Brent S. Sumerlin

New directions in thermoresponsive polymers

Interest in thermoresponsive polymers has steadily grown over many decades, and a great deal of work has been dedicated to developing temperature sensitive macromolecules that can be crafted into new smart materials. However, the overwhelming majority of previously reported temperature-responsive polymers are based on poly(N-isopropylacrylamide) (PNIPAM), despite the fact that a wide range of other thermoresponsive polymers have demonstrated similar promise for the preparation of adaptive materials. Herein, we aim to highlight recent results that involve thermoresponsive systems that have not yet been as fully considered. Many of these (co)polymers represent clear opportunities for advancements in emerging biomedical and materials fields due to their increased biocompatibility and tuneable response. By highlighting recent examples of newly developed thermoresponsive polymer systems, we hope to promote the development of new generations of smart materials.

Smart hybrid materials by conjugation of responsive polymers to biomacromolecules

The chemical structure and function of biomacromolecules has evolved to fill many essential roles in biological systems. More specifically, proteins, peptides, nucleic acids and polysaccharides serve as vital structural components, and mediate chemical transformations and energy/information storage processes required to sustain life. In many cases, the properties and applications of biological macromolecules can be further expanded by attaching synthetic macromolecules. The modification of biomacromolecules by attaching a polymer that changes its properties in response to environmental variations, thus affecting the properties of the biomacromolecule, has led to the emergence of a new family of polymeric biomaterials. Here, we summarize techniques for conjugating responsive polymers to biomacromolecules and highlight applications of these bioconjugates reported so far. In doing so, we aim to show how advances in synthetic tools could lead to rapid expansion in the variety and uses of responsive bioconjugates.

Triply-responsive boronic acid block copolymers: solution self-assembly induced by changes in temperature, pH, or sugar concentration.

Boronic acid-containing block copolymers capable of solution self-assembly into micelles and reverse micelles in response to changes in temperature, pH, and sugar concentration were prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization.

Stimuli responsive materials

Dramatic developments in the burgeoning field of polymer science are enabling new materials designs, synthetic methods, functional architectures, and applications. Today’s polymers are finding utility in broad areas, ranging from everyday commodity plastics to emerging, specialized, and high-tech materials. Moreover, it is apparent that the continued development of polymeric systems will be facilitated by ever-increasing understanding of advanced polymer synthesis and characterization techniques. This enhanced toolbox and knowledge-base will foster the facile design of next-generation precision materials with predictable and changeable properties. The present themed issue focuses on recent developments in the design of polymers that change properties in response to a single stimulus or multiple stimuli. These so-called ‘smart’ or stimuliresponsive polymers represent a growing cadre of materials that support various applications (e.g., controlled release agents, responsive coatings, and adaptive shape memory materials). Stimuli-responsive materials have benefited from significant advances in polymer science in recent years, and this themed issue highlights several of the fascinating developments that could have a major impact on the implementation of new smart materials. To fully address the field of stimuli responsive polymers, first we must understand the breadth of available stimuli that can induce a desired response, then we must design the polymer functionalities and systems that enable such a response; finally, we must develop methods to characterize the macromolecular changes as a result of that response. As demonstrated in this issue, many of the interesting properties of responsive materials arise from a transition in solubility or conformation of a macromolecule in the presence of a solvent. In this manner, transitions at the molecular level can be amplified to result in a change in nanoscale structure and/or materials properties. Gibson and O’Reilly (DOI: 10.1039/C3CS60035A) overview these transitions in the specific area of thermoresponsive polymers with particular attention to the effect of nanoscale geometry on the resulting change in chain conformation following a temperature change. Sumerlin and co-workers (DOI: 10.1039/ C3CS35499G) also highlight temperatureresponsive polymers with particular emphasis on design parameters that facilitate tuning of the specific transition temperatures. Light-responsive materials have received significant attention, as discussed by Gohy and Zhao (DOI: 10.1039/ C3CS35469E) in a review focused on reversible and irreversible transitions of photoresponsive copolymer micelles. Further, many systems can be designed a Institute for Technical and Macromolecular Chemistry, University of Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany. E-mail: theato@chemie.uni-hamburg.de b George & Josephine Butler Polymer Research Laboratory, Department of Chemistry, University of Florida, Gainesville, FL 32611, USA. E-mail: sumerlin@chem.ufl.edu c Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. E-mail: Rachel.OReilly@warwick.ac.uk d Department of Chemical & Biomolecular Engineering, University of Delaware, 150 Academy Street, Newark, DE 19716, USA. E-mail: thepps@udel.edu

Folate-Conjugated Thermoresponsive Block Copolymers: Highly Efficient Conjugation and Solution Self-Assembly

A combination of controlled radical polymerization and azide-alkyne click chemistry was employed to prepare temperature-responsive block copolymer micelles conjugated with biological ligands with potential for active targeting of cancer tissues. Block copolymers of N-isopropylacrylamide (NIPAM) and N,N-dimethylacrylamide (DMA) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization with an azido chain transfer agent (CTA). Pseudo-first-order kinetics and linear molecular weight dependence on conversion were observed for the RAFT polymerizations. CuI-catalyzed coupling with propargyl folate resulted in folic acid residues being efficiently conjugated to the alpha-azido chain ends of the homo and block copolymers. Temperature-induced self-assembly resulted in aggregates capable of controlled release of a model hydrophobic drug. CuI-catalyzed azide-alkyne cycloaddition has proven superior to conventional methods for conjugation of biological ligands to macromolecules, and the general strategy presented herein can potentially be extended to the preparation of folate-functionalized assemblies with other stimuli susceptibility (e.g., pH) for therapeutic and imaging applications.

Dynamic-Covalent Macromolecular Stars with Boronic Ester Linkages

Macromolecular stars containing reversible boronic ester linkages were prepared by an arm-first approach by reacting well-defined boronic acid-containing block copolymers with multifunctional 1,2/1,3-diols. Homopolymers of 3-acrylamidophenylboronic acid (APBA) formed macroscopic dynamic-covalent networks when cross-linked with multifunctional diols. On the other hand, adding the diol cross-linkers to block copolymers of poly(N,N-dimethylacrylamide (PDMA))-b-poly(APBA) led to nanosized multiarm stars with boronic ester cores and PDMA coronas. The assembly of the stars under a variety of conditions was considered. The dynamic-covalent nature of the boronic ester cross-links allowed the stars to reconfigure their covalent structure in the presence of monofunctional diols that competed for bonding with the boronic acid component. Therefore, the stars could be induced to dissociate via competitive exchange reactions. The star formation-dissociation process was shown to be repeatable over multiple cycles.

RAFT-synthesized diblock and triblock copolymers: thermally-induced supramolecular assembly in aqueous media

This review highlights recent advances in the synthesis of functional, temperature-responsive, water-soluble block copolymers, including particular focus on the results obtained by employing reversible addition–fragmentation chain transfer (RAFT) polymerization. The applicability of the RAFT process for the polymerization of functional monomers under a diverse range of experimental conditions has facilitated the synthesis of water-soluble (co)polymers that were previously inaccessible. Unprecedented control afforded by RAFT in homogeneous aqueous media allows well-defined polymeric systems to be prepared without stringent purification techniques and under increasingly “green” conditions while maintaining the ability to tailor many of the macromolecular characteristics (molecular weight, chain topology, copolymer composition, functionality, etc.) that affect self-assembly in solution. Block copolymer formation and postpolymerization modification utilizing crosslinking and copper-catalyzed azide–alkyne “click” chemistry are described, with attention being paid to their ability to control copolymer structure for subsequent self-assembly in response to changes in temperature.

Temperature and redox responsive hydrogels from ABA triblock copolymers prepared by RAFT polymerization

Triblock copolymers prepared by reversible addition–fragmentation chain transfer polymerization were capable of forming hydrogels that were both temperature- and redox-responsive, as a result of thiol-disulfide chemistry provided by aminolysis of an internal trithiocarbonate linkage.

Conjugation of RAFT-generated polymers to proteins by two consecutive thiol–ene reactions

Well-defined temperature-responsive polymers were covalently conjugated to model proteins by two consecutive Michael addition thiol–ene reactions. Poly(N-isopropylacrylamide) (PNIPAM) prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization was aminolyzed to yield thiol-terminated chains that were subsequently reacted with excess 1,8-bis-maleimidodiethyleneglycol. The resulting maleimide-terminated polymer was reacted with bovine serum albumin and ovalbumin to yield polymer–protein conjugates by a “grafting-to” approach. The thermoresponsive nature of PNIPAM was conferred to the conjugate, as demonstrated by dynamic light scattering analysis that indicated the formation of intermolecular aggregates at elevated temperatures.

Tuning the Magnetic Resonance Imaging Properties of Positive Contrast Agent Nanoparticles by Surface Modification with RAFT Polymers

A novel surface modification technique was employed to produce a polymer modified positive contrast agent nanoparticle through attachment of well-defined homopolymers synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. A range of RAFT homopolymers including poly[N-(2-hydroxypropyl)methacrylamide], poly(N-isopropylacrylamide), polystyrene, poly(2-(dimethylamino)ethyl acrylate), poly(((poly)ethylene glycol) methyl ether acrylate), and poly(acrylic acid) were synthesized and subsequently used to modify the surface of gadolinium (Gd) metal-organic framework (MOF) nanoparticles. Employment of a trithiocarbonate RAFT agent allowed for reduction of the polymer end groups under basic conditions to thiolates, providing a means of homopolymer attachment through vacant orbitals on the Gd3+ ions at the surface of the Gd MOF nanoparticles. Magnetic resonance imaging (MRI) confirmed the relaxivity rates of these novel polymer modified structures were easily tuned by changes in the molecular weight and chemical structures of the polymers. When a hydrophilic polymer was used for modification of the Gd MOF nanoparticles, an increase in molecular weight of the polymer provided a respective increase in the longitudinal relaxivity. These relaxivity values were significantly higher than both the unmodified Gd MOF nanoparticles and the clinically employed contrast agents, Magnevist and Multihance, which confirmed the constructs ability to be utilized as a positive contrast nanoparticle agent in MRI. Further characterization confirmed that increased hydrophobicity of the polymer coating on the Gd MOF nanoparticles yielded minimal changes in the longitudinal relaxivity properties but large increases in the transverse relaxivity properties in the MRI.