LCST Polymer Research Articles

A review of thermoresponsive drug delivery systems based on LCST/UCST polymer nanofibers

Drug delivery systems and thermoresponsive polymers are garnering more interest due to technological advancement. The synthesis, characteristics, and uses of stimuli-responsive polymers in drug delivery systems are discussed in this paper. LCST and UCST polymers, two subtypes of thermoresponsive polymers, are also discussed, along with their processes and biomedical applications. The paper also discusses the use of conventional nanofibers and stimuli-responsive nanofibers for drug delivery systems and the most recent developments in electrospinning technology. The article also analyses the difficulties facing drug delivery systems today. This paper makes the case that novel electrospinning technologies must be developed in addition to further research into drug delivery systems based on UCST polymers with strong biocompatibility and biodegradability.

NIPAm-Based Modification of Poly(L-lysine): A pH-Dependent LCST-Type Thermo-Responsive Biodegradable Polymer.

Polylysine is a biocompatible, biodegradable, water soluble polypeptide. Thanks to the pendant primary amines it bears, it is susceptible to modification reactions. In this work Poly(L-lysine) (PLL) was partially modified via the effortless free-catalysed aza-Michael addition reaction at room temperature by grafting N-isopropylacrylamide (NIPAm) moieties onto the amines. The resulting PLL-g-NIPAm exhibited LCST-type thermosensitivity. The LCST can be tuned by the NIPAm content incorporated in the macromolecules. Importantly, depending on the NIPAm content, LCST is highly dependent on pH and ionic strength due to ionization capability of the remaining free lysine residues. PLL-g-NIPAm constitutes a novel biodegradable LCST polymer that could be used as “smart” block in block copolymers and/or terpolymers, of any macromolecular architecture, to design pH/Temperature-responsive self-assemblies (nanocarriers and/or networks) for potential bio-applications.

Mechanism insights in controlling host–guest (de)complexation by thermoresponsive polymer phase transitions

The hydrophobic interactions involved in phase separation of LCST polymers are the critical factor inducing the BBox release from the BBox/naphthalene while the host-guest complexes remain stable during phase separation of UCST polymers upon cooling.

Structural Insights into Polymethacrylamide-Based LCST Polymers in Solution: A Small-Angle Neutron Scattering Study

Structural Insights into Polymethacrylamide-Based LCST Polymers in Solution: A Small-Angle Neutron Scattering Study

Insights in the Thermal Volume Transition of Poly(2‐oxazoline) Hydrogels

AbstractPolymers with a lower or an upper critical solution temperature (LCST or UCST) can precipitate in a very narrow temperature range. Cross‐linking of such polymers and adding them to suited solvent results in smart gels that are capable of greatly changing their dimensions with changing temperature. This transition occurs very often in a broad temperature range, which limits the applicability of smart materials. To shed some light into the design of thermo‐responsive hydrogels with a narrow phase transition, poly(2‐ethyl‐2‐oxazoline) (PEtOx), poly(2‐isopropyl‐2‐oxazoline), and statistical copolymers of 2‐butyl‐2‐oxazoline and 2‐ethyl‐2‐oxazoline, respectively, are synthesized and the concentration‐dependent cloud point temperatures (Tcp) of the free polymers in aqueous media are determined in relation to the thermo‐responsive swelling behavior of the respective hydrogels. A narrow thermal transition of the hydrogels can only be achieved when the Tcp of the free polymers in water is independent on the concentration. Aqueous salt solutions can render even PEtOx into a concentration independent LCST polymer. However, this salt effect does not work for hydrogels.

LCST polymers with UCST behavior.

In this study, temperature dependent behavior of dense dispersions of core crosslinked flower-like micelles is investigated. Micelles were prepared by mixing aqueous solutions of two ABA block copolymers with PEG B-blocks and thermosensitive A-blocks containing PNIPAM and crosslinkable moieties. At a temperature above the lower critical solution temperature (LCST), self-assembly of the polymers resulted in the formation of flower-like micelles with a hydrophilic PEG shell and a hydrophobic core. The micellar core was stabilized by native chemical ligation (NCL). Above the LCST, micelles displayed a radius of ∼35 nm, while a radius of ∼48 nm was found below the LCST due to hydration of the PNIPAM core. Concentrated dispersions of these micelles (≥7.5 wt%) showed glassy state behavior below a critical temperature (Tc: 28 °C) which is close to the LCST of the polymers. Below this Tc, the increase in the micelle volume resulted in compression of micelles together above a certain concentration and formation of a glass. We quantified and compared micelle packing at different concentrations and temperatures. The storage moduli (G') of the dispersions showed a universal dependence on the effective volume fraction, which increased substantially above a certain effective volume fraction of φ = 1.2. Furthermore, a disordered lattice model describing this behavior fitted the experimental data and revealed a critical volume fraction of φc = 1.31 close to the experimental value of φ = 1.2. The findings reported provide insights for the molecular design of novel thermosensitive PNIPAM nanoparticles with tunable structural and mechanical properties.

Observing the Current Change with Increasing Temperature in Thermo-Responsive Polymer Solution Using Electrochemical Method

The behavior of redox in thermo-responsive polymer solution while heating was electrochemically observed and analyzed in this research. Temperature responsive polymers are intensively applied to various research fields and industries such as drug carriers, lithium ion batteries, temperature sensitive films, and sensor technology. For this reason, measuring the critical point and analyzing the phase transition of temperature stimuli responsive polymer are very important.In previous studies, the phase behavior of polymers according to the temperature was examined by measuring the transmittance of solution using ultraviolet–visible (UV-vis) spectroscopy and the size of polymer particles in solution using dynamic light scattering (DLS). As an electrochemical method, a collision method was used for detecting current decrease caused by aggregated polymer which blocked the electrode surface. These methods, however, were unable to track the behavior of polymer in solution during continuous temperature increase in real time easily. The temperature was increased at intervals of 5 ℃ to measure the absorbance of solution in UV-vis spectroscopy and only specific temperature and time could be used to observe the blocking signal in the electrochemical collision method. In this study, we offer the easy and novel way to monitor the thermal induced change of polymer and redox with continuous temperature increase using the electrochemical system.Lower critical solution temperature (LCST) polymer was used as the thermo-responsive polymer in this research. Dissolving the LCST polymer in organic media containing the redox, we measured the current with increasing temperature in real time. The experiment was conducted using electrochemical method with an ultramicroelectrode (UME) and the current transition according to the temperature growth was monitored. As a result, the specific current changes were obtained. Analyzing these specific current changes can be used to confirm the phase transition behavior of the temperature responsive polymer and redox in polymer solution. This study will be applied for further research with controlling the various conditions.

LCST polymers: Thermoresponsive nanostructured assemblies towards bioapplications

Thermoresponsive polymers constitute an important class of materials for biomedical application due to their thermally reversible coil-to-globule transition which can be exploited in a multitude of biomedical applications spanning from triggered drug delivery systems in the form of bulk hydrogels and nanoparticles, “smart” cell culture setups, sensors and actuators, and separation technologies. In this perspective article we present the basic physicochemical properties of poly (N-isopropylacrylamide) (PNIPAM), which is the most widely studied thermoresponsive polymer with a lower critical solution temperature. We describe the basic thermodynamic and physicochemical parameters that affect the LCST and present selective applications that utilize thermoresponsive polymers in the form of nano-assemblies including micelles, polymersomes, microcapsules and microgels, as well as injectable hydrogels for biomedical applications.

Isothermal kinase-triggered supramolecular assemblies as drug sensitizers.

Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitizes cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer.

Nanoparticles influence miscibility in LCST polymer blends: from fundamental perspective to current applications.

Polymer blending is an effective method that can be used to fabricate new versatile materials with enhanced properties. The blending of two polymers can result in either a miscible or an immiscible polymer blend system. This present review provides an in-depth summary of the miscibility of LCST polymer blend systems, an area that has garnered much attention in the past few years. The initial discourse of the present review mainly focuses on process-induced changes in the miscibility of polymer blend systems, and how the preparation of polymer blends affects their final properties. This review further highlights how nanoparticles induce miscibility and describes the various methods that can be implemented to avoid nanoparticle aggregation. The concepts and different state-of-the-art experimental methods which can be used to determine miscibility in polymer blends are also highlighted. Lastly, the importance of studying miscible polymer blends is extensively explored by looking at their importance in barrier materials, EMI shielding, corrosion protection, light-emitting diodes, gas separation, and lithium battery applications. The primary goal of this review is to cover the journey from the fundamental aspects of miscible polymer blends to their applications.

Recovery of CO2 Using Temperature‐Responsive Amine Gel Slurry

Temperature‐responsive change in pKa of tertiary amines that are immobilized in the cross‐linked LCST polymer chains (temperature‐responsive amine gels) is applied to the separation and recovery of CO2 gas. Adsorption and desorption behaviors of CO2 gas on the temperature‐responsive amine gels are experimentally investigated using a temperature‐controlled gas‐liquid contact reactor with the slurries of the gels. Based on the control of the swelling volume of the temperature‐responsive gels via temperature swing, pKa of the amines in the gels was controlled. Influences of monomer composition in the gels and solvent composition in the slurry on the performance of CO2 recovery were investigated.

A Synthetic, Transiently Thermoresponsive Homopolymer with UCST Behaviour within a Physiologically Relevant Window

Interactive materials that can respond to a trigger by changing their morphology, but that can also gradually degrade into a fully soluble state, are attractive building blocks for the next generation of biomaterials. Herein, we design such transiently responsive polymers that exhibit UCST behaviour while gradually losing this property in response to a hydrolysis reaction in the polymer side chains. The polymers operate within a physiologically relevant window in terms of temperature, pH, and ionic strength. Whereas such behaviour has been reported earlier for LCST systems, it is at present unexplored for UCST polymers. Furthermore, we demonstrate that, in contrast to LCST polymers, in aqueous medium the UCST polymer forms a coacervate phase below the UCST, which can entrap a hydrophilic model protein, as well as a hydrophobic dye. Because of their non-toxicity, we also provide in vivo proof of concept of the use of this coacervate as a protein depot, in view of sustained-release applications.

Thermoresponsive Toughening in LCST-Type Hydrogels: Comparison between Semi-Interpenetrated and Grafted Networks

Hydrophilic and LCST polymer chains, poly(N,N-dimethylacrylamide) (PDMA) and poly(Nisopropylacrylamide)(PNIPA), were combined in semi-interpenetrated architectures toinvestigate their responsive properties in swollen isochoric conditions comparatively tografted network structures. Using equal weight fractions of PDMA and PNIPA, semi-IPNdesigned with opposite topologies have demonstrated a thermoresponsive behavior with verydifferent structure/properties relationships as investigated by calorimetry, swellingexperiments, tensile tests and 2D neutron scattering at rest and under deformation. In the caseof the PDMA network interpenetrated by linear PNIPA chains, the phase transition of PNIPAgives rise to the formation of large microdomains, loosely percolating the PDMA network.Above the transition, the enhancement of the mechanical properties remains low in terms ofelastic modulus and fracture energy. Conversely, the opposite topology, with PDMA chainsinterpenetrating the crosslinked PNIPA network, brings a large improvement of themechanical properties at high temperature with a 10-fold increase of the modulus and veryhigh fracture energy. By comparison with grafted hydrogels of similar composition anddifferent topologies, the impact of the primary structure over the phase-separated morphologyand the resulting mechanical properties was clearly highlighted.

Thermoresponsive Toughening in LCST-Type Hydrogels with Opposite Topology: From Structure to Fracture Properties

The challenge of this work was to investigate the role of topology in LCST hydrogels that strongly and reversibly thermo-reinforce their mechanical strength under isochoric conditions. To achieve this, two different hydrogels with opposite topologies were designed on the basis of grafted architectures using equal amounts of water-soluble chains (poly(N,N-dimethylacrylamide) = PDMA) and LCST polymer chains (poly(N-isopropylacrylamide) = PNIPA). By working under isochoric conditions, with almost 85 wt % of water in the whole temperature range (20–60 °C), we were able to clearly highlight the impact of the phase transition of PNIPA on the mechanical reinforcement of the gel without any interference of the volume transition. These graft hydrogels, designed with PNIPA in the backbone (GPN-D) or as pendant chains (GPD-N), have been studied more specifically by tensile tests and 2D neutron scattering at rest and under deformation. From these complementary techniques, we show that PNIPA side-chains in GPD-N self-...

Nanoparticle induced miscibility in LCST polymer blends: critically assessing the enthalpic and entropic effects.

The use of copolymer and polymer blends widened the possibility of creating materials with multilayered architectures. Hierarchical polymer systems with a wide array of micro and nanostructures are generated by thermally induced phase separation (TIPS) in partially miscible polymer blends. Various parameters like the interaction between the polymers, concentration, solvent/non-solvent ratio, and quenching temperature have to be optimized to obtain these micro/nanophase structures. Alternatively, the addition of nanoparticles is another strategy to design materials with desired hetero-phase structures. The dynamics of the polymer nanocomposite depends on the statistical ordering of polymers around the nanoparticle, which is dependent on the shape of the nanoparticle. The entropic loss due to deformation of polymer chains, like the repulsive interactions due to coiling and the attractive interactions in the case of swelling has been highlighted in this perspective article. The dissipative particle dynamics has been discussed and is correlated with the molecular dynamics simulation in the case of polymer blends. The Cahn-Hillard-Cook model on variedly shaped immobile fillers has shown difference in the propagation of the composition wave. The nanoparticle shape has a contributing effect on the polymer particle interaction, which can change the miscibility window in the case of these phase separating polymer blends. Quantitative information on the effect of spherical particles on the demixing temperature is well established and further modified to explain the percolation of rod shaped particles in the polymer blends. These models correlate well with the experimental observations in context to the dynamics induced by the nanoparticle in the demixing behavior of the polymer blend. The miscibility of the LCST polymer blend depends on the enthalpic factors like the specific interaction between the components, and the solubility product and the entropic losses occurring due to the formation of any favorable interactions. Hence, it is essential to assess the entropic and enthalpic interactions induced by the nanoparticles independently. The addition of nanoparticles creates heterogeneity in the polymer phase it is localized. This can be observed as an alteration in the relaxation behavior of the polymer. This changes the demixing behavior and the interaction parameter between the polymers. The compositional changes induced due to the incorporation of nanoparticles are also attributed as a reason for the altered demixing temperature. The particle shape anisotropy causes a direction dependent depletion, which changes the phase behavior of the blend. The polymer-grafted nanoparticles with varying grafting density show tremendous variation in the miscibility of the blend. The stretching of the polymer chains grafted on the nanoparticles causes an entropy penalty in the polymer blend. A comparative study on the different shaped particles is not available up to date for understanding these aspects. Hence, we have juxtaposed the various computational studies on nanoparticle dynamics, the shape effect of NPs on homopolymers and also the cases of various polymer blends without nanoparticles to sketch a complete picture on the effect of various particles on the miscibility of LCST blends.

Influence of topology of LCST-based graft copolymers on responsive assembling in aqueous media

This work, based on structure/properties relationships of associating polymers, aims to investigate the role of topology in the self-assembling behavior of responsive graft copolymers. For that purpose, two graft copolymers with inverse topologies were prepared with similar amounts of water-soluble chains (poly(N,N-dimethylacrylamide) = PDMA) and LCST polymer chains (poly(N-isopropylacrylamide) = PNIPA). In pure water, and above 3 wt%, PNIPA-g-PDMA and PDMA-g-PNIPA exhibit very similar macroscopic properties with a sol/gel transition above 35 °C related to the microphase separation of PNIPA sequences. From complementary experiments, performed by DSC, 1H NMR and small angle neutron scattering, we show that the phase transition of PNIPA is more abrupt when NIPA units are located within the backbone, compared to side-chains. Nevertheless, well above their transition temperature, the two copolymers display very similar bicontinuous structures where PNIPA sequences self aggregate into concentrated percolating domains (about 70 wt% at 60 °C) characterized by a frozen dynamics. On the other hand, when salt or surfactant molecules are added into unentangled semi-dilute aqueous solution, the PNIPA-g-PDMA sample does not percolate anymore above the transition temperature while PDMA-g-PNIPA still demonstrate thermothickening properties that are correlated to the ability of water-soluble PDMA chains to bridge PNIPA aggregates.

Anomalous phase separation behavior in dynamically asymmetric LCST polymer blends

The interplay of thermodynamic forces and self-generated stresses induced in different compositions, and at different quench depths on the phase behavior of dynamically asymmetric PS/PVME blends are studied. The thermodynamic phase diagram is obtained from dynamic temperature sweep experiments. Phase contrast optical microscopy and rheological measurements including linear viscoelastic behavior and the stress growth behavior are employed to investigate the time evolution of the different phase-separating morphologies. At an intermediate quench depth of 14 °C, in addition to thermodynamically controlled phase separation mechanisms (nucleation and growth, NG, and spinodal decomposition, SD), three different kinds of phase separation behavior are induced by transient gel formation due to self-induced stresses in the early stage of phase separation: (i) conventional viscoelastic phase separation (VPS), (ii) nucleation of aggregate-like PS-rich phase and subsequent formation of a percolated network by coalescence, and (iii) nucleation of an aggregate-like PS-rich phase while the dispersed-matrix morphology is preserved in the later stages of phase separation. While it is generally accepted that VPS occurs at deep quench depths, we observe the VPS mechanism at shallow quench depths which is attributed to dynamic heterogeneity in the phase-separated domains. A dynamic phase diagram which shows the effect of dynamic asymmetry on phase behavior is proposed.

Hydroxyl end-functionalized poly(2-isopropyl oxazoline)s used as nano-sized colloidal templates for preparation of hollow polymeric nanocapsules

Hollow polymeric nanocapsules with a thermosensitive membrane are prepared and characterized. They reversibly change their dimensions during temperature variations below and above the transition of the membrane. The nanocapsules were prepared by three steps: (i) well-defined mesoglobules prepared from an LCST polymer (hydroxyl end functionalized poly(2-isopropyl-2-oxazoline), PiPOZ-OH) were coated with a thermo-sensitive cross-linked shell formed via seeded radical copolymerization of N-isopropylacrylamide (NIPAM) and N,N′-bis-methylene acrylamide to produce core–shell nanoparticles (ii), which were subjected to extensive dialysis below the LCSTs of both the core-forming PiPOZ-OH and shell-forming PNIPAM to remove the core (iii). The use of a core-forming polymer of low molecular weight (<8900 g mol−1), narrow dispersity (<1.15) and relatively low Tg (52–68 °C) is beneficial as far as the effectiveness of the removal of the cores is concerned. The inherent immiscibility between PiPOZ-OH and PNIPAM as well as the specific raspberry-like structure of the core–shell particles also contributed for enhancement of the core removal effectiveness.

Saccharide effect on the LCST property of a polyether: Influence of structure and length

Saccharides and especially monosaccharides are well-known to affect the thermal transition of the LCST polymer solution. The studied LCST system is an aqueous polyetheramine solution under unprotected form. The role of saccharide has clearly been highlighted through thermal measurements (absorbance and μDSC) and structural techniques (NMR). Moreover, the impact of the structure and the number of the saccharides unit have been disclosed on the cloud point temperature. The phase transition became lowered upon sugar addition.

Demonstration of Molecular Sensing Using QCM Device Coated with Stimuli-sensitive Hydrogel

ABSTRACTMolecular sensing using stimuli-responsive viscoelastic property of amphiphilic polymer hydrogel was demonstrated. Thermo-responsive poly(N-isopropylacrylamide); NIPA, hydrogel immobilizing bovine serum albumin (BSA) in its polymer chain was synthesized on the AT-cut QCM (Quartz crystal microbalance). The device was provided to the sensing of anti-BSA antibody. The resonance behavior of QCM in response to the adsorption of anti-BSA antibody on the hydrogel was observed based on both the resonance frequency and resistance of QCM with impedance analysis. The QCM device coated with the LCST polymer hydrogel revealed a characteristic resonance behavior in response to the adsorption of anti-BSA antibody in the collapse phase of gel at which the gel lost most of its hydrated water. The resonance frequency and resistance in the collapsed gel were highly sensitive and their changes in response to the target adsorption were much larger than in the swelling state of gel. The use of the device at the LCST of NIPA gel is ideal because the largest amplification of the adsorption signal is available along with the largest phase change of NIPA gel.