA) protein-polymer bio-conjugate in water has been demonstrated through a selective host–guest interaction with the macrocycle cucurbit[8]uril (CB[8]). Both BSA and poly(ethylene glycol) were functionalised with either an electron-deficient first guest viologen or an electron-rich second guest naphthalene for the formation of the CB[8] ternary complex. With the help of spectroscopic (NMR, DOSY-NMR, DLS, UV/vis, fluorescence) and calorimetric (ITC) techniques, it was shown that a strong and specific binding interaction took place between the complementary labeled polymer and protein only in the presence of the macrocyclic host CB[8]. Moreover, we demonstrated that controlled formation of a supramolecular protein-protein complex was also possible through the use of CB[8] ternary formation.

Benzobis(imidazolium)–Cucurbit[8]uril Complexes for Binding and Sensing Aromatic Compounds in Aqueous Solution

The utilities of benzobis(imidazolium) salts (BBIs) as stable and fluorescent components of supramolecular assemblies involving the macrocyclic host, cucurbit[8]uril (CB[8]), are described. CB[8] has the unusual ability to bind tightly and selectively to two different guests in aqueous media, typically methyl viologen (MV) as the first guest, followed by an indole, naphthalene, or catechol-containing second guest. Based on similar size, shape, and charge, tetramethyl benzobis(imidazolium) (MBBI) was identified as a potential alternative to MV that would increase the repertoire of guests for cucurbit[8]uril. Isothermal titration calorimetry (ITC) studies showed that MBBI binds to CB[8] in a 1:1 ratio with an equilibrium association constant (K(a)) value of 5.7×10(5) M(-1), and that the resulting MBBI·CB[8] complex binds to a series of aromatic second guests with K(a) values ranging from 10(3) to 10(5) M(-1). These complexation phenomena were supported by mass spectrometry, which confirmed complex formation, and a series of NMR studies that showed the expected upfield perturbation of aromatic peaks and of the MBBI methyl peaks. Surprisingly, the binding behavior of MBBI is strikingly similar to that of MV, and yet MBBI offers a number of substantial advantages for many applications, including intrinsic fluorescence, high chemical stability, and broad synthetic tunability. Indeed, the intense fluorescence emission of the MBBI·CB[8] complex was quenched upon binding to the second guests, thus demonstrating the utility of MBBI as a component for optical sensing. Building on these favorable properties, the MBBI·CB[8] system was successfully applied to the sequence-selective recognition of peptides as well as the controlled disassembly of polymer aggregates in water. These results broaden the available guests for the cucurbit[n]uril family and demonstrate potentially new applications.

Discrete, multi-component complexes with cucurbit[8]uril in the gas-phase

The formation of modular, multi-component, host-guest complexes stable both in water and in the gas-phase is described; by modulating the stoichiometry of the different subunits in aqueous solution, quantitative self-assembly of the predicted and desired architecture is achieved, even allowing for ABA triblock copolymer assemblies stable in the gas-phase.

Probing cucurbit[8]uril-mediated supramolecular block copolymer assembly in water using diffusion NMR

Diffusion NMR and solution viscometry were used to probe the cucurbit[8]uril-mediated host–guest self assembly of multiple molecular guests to form 5-component supramolecular ABA triblock copolymers in aqueous solution.

An Aqueous Supramolecular side-chain polymer: Designed for Molecular Loading

Hydrophilic copolymers containing recognition motifs based on 2-naphthol moieties in their side chains for the self-assembly with cucurbit[8]uril (CB[8]), have been prepared by reversible addition–fragmentation chain transfer polymerization. Self-assembly of the copolymer with both redox sensitive hydrophilic and hydrophobic viologen derivatives in the presence of CB[8] has been investigated.

A Facile Route to Viologen Functional Macromolecules through Azide–Alkyne [3+2] Cycloaddition

Viologen end and side-chain functional macromolecules are synthesized through a high-yielding, copper-mediated azide-alkyne [3+2] cycloaddition reaction. Specifically, poly(ethylene glycol) (PEG) and the C-terminus of a model oligopeptide are quantitatively end-coupled to a viologen moiety as confirmed by (1) H NMR, gel permeation chromatography (GPC), and mass spectrometry (MS). Side-chain functionalization of a styrene backbone is also readily achieved forming a polyelectrolyte species and demonstrating the applicability of this method across a range of macromolecular species. It is found that viologen itself slows the reaction and that careful choice of counter ions, the specific chelating ligand for the copper-mediated reaction, solvent, as well as the amount of copper also play major roles in the time to completion of the reaction and hence the yield. Macromolecules formed through this route bind effectively with supramolecular host molecule cucurbit[8]uril allowing for controlled solution-phase self-assembly, for example of a supramolecular star polymer.

Dynamic Supramolecular Polymers

This chapter focuses on the utilization of strong, specific, directional noncovalent interactions to develop controlled, selective, stimuli-responsive, and complex macromolecular systems. The chapter progresses from the preparation of linear, main-chain supramolecular polymers from discrete monomeric units to the incorporation of supramolecular moieties into macromolecular architectures for the development of hierarchical self-assembled functional structures. The dynamic, stimuli-responsive nature of the noncovalent interactions yields materials that exhibit properties similar to traditional, noncovalent polymers, yet allow direct control and modulation through external triggers. In addition, a range of supramolecular motifs, which have been developed to function orthogonally, are discussed. It is clear that numerous opportunities have been afforded by coupling of selective, stimuli-responsive noncovalent interactions with traditional polymer science and has led to important advances in the macromolecular sciences.