Thermoresponsive Self-Assembly Research Articles

Thermoresponsive Self-Assembly of Twofold Fluorescently Labeled Block Copolymers in Aqueous Solution and Microemulsions.

A nonionic double hydrophilic block copolymer with a long permanently hydrophilic and a small thermoresponsive block is synthesized by reversible addition-fragmentation chain-transfer polymerization (RAFT). By employing a specifically designed chain-transfer agent, the polymer is functionalized with complementary end groups which are suited for Förster resonance energy transfer (FRET). The end group attached to the permanently hydrophilic block of poly(N,N-dimethylacrylamide) pDMAm is designed as a permanently hydrophobic segment ("sticker") comprising a long alkyl chain and the 4-aminonaphthalimide fluorophore. The other end attached to the thermoresponsive block of poly(N-isopropylacrylamide) pNiPAm incorporates a coumarin fluorophore. The temperature-dependent self-assembly of the twofold fluorescently labeled copolymer is studied in pure aqueous solution as well as in an o/w microemulsion by several techniques including turbidimetry, dynamic light scattering (DLS), and fluorescence spectroscopy. It is compared to the behaviors of the analogous twofold-labeled pDMAm and pNiPAm homopolymer references. The findings indicate that the block copolymer behaves as a polymeric surfactant at low temperatures, with one relatively small hydrophobic end block and an extended hydrophilic chain forming "hairy micelles". At elevated temperatures above the LCST phase transition of the pNiPAm block, however, the copolymer behaves as an associative telechelic polymer with two nonsymmetrical hydrophobic end blocks, which do not mix. Thus, instead of a network of bridged "flower micelles", large dynamic aggregates are formed. These are connected alternatingly by the original micellar cores as well as by clusters of the collapsed pNiPAm blocks. This type of structure is even more favored in the o/w microemulsion than in pure aqueous solution, as the microemulsion droplets constitute an attractive anchoring point for the hydrophobic dodecyl sticker but not for the collapsed pNiPAm chains.

Thermo-Responsive self-assembly of a dual glucagon-like peptide and glucagon receptor agonist

The human peptide hormone Oxyntomodulin (Oxm) is known to induce satiety, increase energy expenditure, and control blood glucose in humans, making it a promising candidate for treatment of obesity and/or type 2 diabetes mellitus. However, a pharmaceutical exploitation has thus far been impeded by fast in vivo clearance and the molecule‘s sensitivity to half-life extending structural modifications. We recently showed that Oxm self-assembles into amyloid-like nanofibrils that continuously release active, soluble Oxm in a peptide-deprived environment. S.c. injected Oxm nanofibrils extended plasma exposure from a few hours to five days in rodents, compared to s.c. applied soluble Oxm. Here we show that Oxm fibril elongation kinetics and thermodynamics display a uniquely low temperature optimum compared to previously reported amyloid-like peptide and protein assemblies. Elongation rate is optimal at room temperature, with association rates 2–3 times higher at 25 °C than at ≥37 °C or ≤20 °C. We deduce from a combination of Cryo electron microscopy and spectroscopic methods that Oxm fibrils have a double-layered, triangular cross-section composed of arch-shaped monomers. We suggest a thermodynamic model that links the necessary molecular rearrangements during fibrillation and peptide release to the unique temperature effects in Oxm self-assembly and disassembly.

Micellar Organocatalysis Using Smart Polymer Supports: Influence of Thermoresponsive Self-Assembly on Catalytic Activity.

Micellar catalysts with a switchable core are attractive materials in organic synthesis. However, little is known about the role of the shell forming block on the performance of the catalyst. Thermoresponsive block copolymers based on poly(N-isopropylacrylamide-co-vinyl-4,4-dimethylazlactone) attached to different permanently hydrophilic blocks, namely poly(ethylene glycol), poly(N,N-dimethylacrylamide), and poly(2,3-dihydroxypropyl acrylate), were successfully synthesized via reversible addition/fragmentation chain transfer radical polymerization (RAFT). Post-polymerization attachment of an amino-functionalized L-prolineamide using the azlactone ring-opening reaction afforded functionalized thermoresponsive block copolymers. Temperature-induced aggregation of the functionalized block copolymers was studied using dynamic light scattering. It was shown that the chemical structure of the permanently hydrophilic block significantly affected the size of the polymer self-assemblies. The functionalized block copolymers were subjected to an aldol reaction between p-nitrobenzaldehyde and cyclohexanone in water. Upon temperature-induced aggregation, an increase in conversion was observed. The enantioselectivity of the polymer-bound organocatalyst improved with an increasing hydrophilic/hydrophobic interface as a result of the different stability of the polymer aggregates.

Design of Polysaccharide-b-Elastin-Like Polypeptide Bioconjugates and Their Thermoresponsive Self-Assembly.

The advantageous biological properties of polysaccharides and precise stimuli-responsiveness of elastin-like polypeptides (ELPs) are of great interest for the design of polysaccharide- and polypeptide-based amphiphilic block copolymers for biomedical applications. Herein, we report the synthesis and characterization of a series of polysaccharide-block-ELP copolymers, containing two biocompatible and biodegradable blocks coupled via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The resulting bioconjugates are capable of self-assembling into well-defined nanoparticles in aqueous solution upon raising the solution temperature above a specific transition temperature (Tt)-a characteristic of the ELP moiety. To the best of our knowledge, this is the first study where polysaccharides were combined with a stimuli-responsive ELP for the preparation of thermosensitive self-assemblies, providing insight into novel pathways for designing bioinspired stimuli-responsive self-assemblies for biomedical applications.

Galactose-Functionalized Double-Hydrophilic Block Glycopolymers and Their Thermoresponsive Self-Assembly Dynamics.

Glycopolymers with large galactose units are attractive in biological processes because of their ability to selectively recognize lectin proteins. Recently, thermoresponsive double-hydrophilic block glycopolymers (TDHBGs) have been designed, which allow sugar residues to expose or hide via the lower critical solution temperature (LCST)-type phase transition. In this work, we first synthesize a new type of TDHBGs, composed of a thermoresponsive poly(di(ethylene glycol)methyl ether methacrylate) block and a galactose-functionalized, poly(6- O-vinyladipoyl-d-galactose) (POVNG) block. The LCST can be tuned by varying the size of the POVNG block. Then, we have systematically investigated their thermoresponsive self-assembly behavior, using static and dynamic light scattering techniques, combined with transmission electron microscopy (TEM) imaging. It is found that the TDHBGs possess both micellization and LCST-type transition, and there exist strong interactions between them, depending on the concentration and structure of the TDHBGs. It is particularly interesting that for the same type of TDHBGs under different conditions, such interactions result in rich morphologies of the formed micelles (or nanoparticles) such as spheres, hollow spheres, prolate ellipsoids, crystal-like, and so on, thus potentially enriching their biological applications by noting that they are hepatoma-targeting glycopolymers.

PH- and Thermoresponsive Self-Assembly of Cationic Triblock Copolymers with Controlled Dynamics

Transient hydrogels formed by cationic BAB triblock copolymers consisting of a hydrophilic poly(dimethylaminoethyl methacrylate) (P(DMAEMA)) A block and amphiphilic B blocks composed of randomly distributed DMAEMA and n-butyl methacrylate (nBMA) units were investigated. Oscillatory shear measurements revealed formation of dynamic networks with terminal relaxation times that can be controlled by tuning the ionization degree (α) of the DMAEMA units or the temperature up until 50 °C. A sol–gel transition could be induced by increasing the pH. Above 50 °C irreversible aggregation was observed. The behavior of these pH-sensitive cationic copolymers is compared with that of pH-sensitive anionic copolymers, revealing that incorporating stimuli-responsive hydrophilic units within the hydrophobic blocks of amphiphilic block copolymers may be a general way to control the exchange dynamics of the latter.

RAFT Copolymerization of Vinyl Acetate and N-Vinylcaprolactam: Kinetics, Control, Copolymer Composition, and Thermoresponsive Self-Assembly

Well-defined thermoresponsive amphiphilic statistical copolymers based on N-vinylcaprolactam (VCL) and vinyl acetate (VAc) were successfully synthesized by RAFT/MADIX polymerization mediated by O-ethyl-S-(1-ethoxycarbonyl)ethyldithiocarbonate chain transfer agent at 65 °C. We achieved the synthesis of a series of copolymers with controlled molar masses and low dispersities over a wide range of monomer feed ratios (0 < fVAc,0 < 1). Both conventional linearization methods and a nonlinear least-squares methods (NLLS) were applied to estimate reliable values of reactivity ratios for VAc and VCL radical polymerization in regards to the disparate values previously reported in the literature. The highest measurement precision was observed for the NLLS method based on the integrated form of the copolymerization equation developed by Skeist. The calculated values of the reactivity ratios (rVAc = 0.33 ± 0.10 and rVCL = 0.29 ± 0.15) perfectly fitted the drift in monomer feed ratio versus conversion. The VCL and VAc ...

Multimode Self-Folding Polymers via Reversible and Thermoresponsive Self-Assembly of Amphiphilic/Fluorous Random Copolymers

Multimode self-folding polymers were created via the reversible and thermoresponsive self-assembly of amphiphilic/fluorous random copolymers bearing poly(ethylene glycol) (PEG) and perfluoroalkyl pendants in water, N,N-dimethylformamide (DMF), and 2H,3H-perfluoropentane (2HPFP). The random copolymers with precision primary structure were synthesized by ruthenium-catalyzed living radical copolymerization of PEG methyl ether methacrylates and perfluoroalkyl methacrylates. Owing to three distinct properties of the hydrophobic backbone, hydrophilic PEG chains, and fluorous perfluorinated pendants, the random copolymers allowed various self-assembly modes for different folded structures by changing solvents. Namely, they form self-folding polymers of fluorous and/or hydrophobic cores in water or DMF, while they in turn provide reverse self-folding polymers of hydrophilic PEG cores in 2HPFP. The reverse folding in 2HPFP was further promoted by lower critical solution temperature-type phase separation of the PEG...

Self-Assembly of Polyether Diblock Copolymers in Water and Ionic Liquids.

Here the thermoresponsive self-assembly of diblock copolymers comprising poly(ethyl glycidyl ether) (PEGE) and poly(ethylene oxide) (PEO) in water and ionic liquids (ILs) is investigated. PEGE undergoes lower critical solution temperature (LCST) phase separation in both water and 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([C2 mim][NTf2 ]), while PEO is a compatible segment for these solvents. The diblock copolymers, PEGE-b-PEO, undergo thermosensitive unimer-micelle transitions at temperatures close to the LCST point (TLCST ) of the PEGE homopolymer in water but not in [C2 mim][NTf2 ], even at temperatures much higher than TLCST . The difference in the thermoresponsivity of these solutions is explored using differential scanning calorimetry results from rather small magnitudes of the thermodynamic parameters for the phase transition of the PEGE segment in [C2 mim][NTf2 ], compared with those in water. Due to such small magnitudes, TLCST of the PEGE segment for the block copolymers in the IL is greatly affected by the elongation of soluble PEO segments.

Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior in ethanol–water mixtures

The development of responsive and multiresponsive polymers is gaining interest as they enable the development of more and more complex responsive materials. In this contribution, the synthesis and solubility behavior of well-defined poly(methyl acrylate) (PMA) and poly(diethylene glycol ethyl ether acrylate) (PDEGEA) homopolymers as well as PMA-block-PDEGEA block copolymers is reported. At first, a solubility screening of the homopolymers in ethanol–water solvent mixtures was performed in a high-throughput experimentation (HTE) manner using parallel turbidimetry, which revealed that in 35wt% ethanol PMA undergoes an upper critical solution temperature (UCST) phase transition while PDEGEA undergoes a lower critical solution temperature phase transition in this solvent mixture. Moreover, the thermoresponsive self-assembly of PMA-b-PDEGEA block copolymers in water and ethanol were investigated by turbidimetry and DLS revealing UCST-induced disassembly of the micelles in ethanol and LCST-induced clustering of the micelles in water. Finally schizophrenic behavior of the PMA-b-PDEGEA block copolymers in 35wt% ethanol is demonstrated.

Supramolecular glycopolymers with thermo-responsive self-assembly and lectin binding

Incorporating monomers into sequence-defined synthetic macromolecules endows them to mimic nature which results in key residues being anchored in the molecular recognition pattern.

Thermoresponsive Self-assembly and Conformational Changes of Amphiphilic Monodisperse Short Poly(ethylene glycol)s in Water

Abstract Physicochemical and supramolecular properties of monodisperse amphiphilic short poly(ethylene glycol)s (PEGs) bearing a phenyl group at the one end are studied to investigate the effects of substitution and length of the PEG unit on these properties. It was found that the aromatic substitution encourages these molecules to adopt gauche conformation at the neighboring ethylene units of PEGs and that the octaethylene glycol derivative revealed more PEG-like thermal response of aggregation than the tetraethylene glycol derivative.

Dual pH-and Thermo-Responsive Self-Assembly of the P(NIPAM-&lt;em&gt;co&lt;/em&gt;-AA) Hydrophilic Random Copolymer in Pure Aqueous Solution

从N-异丙基丙烯酰胺（NIPAM）和丙烯酸（AA）单体合成了一种全亲水无规共聚物P（NIPAM-co-AA），实验发现该聚合物在水相中可以产生pH或温度双重刺激响应性自组装。采用透射电子显微镜（TEM）观察了自组装体的形貌，采用动态光散射（DLS）和静态光散射（SLS）观察了其粒径及粒径分布。测定了该聚合物水溶液的最低临界溶解温度（LCST）及其zeta电位随pH的变化，通过分析NIPAM和AA两种链节的质子化状态随温度和pH变化的趋势，阐释了其在水相中产生双重响应性自组装的推动力；并结合傅里叶红外（FT-IR）光谱测定自组装体表面富集基团的结果，进一步阐释了不同环境下自组装体的微结构。这类全亲水无规共聚物的合成方法简单，具有pH和温度双重响应性，其全水相中的刺激响应性自组装行为在药物释放等方面具有潜在的应用价值。

Thermoresponsive self-assembled elastin-based nanoparticles for delivery of BMPs

Elastin-like polymers are a new type of protein-based polymers that display interesting properties in the biomaterial field. Bone morphogenetic proteins (BMPs) are cytokines with a strong ability to promote new bone formation. In this work, we explored the use of elastin-like nanoparticles (average size 237.5 ± 3.0 nm), created by thermoresponsive self-assembly, for the combined release of bone morphogenetic protein-2 (BMP-2) and bone morphogenetic protein-14 (BMP-14). These BMPs could be encapsulated at high efficiency into the elastin-like particles and delivered in a sustained way for 14 days. The activity of the growth factors was retained, as shown by the induction of ALP activity and osteogenic mineralization in C2C12 cells. Increased bioactivity was observed with a combined release of BMP-2 and BMP-14. This approach shows a significant potential for future tissue engineering applications in bone.

Tuning of Thermo-responsive Self-Assembly Monolayers on Gold for Cell-Type-Specific Control of Adhesion

Self-assembled monolayers (SAMs) on gold containing a thermo-responsive poly( N-isopropylacrylamide)-poly(ethylene glycol)-thiol copolymer were formed. These layers show considerable potential for inducing enzyme-free and gentle detachment of cultivated cells. In an effort to optimize detachment of cells, including strongly adhering ones, two approaches are presented. First, two thermo-responsive copolymers with different poly(ethylene glycol) (PEG) contents of 15 wt % ("P15") and 19 wt % ("P19") were grafted to Au surfaces. Second, mixed monolayers were formed containing P19 and various concentrations of thiol bearing PEG. X-ray photoelectron spectroscopy (XPS) on pure and mixed P19 containing layers confirmed the expected layer compositions. Contact angle measurements showed good functionality of all surfaces prepared. Upon a temperature decrease below the lower critical solution temperature (LCST), the duration until cultivated fibroblasts detached from pure P19 surfaces was half of the one determined on P15. Strongly adherent human osteosarcoma cells could not be detached from pure P19 layers. Through co-adsorption of P19 and thiol-bearing PEG of a molar composition of 1:6, layers were formed that allowed good spreading of osteosarcoma cells above LCST and their efficient detachment below LCST.