Controlling macromolecular and supramolecular architectures based on poly(2-oxazoline)s

The evolution of human civilization is based on finding new materials and devising new tools to control the environment. The paradigm that prevailed throughout history was creating materials adapted to a specific function that would be as immutable as possible from the outside world. In a way, mankind was thus walking against the natural forces. However, our current understanding of nature and the chemistry behind its marvels, is rapidly shifting this paradigm towards a more subtle and intelligent approach. Now, we focus our efforts not on immobile materials adapted to a function, but on materials that embrace the function and can adapt to an evolving environment. The development of living and controlled polymerization techniques has empowered us with the necessary tools to realize these responsive functional materials, in analogy to the strategies found in natural systems. Controlling the synthesis of defined polymers allows us to establish structure-property relationships to drive the polymeric chains into functional conformations at the nanoscale, in analogy to natural polymers, such as proteins and DNA. The biomedical field has been the first scientific area taking advantage from these new polymer-based materials, as has been reviewed in the introductory chapter of this thesis. As has been seen, poly(2-alkyl/aryl-2-oxazoline)s (PAOx) will have a preeminent role to play in this new rapid development, and research has already resulted in chemistries to produce safer implants, more effective tablets, convenient tissue tapes, or advanced targeted therapies, some of them soon to be realized in the first commercial products. Notwithstanding the importance of devising new applications and functionalities, screening recent PAOx literature reveals the scarcity of recent papers devoted to the detailed study of polymer synthesis and its effect on composition or molecular weight distribution. This is especially evident in literature regarding PEI synthesis. Therefore, in the course of this thesis, the synthesis and functionalization of PAOx have been studied in detail, with the aim of optimizing their preparation in a fast and reproducible manner. In addition, the synthesis of PEI from the selective or partial hydrolysis of PAOx has been investigated, resulting in useful methodologies to obtain vectors for gene-delivery and to facilitate the expansion of the PAOx structural and functional versatility. These topics are covered in Chapters 2 and 3 of this thesis. As stated earlier, understanding the structure-property relationships that dictate polymer conformational changes into complex architectures at the nanoscale is of major importance to develop responsive and functional materials. Therefore, in Chapter 3, the composition of amphiphilic block copolymers based on PAOx-polycarbonates, the latter chosen as biodegradable polymer block, is varied to modulate their self-assembly in solution. A wide range of morphologies were obtained, from star-shaped to crew-cut micelles and polymersomes, the structure-property relationships were investigated to enable rational design of novel vehicles for drug delivery or diagnostics. The second part of this thesis focuses on the development of smart materials that are able to respond to environmental changes in solution. In Chapter 4, a new functionalization strategy was developed to enable straightforward grafting of PAOx onto gold surfaces, with potential uses in the development of highly sensitive sensing devices. These novel PAOx were used to synthesize PAOx-gold nanoparticle (AuNP) hybrids that exhibited dual responsiveness to temperature and to the presence of electrolytes in solution, resulting in colorimetric logic gates. Importantly, the responsiveness and thermal trigger input signal could be tuned by variation of the PAOx composition. The ability of PAOx to respond to temperature was further exploited in combination with supramolecular hosts in aqueous solution. Surprisingly, to the best of our knowledge there is no systematic study dedicated to the modulation of a thermoresponsive polymer phase transition temperature by using supramolecular host-guest interactions. The reported systems generally utilize ill-defined polymers synthesized by free-radical polymerization, which hampers the establishment of structure-property relationships, and do not include detailed evaluation of the influence of the macromolecular host on the self-assembly behavior of the system. To shed light onto this fascinating field, we performed a systematic study of the thermoresponsive properties of a series of well-defined PAOx amphiphilic copolymers in combination with various macromolecular hosts. The temperature triggered transition temperature of the copolymers could be tuned in an extraordinarily broad temperature range. More importantly, these detailed investigations allowed us to establish structure-property relationships that permit the control on the reversibility of the transition, and to record thermal information in the supramolecular structures. This research, in which the synergy of polymer and supramolecular chemistry is highlighted, is covered in Chapters 5 and 6 of the thesis

End-group functionalization of poly(2-oxazoline)s using methyl bromoacetate as initiator followed by direct amidation

Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are an alluring class of polymers for many applications due to the broad chemical diversity that is accessible for these polymers by simply changing the initiator, terminating agent and the monomer(s) used in their synthesis. Additional functionalities (that are not compatible with the cationic ring-opening polymerization) can be introduced to the polymers via orthogonal post-polymerization modifications. In this work, we expand this chemical diversity and demonstrate an easy and straightforward way to introduce a wide variety of functional end-groups to the PAOx, by making use of methyl bromoacetate (MeBrAc) as a functional initiator. A kinetic study for the polymerization of 2-ethyl-2-oxazoline (EtOx) in acetonitrile (CH3CN) at 140 degrees C revealed relatively slow initiation and slower polymerization than the commonly used initiator, methyl tosylate (MeOTs). Nonetheless, well-defined polymers could be obtained with MeBrAc as initiator, yielding polymers with near-quantitative methyl ester end-group functionality. Next, the post-polymerization modification of the methyl ester end-group with different amines was explored by introducing a range of functionalities, i.e. hydroxyl, amino, allyl and propargyl end-groups. The lower critical solution temperature (LCST) behavior of the resulting poly(2-ethyl-2-oxazoline)s was found to vary substantially in function of the end-group introduced, whereby the hydroxyl group resulted in a large reduction of the cloud point transition temperature of poly(2-ethyl-2-oxazoline), ascribed to hydrogen bonding with the polymer amide groups. In conclusion, this paper describes an easy and fast modular approach for the preparation of end-group functionalized PAOx

Thermoresponsive laterally-branched polythiophene phenylene derivative as water-soluble temperature sensor

Polymers with thermoresponsive properties have received a strong interest due to their potential applications. Here we report the synthesis and characterisation of a water soluble and thermoresponsive polythiophene derivative. Firstly, a polythiophene phenylene (PThP) functionalised with an initiator for atom transfer radical polymerization (ATRP) and azide groups on the side chains was synthesised. Secondly, ATRP was employed to graft poly(ethylene glycol) methacrylate (PEGMA) from the PThP to create a permanently water soluble conjugated polymer. Further functionalisation was then conducted through the `click' reaction with propargyl functionalised poly(2-n-propyl-2-oxazoline) to introduce thermoresponsivness. The polymer displayed lower critical solution temperature (LCST) behavior, as revealed by fluorescence and UV-Vis spectroscopy with potential use as soluble polymeric thermometer

Poly(2-oxazoline)s as materials for biomedical applications

The conjunction of polymers and medicine enables the development of new materials that display novel features, opening new ways to administrate drugs, design implants and biosensors, to deliver pharmaceuticals impacting cancer treatment, regenerative medicine or gene therapy. Poly(2-oxazoline)s (POx) constitute a polymer class with exceptional properties for their use in a plethora of different biomedical applications and are proposed as a versatile platform for the development of new medicine. Herein, a global vision of POx as a platform for novel biomaterials is offered, by highlighting the recent advances and breakthroughs in this fascinating field

Solution polymeric optical temperature sensors with long-term memory function powered by supramolecular chemistry

A poly[(2-ethyl-2-oxazoline)-ran-(2-nonyl-2-oxazoline)] copolymer in combination with hydroxypropylated cyclodextrins has been demonstrated to lead to a supramolecular self-assembly process that results in the formation of kinetically trapped thermoresponsive nanoparticles. Selection of the cyclodextrin type provides control over the nanoparticle phase-transition thermodynamics, thus affording optical temperature sensors with an unprecedented, long-term thermal memory function, which is reversible or irreversible. This research also sheds light onto kinetic and dynamic supramolecular assemblies, thus providing important insight because similar supramolecular processes are at the foundation of living matter

Poly(2-oxazoline)-protein conjugates

Poly(2-oxazoline)s (in literature abbreviated as PAOx, POx, or POZ, herein referred to as PAOx) represent an emerging class of biocompatible polymers outperforming polyethylene glycol (PEG) in many aspects, including their high synthetic versatility and structural modularity. In this review, we provide a brief introduction to PAOx chemistry and biology to sketch their potential in biomaterials science. Further, we provide a detailed comprehensive overview of the literature on PAOx-protein conjugates with emphasis on their critical evaluation and comparison with analogous systems based on PEG. Based on this literature overview, PAOx seem to be an excellent alternative to PEG in the construction of therapeutic polymer-protein conjugates

Supramolecular control over thermoresponsive polymers

Thermoresponsive polymers facilitate the development of a wide range of applications in multiple areas spanning from construction or water management to lab-on-a-chip technologies and biomedical sciences. The combination of thermoresponsive polymers with supramolecular chemistry, inspired by the molecular mechanisms behind natural systems, is resulting in adaptive and smart materials with unprecedented properties. This work reviews the past advances on the combination of this young field of research with polymer chemistry that is enabling a high level of control on polymer architecture and stimuli-responsiveness in solution. We will discuss how such polymer systems are able to store thermal information, respond to multiple stimuli in a reversible manner, or adapt their morphology on demand, all powered by the synergy between polymer chemistry and supramolecular chemistry

First symposium on poly(2-oxazoline)s and related pseudo-polypeptide structures

The first symposium on poly(2-oxazo-line)s and related pseudo-polypeptide structures was held as part of the 243rd American Chemical Society National Meeting in San Diego (CA) from the 27th to the 29th of March 2012. The scientists will gather again to discuss the progress in the field at the second symposium on poly(2-oxazoline)s and pseudo-polypeptides at the ACS National Meeting in San Francisco, to be held in August 2014

Tuning temperature responsive poly(2-alkyl-2-oxazoline)s by supramolecular host-guest interactions

A poly[(2-ethyl-2-oxazoline)-ran-(2-nonyl-2-oxazoline)] random copolymer was synthesized and its thermoresponsive behavior in aqueous solution modulated by the addition of different supramolecular host molecules. The macrocycles formed inclusion complexes with the nonyl aliphatic side-chains present in the copolymer, increasing its cloud point temperature. The extent of this temperature shift was found to depend on the cavitand concentration and on the strength of the host–guest complexation. The cloud point temperature could be tuned in an unprecedented wide range of 30 K by supramolecular interactions. Since the temperature-induced breakage of the inclusion complexes constitutes the driving force for the copolymer phase transition, the shift in cloud point temperature could be utilized to estimate the association constant of the nonyl side chains with the cavitands