Thermoresponsive core-shell-corona micelles of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene

Core-shell-corona micelles with a thermoresponsive shell self-assembled by triblock copolymer of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene (PEG₄₅-b-PNIPAM₁₆₈-b-PS₄₆) are studied by ¹H NMR, light scattering and atomic force microscopy. The thermoresponsive triblock copolymer, which has a relatively short hydrophobic PS block, can disperse in water at room temperature to form core-shell-corona micelles with the hydrophobic PS block as core, the thermoresponsive PNIPAM block as shell and the hydrophilic PEG block as corona. At temperature above lower critical solution temperature (LCST) of the PNIPAM block, the PNIPAM chains gradually collapse on the PS core to shrink the size and change the structure of the resultant core-shell-corona micelles with temperature increasing. It is found that there possibly exists an interface between the PNIPAM shell and PEG corona of the core-shell-corona micelles at temperature above LCST of the PNIPAM block.     

Synthesis of thermoresponsive poly(N-isopropylmethacrylamide) and poly(acrylic acid) block copolymers via post-functionalization of poly(N-methacryloxysuccinimide)

Polymers exhibiting a thermoresponsive, lower critical solution temperature (LCST) phase transition have proven to be useful for many applications as “smart” or “intelligent” materials. A series of poly(N-isopropylmethacrylamide) (PNIPMAM) polymer, poly(N-isopropylmethacrylamide)-b-poly(acrylic acid) (PNIPMAM-b-PAA) diblock, and poly(acrylic acid)-b-poly(N-isopropylmethacrylamide)-b-poly(acrylic acid) (PAA-b-PNIPMAM-b-AA) triblock copolymer samples were synthesized via ATRP. A facile post-functionalization route was developed that uses an activated ester functionality to convert poly(N-methacryloxysuccinimide) (PMASI) blocks to LCST capable polyacrylamide, while poly(t-butyl acrylate) (PtBA) blocks were converted to water-soluble poly(acrylic acid) (PAA). The post-functionalization was monitored via ¹H NMR and ATR-FTIR. The aqueous solution properties were explored and the PNIPMAM polymers were shown to have a LCST phase transition varying from 35 to 60 °C. The ability to synthesize block copolymers that are thermoresponsive and water-soluble will be of great benefit for broader applications in drug delivery, bioengineering, and nanotechnology.     

Super porous organic-inorganic poly(N-isopropylacrylamide)-based hydrogel with a very fast temperature response

Porous organic-inorganic (O-I) hydrogels showing a very fast temperature response, including very fast reswelling were prepared: only 6 s are needed for 72% deswelling (gel collapse) as well as for 72% reswelling. Both deswelling and reswelling are practically complete in 14 s. The gels were prepared from N-isopropylacrylamide (NIPA), N,N′-methylenebisacrylamide (BAA) and tetramethoxysilane (TMOS) by simultaneous radical polymerization and hydrolytic polycondensation of TMOS. The syntheses were carried out at temperatures below the lower critical solution temperature (LCST) of poly(NIPA) in two steps: during the first stage the temperature was held at T = +15 °C and during the second the temperature was lowered below the freezing point of the reaction mixture, T = −18 °C. The ice crystals, which grew during the second stage, served as the pore-forming agent. The best samples were obtained if the second stage was started shortly before the gel point of the reaction mixture. The introduction of the inorganic phase (silica) is necessary for the ability of fast reswelling and also results in a strong improvement of the hydrogels' mechanical properties, while the maximum swelling degree remains nearly unaffected.     

Real-time observation of coil-to-globule transition in thermosensitive poly(N-isopropylacrylamide) brushes by quartz crystal microbalance

Thermosensitive poly(N-isopropylacrylamide) (PNIPAm) brushes grafted on SiO₂-coated quartz crystal surface were prepared by the surface initiated radical polymerization. Using X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM), about 50 nm thickness of PNIPAm brushes were successfully formed. Quartz crystal microbalance with dissipation (QCM-D) is employed to investigate the collapse and swelling behavior of the PNIPAm brushes in water in real time. Both frequency and dissipation of PNIPAm layer were found to change gradually over the temperature range 15-50 °C, indicating that the brushes undergo a continuous transition. This continuous change is attributed to the nonuniformity and stretching of PNIPAm brushes as well as the cooperativity between collapse and dehydration transition.     

Synthesis and properties of thermosensitive, crown ether incorporated poly(N-isopropylacrylamide) hydrogel

A crown ether derivative (4′-allyldibenzo-18-crown-6, CE) was covalently incorporated into the network of temperature sensitive poly(N-isopropylacrylamide) (PNIPA) hydrogels by copolymerization in a mixed solvent of water and tetrahydrofuran (H₂O/THF). The poly(N-isopropylacrylamide-co-4′-allyldibenzo-18-crown-6) (poly(NIPA-co-CE)) hydrogels exhibited dramatically faster deswelling rates than normal PNIPA hydrogels at a temperature (50 °C) above their lower critical solution temperatures. The effect of the solvent component ratio in the mixed solvent during the copolymerization on the swelling properties of the poly(NIPA-co-CE) hydrogel was investigated. The thermosensitive poly(NIPA-co-CE) hydrogels have potential applications in the extraction of cations and separation of chiral drugs.     

Synthesis and characterization of temperature-responsive copolymer of PELGA modified poly(N-isopropylacrylamide)

Novel amphiphilic PELGA modified temperature-responsive copolymer, [(poly(methoxyethylene glycol)-co-poly(lactic acid)-co-poly-(glycolic acid))acrylate-co-poly(N-isopropylacrylamide)-co-poly(N-hydroxymethylacrylamide)] (PELGAA-co-PNIPAAm-co-PNHMAAm) was synthesized by incorporating PELGA as the amphiphilic moiety into poly(N-isopropylamide) with various LA/GA ratios. Polymers obtained were characterized by FT-IR, GPC, ¹H-NMR and DSC. The lower critical solution temperature (LCST) of the copolymeric nanoparticles was 40±0.6 °C, the critical aggregation concentration (CAC) was 18 mg L⁻¹, and reversible change in nanoparticle size related to temperature was fluctuated between 210±10 and 109±26 nm, while change in zeta potential of the nanoparticles was between −36±6 and −26±4 mV. The transmission electron microscopy (TEM) images of nanoparticles were also presented.     

Thermosensitive poly(N-isopropylacrylamide) nanocapsules with controlled permeability

In this paper, novel thermosensitive poly(N-isopropylacrylamide) (PNIPAM) nanocapsules with temperature-tunable diameter and permeability are reported. Firstly, the core-shell composite microparticles were synthesized by precipitation polymerization with isothiocyanate fluorescein (FITC) entrapped SiO₂ as core and cross-linked PNIPAM as shell. Then, the SiO₂ core was etched by hydrofluoric acid at certain condition and the pre-trapped FITC molecules remained within the inner cavity. The FITC release profile and TEM studies clearly indicate that the release behavior of FITC could be controlled effectively by the external temperature. Above the LCST of PNIPAM (32 °C), the dehydrated PNIPAM shell inhibited the release of FITC from the internal cavity while below its LCST, the fluorophore could permeate the swollen shell easily.     

Thermosensitive poly(N-isopropylacrylamide)-b-poly(ε-caprolactone) nanoparticles for efficient drug delivery system

To investigate thermosensitive polymeric nanoparticle, amphiphilic block copolymers of poly(N-isopropylacrylamice)-b-poly(ε-caprolactone) (PNPCL) with different PCL block lengths were synthesized by hydroxy-terminated poly(N-isopropyoacrylamide) (PNiPAAm) initiated ring opening polymerization of ε-caprolactone. Owing to their amphiphilic characteristics, the block copolymers formed self-assembled polymeric nanoparticles in aqueous milieus with thermosensitive PNiPAAm shell compartment. The characterizations of the nanoparticles revealed that the PNPCL nanoparticles showed PCL block length dependent physicochemical characters such as particle sizes, critical aggregation concentrations, and core hydrophobicities. Moreover, the thermosensitive PNiPAAm shells conferred unique temperature responsive properties such as phase transitions with temperature elevation over its lower critical solution temperature (LCST). The temperature induced phase transition resulted in the formation of PNiPAAm hydrogel layer on the PNPCL nanoparticle surface. The drug release tests revealed that the formation of thermosensitive hydrogel layer resulted in the enhanced sustained drug release patterns by acting as an additional diffusion barriers. Therefore, the introduction of thermosensitive polymers on polymeric nanoparticles might be a potential approaches to modulate drug release behaviors.     

Rapid swelling and deswelling of thermoreversible hydrophobically modified poly(N-isopropylacrylamide) hydrogels prepared by freezing polymerisation

Rapid response thermally sensitive hydrophobically modified poly(N-isopropylacrylamide) hydrogels have been synthesised successfully using a two-step polymerisation method, the initial polymerisation being carried out at 20 °C, followed by polymerisation at −28 °C for 24 h. The results show that the swelling/deswelling rates of poly[N-isopropylacrylamide-co-(di-n-propylacrylamide)] P(NIPA-co-DPAM) hydrogels prepared by two-step polymerisation are much faster than for the same type of hydrogels prepared via conventional methods (30 °C for 24 h), i.e. the time for the former xerogel to absorb 70 and 90 wt% is just 30 and 240 min, respectively, compared to the latter xerogel which takes 1600 and 2500 min to absorb the same amounts of water. During deswelling (shrinking), the hydrogel loses 95 wt% water in 1 min, compared to a timescale for the corresponding cross-linked copolymers prepared by conventional methods of about 5 h for 50 wt% water loss. Scanning electron microscopy, and flotation experiments together with swelling ratio studies reveal that the polymeric network of the former hydrogel is characterised by an open structure with more pores and higher swelling ratio but lower mechanical strength compared to the latter hydrogels. Such rapid response hydrogels have potential applications in separation and drug release technologies for example.     

Reentrant swelling behavior of thermosensitive N-isopropylacrylamide nano-sized gel particles

The closed-loop phase diagram of poly N-isopropylacrylamide (PNIPA) in a water-N,N-dimethylformamide (DMF) system was measured by thermooptical analysis (TOA). The reentrant swelling behavior of N-isopropylacrylamide (NIPA) nano-sized gel particles in the water-DMF system was measured by using photon correlation spectroscopy (PCS) technique. Theoretically, a modified double lattice model (MDL) can be used to describe the closed-loop phase behavior of linear PNIPA in water-DMF systems. For crosslinked NIPA nano-sized gel particles in a water-DMF system, we combined MDL theory for the mixing contribution and Flory-Erman theory for the elastic contribution. Molecular interaction parameters obtained from the PNIPA solution were used to directly predict the swelling-ratio curves for the NIPA gel. Using our model, the calculated results were in good agreement with the experimental data using only one adjustable parameter.     

Preparation of hydrogel nanoparticles by atom transfer radical polymerization of N-isopropylacrylamide in aqueous media using PEG macro-initiator

PEG-b-PNIPAM block copolymers are synthesized by the atom transfer radical polymerization of NIPAM using PEG macro-initiator. When the polymerization temperature is 25 °C, the block copolymer is soluble in water, whereas the block copolymer is phase-separated to form micelles during polymerization as the polymerization temperature is raised to 50 °C, the temperature above the LCST of PEG-b-PNIPAM. To prepare stable hydrogel nanoparticles in water at room temperature, a small amount of N,N′-ethylenebisacrylamide is added as a cross-linker to the reaction system, where the size of nanoparticles is controlled by the composition of mixed solvent.     

Microscopic implication of rapid shrinking of comb-type grafted poly(N-isopropylacrylamide) hydrogels

The shrinking mechanism of comb-type grafted poly(N-isopropylacrylamide) gel was investigated by small-angle X-ray scattering (SAXS). The SAXS reveals that the microdomain structure with characteristic spacing of 460 Å is developed in the comb-type grafted poly(N-isopropylacrylamide) gel during the shrinking process. These observations suggest that the freely mobile characteristics of the grafted chains are expected to show the rapid dehydration to make tightly packed globules with temperature, followed by the subsequent hydrophobic intermolecular aggregation of the dehydrated graft chains. The dehydrated grafted chains created the hydrophobic cores, which enhance the hydrophobic aggregation of the networks. These aggregations of the NIPA chains contribute to an increase in void volume, which allow the gel having a pathway of water molecules by the phase separation.     

Dependence of shrinking kinetics of poly(N-isopropylacrylamide) gels on preparation temperature

Preparation temperature dependence of equilibrium swelling degree and shrinking kinetics of poly(N-isopropylacrylamide) gel has been investigated by optical microscopic measurements. The degree of swelling, d/d₀, at 20 °C was found to be strongly dependent on the preparation temperature, T_prep, where d and d₀ are the diameter of gel during observation and preparation, respectively. The value of d/d₀ was about 1.2 for T_prep=20 °C, but steeply increased by approaching the phase separation temperature ≈32.0 °C. Above 32.0 °C, d/d₀ decreases stepwise to 1.46. This upturn in d/d₀ was correlated with spatial inhomogeneities in gels. That is, the gel became opaque by increasing T_prep. Though the shrinking half-time, t_1/2, of gel was on the order of 500 min for T_prep≤20 °C, t_1/2 decreased to 2 min for T_prep≥26 °C. Hence, a rapid shrinking was attained by simply increasing T_prep. The physical implication of this rapid shrinking in gels was discussed in conjunction with the gel inhomogeneities and a thermodynamic theory of swelling equilibrium.     

Effect of salt on the elastic modulus of poly(N-isopropylacrylamide) gels

The measurement of tensile modulus of poly(N-isopropylacrylamide) (PNIPA) gel in the solution of NaCl, NaI, LiNO₃ and NaNO₃ was carried out. It was confirmed that the tensile modulus of PNIPA gel in the solution of salt depends on the volume of gel regardless of the kind and concentration of salts. This result leads us to the conclusion that the addition of salt effect only on the mixing contribution to the Flory's type free energy of gel especially in the swollen state. Therefore, our result is in agreement with a recent remarkable discovery that the volume of PNIPA gel depends only on the chemical potential of water in spite of the kind of additives. On the other hand, it was found that on the volume phase transition point and in the deswollen state, the elasticity of PNIPA gel depended on the concentration and kind of the salt because the viscoelasticity emerged due to the shrinkage of polymer network.     

Toward an understanding of thermoresponsive transition behavior of hydrophobically modified N-isopropylacrylamide copolymer solution

Poly(N-isopropylacrylamide-co-vinyl laurate)(PNIPAAm-co-VL) copolymers were prepared at various feed ratios via conventional radical random copolymerization. The formation, composition ratios and molecular weight of copolymers were examined. The thermoresponsive behaviors of PNIPAAm and PNIPAAm-co-VL solutions at low and high concentrations were intensively investigated by turbidity measurement, Micro-DSC, temperature-variable state fluorescence, ¹H NMR and dynamic light scattering (DLS). Several important results were obtained that (1) incorporation of PVL results in much lower and broader LCST regions of the copolymer solutions, and facilitates the formation of hydrophobic microdomains far below LCST, causing a pronounced aggregation in solutions (2) temperature-variable ¹H NMR spectra shows that during the phase transition, the ‘penetration’ of PNIPAAm into the hydrophobic core is a process accompanied with a transition of isopropyl from hydration to dehydration as well as a self-aggregation of hydrophobic chains at different temperature stages (3) according to the ¹H NMR spectra of polymer solutions obtained at varied temperatures, the microdomains from hydrophobic VL moieties have a different accessibility for isopropyl groups and the entire chains during phase transition (4) temperature-variable DLS demonstrates that the temperature-induced transition behavior of copolymers is supposedly divided into three stages: pre-LCST aggregation (<20 °C), coil-globule transition at LCST (20-25 °C) and post-LCST aggregation (>25 °C).     

Photo cross-linkable poly(N-isopropylacrylamide) copolymers III: micro-fabricated temperature responsive hydrogels

Micro-fabricated temperature responsive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels were produced by photolithographic patterning of photo cross-linkable polymers. These polymers were synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and 2-(dimethyl maleimido)-N-ethyl-acrylamide (DMIAAm). The patterning process of polymers with 9.2 mol% DMIAAm and film thickness below 5 μm in the dry state was able to depict a lateral resolution of 4 μm with insignificant shape change. In order to increase the adhesion of the swollen hydrogels, and thus, the resolution of a particular pattern, a special adhesion promoter based on a monochlorosilane anchor group and a chromophore head group was synthesized. If a silicon wafer surface was pretreated with the adhesion promoter, the structures were stable and well adhered even at lower cross-linking densities. The hydrogels are suitable as working substances for micro-actuators because of their thermally induced volume changes. The swelling ratio of the pattern at low temperatures increased with a decreased cross-linking density. As expected from the chemical composition of the gels, the phase transition temperature (T_c) decreased with increasing DMIAAm content. The swelling of microstructures in water in comparison to macroscopic objects occured significantly faster. This behavior was attributed to the small gel dimension but it was even more pronounced because of the sponge-like nanostructure of the hydrogels characterized by high-resolution field emission scanning electron microscopy. Suitable applications of these hydrogels are adjusting limbs in fluid micro-systems such as micro-pumps and micro-valves.     

Thermally responsive poly(N-isopropylacrylamide) monolayer on gold: synthesis, surface characterization, and protein interaction/adsorption studies

This report describes a novel method for preparing a thermally responsive poly(N-isopropylacrylamide) (PNiPAM) monolayer on a gold surface, and demonstrates the function of this monolayer in aqueous media. Thiol (-SH) terminated PNiPAM was synthesized by UV polymerization followed by hydrolysis, and a monolayer of this polymer (2.84±0.2 nm) was prepared on a gold substrate by simply dipping a precleaned gold plate into an aqueous solution of the PNiPAM. Cyclic voltametry and atomic force microscopy studies showed that the gold surface was well covered by the PNiPAM chains, and X-ray photoelectron spectroscopic data showed that this monolayer was chemisorbed on the gold surface. Studies of the water contact angle, protein interaction, and protein adsorption on the PNiPAM monolayer demonstrated that this monolayer shows a temperature dependence of the interfacial properties in aqueous media.     

Effect of hydrophobic polystyrene microphases on temperature-responsive behavior of poly(N-isopropylacrylamide) hydrogels

Reversible addition-fragmentation chain transfer polymerization was employed to prepare the crosslinked poly(N-isopropylacrylamide)-graft-polystyrene networks (PNIPAAm-g-PS). Due to the immiscibility of PNIPAAm with PS, the crosslinked PNIPAAm-g-PS copolymers displayed the microphase-separated morphology. While the PNIPAAm-g-PS copolymer networks were subjected to the swelling experiments, it is found that the PS block-containing PNIPAAm hydrogels significantly exhibited faster response to the external temperature changes according to swelling, deswelling, and reswelling experiments than the conventional PNIPAAm hydrogels. The improved thermo-responsive properties of hydrogels have been interpreted on the basis of the formation of the specific microphase-separated morphology in the hydrogels, i.e., the PS blocks pendent from the crosslinked PNIPAAm networks were self-assembled into the highly hydrophobic nanodomains, which behave as the microporogens and thus promote the contact of PNIPAAm chains and water. The self-organized morphology in the hydrogels was further confirmed by photon correlation spectroscopy (PCS). The PCS shows that the linear model block copolymers of PNIPAAm-g-PS networks were self-organized into micelle structures, i.e., the PS domains constitute the hydrophobic nanodomains in PNIPAAm-g-PS networks.     

Facile preparation of poly(N-isopropylacrylamide)-based hydrogels via aqueous Diels-Alder click reaction

The study reports a facile method of preparing poly(N-isopropylacrylamide)- based hydrogels by means of the Diels-Alder reaction. First, polymeric dienes were synthesized by free radical copolymerization between N-isopropylacrylamide (NIPA) and furfuryl methacrylate (FM), with 2, 2′-azobisisobutyronitrile (AIBN) as an initiator, and polymeric dienophile was obtained by a coupling reaction of poly(ethylene glycol) (PEG) and N-maleoyl-l-leucine (LMI) under N, N′-dicyclohexylcarbodiimide (DCC). Afterwards, the resultant dienes and dienophiles were dissolved in water and put in a refrigerator remaining a temperature of 9 °C, gelation via Diels-Alder reaction was observed after some time. The samples obtained at different steps were characterized by FTIR, NMR, GPC, SEM, CD, etc. It was found that LCST of copolymers decreases with the increase of FM content in copolymers. And the disassembly time of the hydrogels is closely related to the temperature and the solvents used. The swelling behavior study by gravimetric measurement indicates the hydrogels possess thermosensitivity and exhibit considerable swelling in water. Due to the simplicity of synthesis and no need for initiator or catalyzer and organic solvent, the strategy described here could find a promising application in the preparation of hydrogels.     

Direct synthesis of syndiotactic-rich poly(N-isopropylacrylamide) via radical polymerization of hydrogen-bond-complexed monomer

Radical polymerization of N-isopropylacrylamide (NIPAAm) in toluene was investigated in the presence of hexamethylphosphoramide (HMPA). We succeeded in directly preparing syndiotactic-rich poly(NIPAAm), the syndiotacticity of which (r=70%) is the highest among those of radically-prepared poly(NIPAAm)s so far reported, by lowering polymerization temperature to −60 °C in the presence of a two-fold amount of HMPA. The NMR analysis revealed that the induced syndiotactic-specificity was ascribed to 1:1 complex formation between NIPAAm and HMPA. Furthermore, thermodynamic analysis described that the induced syndiotactic-specificity was enthalpically achieved.