Thermo‐Responsive Solid‐Phase Extraction Using Poly(methyl vinyl ether)–Containing Segmented Polymer Networks

Segmented polymer networks containing poly(methyl vinyl ether) (PMVE) segments were prepared by free‐radical‐initiated copolymerization of PMVE‐α,ω‐dimethacrylate with styrene or 2‐hydroxyethyl methacrylate (HEMA). These networks were evaluated as thermo‐responsive solid‐phase extraction materials. Suspension‐derived polymer networks consisting of 80% of PMVE and 20% of HEMA adsorb toluene from an aqueous solution at 40°C and release the adsorbed toluene quantitatively at 20°C.     

Poly(N‐isopropylacrylamide) Phase Diagrams: Fifty Years of Research

In 1968, Heskins and Guillet published the first systematic study of the phase diagram of poly(N‐isopropylacrylamide) (PNIPAM), at the time a “young polymer” first synthesized in 1956. Since then, PNIPAM became the leading member of the growing families of thermoresponsive polymers and of stimuli‐responsive, “smart” polymers in general. Its thermal response is unanimously attributed to its phase behavior. Yet, in spite of 50 years of research, a coherent quantitative picture remains elusive. In this Review we survey the reported phase diagrams, discuss the differences and comment on theoretical ideas regarding their possible origins. We aim to alert the PNIPAM community to open questions in this reputably mature domain.     

Poly(N,N‐diethylacrylamide) microspheres by dispersion polymerization

Poly(N,N‐diethylacrylamide)‐based microspheres were prepared by ammonium persulfate (APS)‐initiated and poly(vinylpyrrolidone) (PVP)‐stabilized dispersion polymerization. The effects of various polymerization parameters, including concentration of N,N′‐methylenebisacrylamide (MBAAm) crosslinker, monomer, initiator, stabilizer and polymerization temperature on their properties were elucidated. The hydrogel microspheres were described in terms of their size and size distribution and morphological and temperature‐induced swelling properties. While scanning electron microscopy was used to characterize the morphology of the microspheres, the temperature sensitivity of the microspheres was demonstrated by dynamic light scattering. The hydrodynamic particle diameter decreased sharply as the temperature reached a critical temperature ～ 30 °C. A decrease in the particle size was observed with increasing concentration of both the APS initiator and the PVP stabilizer. The microspheres crosslinked with 2–15 wt % of MBAAm had a fairly narrow size distribution. It was found that the higher the content of the crosslinking agent, the lower the swelling ratio. High concentration of the crosslinker gave unstable dispersions. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6263–6271, 2008     

Preparation of poly(ethylene oxide)‐block‐poly(isoprene) by nitroxide‐mediated free radical polymerization from PEO macroinitiators

Amphiphilic poly(ethylene oxide)‐block‐poly(isoprene) (PEO‐b‐PI) diblock copolymers were prepared by nitroxide‐mediated polymerization of isoprene from alkoxyamine‐terminal poly(ethylene oxide) (PEO). PEO monomethyl ether (M_n ≈ 5200 g/mol) was functionalized by esterification with 2‐bromopropionyl bromide with subsequent copper‐mediated replacement of the terminal bromine with 2,2,5‐trimethyl‐4‐phenyl‐3‐azahexane‐3‐nitroxide. The resulting PEO‐alkoxyamine macroinitiator was used to initiate polymerization of isoprene in bulk and in solution at 125 °C to yield PEO‐b‐PI block copolymers with narrow molecular weight distributions (M_w/M_n ≤ 1.1). Polymerizations were first order in isoprene through 35% conversion. Micellar aggregates of PEO‐b‐PI in aqueous solution were crosslinked by treatment with a water‐soluble redox initiating system, and persistent micellar structures were observed in the dry state by AFM. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 2977–2984, 2005     

Anionic hydrogen‐transfer polymerization of N‐isopropylacrylamide under microwave irradiation

Anionic hydrogen‐transfer homopolymerization of N‐isopropylacrylamide (NIPAAm) was carried out using t‐BuOK as an initiator in DMF under microwave irradiation. After 100 W of microwave was irradiated to the reaction mixture at 140°C for 6 h in the temperature control mode, corresponding polymer was obtained in 10% yield. In the case of conventional oil bath heating, by contrast, corresponding polymer was not obtained in similar anionic polymerization conditions. With 100 W and 2.45 GHz of microwave irradiation, formation of the polymer was obtained. Microwave‐assisted anionic hydrogen‐transfer copolymerization of NIPPAm and acrylamide (AAm) led to the formation of thermo‐sensitive copolymers whose thermo‐sensitivity was controlled by the NIPAAm/AAm unit ratio. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2415–2419     

Mesoporous silica particles grafted with poly(ethyleneoxide‐block‐N‐vinylcaprolactam)

Mesoporous silica particles were grafted with thermoresponsive poly(ethyleneoxide‐b‐N‐vinylcaprolactam), PEO‐b‐PVCL. N‐vinylcaprolactam was first polymerized on particle surfaces using surface initiated atom transfer radical polymerization (SI‐ATRP) and then, the poly(ethyleneoxide) blocks were attached to the PVCL chain ends with click chemistry. The sizes, thermoresponsiviness, and colloidal stability of SiO₂‐PVCL and SiO₂‐PVCL‐b‐PEO particles and their aqueous dispersions were studied by scanning electron microscopy, turbidimetry, dynamic light scattering, zeta sizer, and microcalorimetry. The phase separation temperature of the PEO‐b‐PVCL grafted particles did not considerably differ from that of the SiO₂‐PVCL particles. The zeta potential of the grafted particles was close to zero at room temperature but decreased strongly upon heating. The decrease is related to the collapse of the PVCL blocks and correspondingly, the exposure of the silica surface toward the aqueous phase. The colloidal stability of the particles could be enhanced by adding PEO blocks to the chain ends of the PVCL grafts. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 5012–5020     

Novel amphiphilic block copolymers derived from the selective fluorination and sulfonation of poly(styrene‐block‐1,3‐cyclohexadiene)

Diblock copolymers of polystyrene‐block‐(1,3‐cyclohexadiene) (PS‐b‐PCHD), with varied molecular weights and compositions, were synthesized by sequential polymerization of styrene and 1,3‐cyclohexadiene (CHD) initiated by sec‐butyllithium in cyclohexane in the presence of appropriate additives during formation of the PCHD block. The residual double bonds in the PCHD block were saturated by addition of in situ generated difluorocarbene and/or hydrogen to enhance thermal and chemical stability. The fluorinated and/or hydrogenated polydiene blocks were chemically stable, allowing for controlled sulfonation of the PS blocks using acetyl sulfate. ¹H NMR and FT‐IR characterization confirmed successful fluorination/hydrogenation and sulfonation of the respective blocks. The resulting amphiphilic block copolymers consist of a semiflexible fluorine‐containing hydrophobic block having a bridged double ring structure and a hydrophilic sulfonated PS block. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Thermosensitive Micelles Based on Folate‐Conjugated Poly(N‐vinylcaprolactam)‐block‐Poly(ethylene glycol) for Tumor‐Targeted Drug Delivery

Thermosensitive PNVCL‐b‐PEG block copolymer coupled with folic acid was prepared as an anti‐cancer drug carrier. This polymer self‐assembled into stable micelles in aqueous solutions at above 33 °C. At 37 °C, the release profile of PNVCL‐b‐PEG‐FA micelles showed a slower and more controlled release of the entrapped 5‐FU than that at 25 °C. The blank and 5‐FU‐loaded PNVCL‐b‐PEG‐FA micelles did not induce remarkable cytotoxicity against the EA.hy 926 human endothelial cell line; however, 5‐FU‐loaded PNVCL‐b‐PEG‐FA micelles showed a cytotoxicity effect against 4T1 mouse mammary carcinoma cells due to the availability of loaded anti‐cancer drugs delivered to the inside of the cancer cells by the folate‐receptor‐mediated endocytosis process.

     

Synthesis and Self‐Assembly of pH‐Responsive Amphiphilic Poly(dimethylaminoethyl methacrylate)‐block‐Poly(pentafluorostyrene) Block Copolymer in Aqueous Solution

We report the synthesis of a novel pH‐responsive amphiphilic block copolymer poly(dimethylaminoethyl methacrylate)‐block‐poly(pentafluorostyrene) (PDMAEMA‐b‐PPFS) using RAFT‐mediated living radical polymerization. Copolymer micelle formation, in aqueous solution, was investigated using fluorescence spectroscopy, static and dynamic light scattering (SLS and DLS), and transmission electron microscopy (TEM). DLS and SLS measurements revealed that the diblock copolymers form spherical micelles with large aggregation numbers, N_agg ≈ 30 where the dense PPFS core is surrounded by dangling PDMAEMA chains as the micelle corona. The hydrodynamic radii, R_h of these micelles is large, at pH 2–5 as the protonated PDMAEMA segments swell the micelle corona. Above pH 5, the PDMAEMA segments are gradually deprotonated, resulting in a lower osmotic pressure and enhanced hydrophobicity within the micelle, thus decreasing the R_h. However, the radius of gyration, R_g remains independent of pH as the dense PPFS cores predominate.

     

Preparation and phase behavior of poly(4‐trimethylsilylstyrene)‐block‐polyisoprene

Three poly(4‐trimethylsilylstyrene)‐block‐polyisoprenes (TIs), the molecular weights of which were 82,000, 152,000 and 291,000 (TI‐82K, TI‐152K, and TI‐291K), were synthesized by sequential anionic polymerizations. The component polymers were a miscible pair that presented a lower critical solution temperature phase diagram if blended. The TI phase behavior was investigated with transmission electron microscopy. The order–disorder transition could be observed at a temperature between 200 °C (the ordered state) and 150 °C (the disordered state) for the block copolymer TI‐152K. The block copolymer TI‐82K presented the disordered state at 200 °C, whereas TI‐291K was in the ordered state at 150 °C. With the Flory–Huggins interaction parameter between poly(4‐trimethylsilylstyrene) and polyisoprene, which was evaluated by small‐angle neutron scattering for the block copolymers, the TI phase behavior could be reasonably explained by mean‐field theory. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 1214–1219, 2005     

Molecular Dynamics Investigation of the Thermo‐Responsive Polymer Poly(N‐isopropylacrylamide)

Using molecular dynamics simulations with an OPLS force field, the lower critical solution temperature (LCST) of single‐ and multiple‐chain PNIPAM solutions in water is investigated. The sample containing ten polymer chains shows a sudden drop in size and volume at 305 K. Such an effect is absent in the single‐chain system. Large fluctuations of the physical properties of a short single‐chain prevent any clear detection of the LCST for the chosen model system, at least on the time scale of 200 ns. The results provide evidence that a critical number of PNIPAM monomer units must be present in the simulated system before MD simulations are capable to detect conformational changes unambiguously.

     

Access to Poly{N‐[3‐(dimethylamino)propyl](meth)acrylamide} via Microwave‐Assisted Synthesis and Control of LCST‐Behavior in Water

In the present paper, the microwave (MW)‐assisted synthesis of the alkaline N‐[3‐(dimethylamino)propyl]methacrylamide ( 4 ) and ‐acrylamide ( 5 ) monomers within minutes is described. The reaction was carried out by mixing and subsequent irradiation of 3‐dimethylamino‐1‐propylamine ( 3 ) and (meth)acrylic acid ( 1 / 2 ) without addition of solvent. After polymerization, the obtained homopolymers ( 6 / 7 ) exhibit lower critical solution temperature (LCST) behavior in water at 35 °C only at pH = 14. The LCST‐behavior can be influenced by N‐oxidation of the tertiary amino group with hydrogen peroxide or by formation of a polymer‐inclusion complex ( 6a ) of 6 and β‐cyclodextrin (β‐CD) by addition of randomly‐methylated β‐CD.

     

pH‐Responsive PEG‐Poly(β‐amino ester) Block Copolymer Micelles with a Sharp Transition

Summary: A pH‐sensitive block copolymer is synthesized by step polymerization and its pH‐sensitive micellization‐demicellization behavior is studied. This polymer has a hydrophilic MPEG (shell) and hydrophobic but pH‐sensitive poly(β‐amino ester) (core), which can form a self‐assembled micelle. As confirmed by fluorescence spectroscopy and dynamic light scattering (DLS), this polymer shows a sharp pH‐sensitive micellization‐demicellization behavior. It is confirmed that the pH sensitivity is affected by the molecular weight ratio between the MPEG and poly(β‐amino ester).

Plots of the intensity ratio I₃₃₇/I₃₃₄ (from pyrene excitation spectra): a) vs. pH for copolymer samples and b) vs. log (concentration) for M1.     

Study of the phase transition of poly(N,N‐diethylacrylamide) in water by rheology and dynamic light scattering

Poly(N,N‐diethylacrylamide) (PDEA) possesses a lower critical solution temperature (LCST) in aqueous media. The solution properties of PDEA at various temperatures have been characterized with techniques such as rheology and dynamic light scattering. There is a decrease in the coil size before the phase transition due to a coil‐to‐globule transition. At the LCST, rheological and dynamic light scattering studies have also confirmed an aggregation phenomenon. This aggregation modifies the rheological properties of the polymer solutions. High frequencies hinder the phase‐transition process and reduce the LCST of the polymers. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1627–1637, 2003     

The Formation of Biodegradable Polymeric Micelles from Newly Synthesized Poly(aspartic acid)‐block‐Polylactide AB‐Type Diblock Copolymers

Summary: A poly(aspartic acid)‐block‐polylactide (PAsp‐block‐PLA) diblock copolymer was synthesized through the polymerization of β‐benzyl‐L ‐aspartate‐N‐carboxyanhydride [Asp(OBzl)‐NCA] with amino‐terminating polylactide (NH₂‐PLA) as a macroinitiator. The chain length of the PAsp segment could be easily controlled by changing the monomer/initiator ratio. Dynamic light scattering measurements of PAsp‐block‐PLA aqueous solutions revealed the formation of polymeric micelles. Changes in the micelles as a function of pH were investigated.

The structure and formation of micelles of the poly(aspartic acid)‐block‐polylactide (PAsp‐block‐PLA) diblock copolymers synthesized here.     

Synthesis of Novel Thermo‐ and pH‐Responsive Poly(L‐lysine)‐Based Copolymer and its Micellization in Water

A series of novel temperature and pH responsive block copolymers composed of poly(N‐isopropylacrylamide) (PNIPAM) and poly(L ‐lysine) (PLL) were synthesized. The effect of pH and the length of PLL on the lower critical solution temperature (LCST) of PNIPAM, and the self‐assembly of these PLL‐based copolymers induced by temperature and pH changes were investigated by the cloud point method, dynamic light scattering (DLS) and environmental scanning electron microscopy (ESEM). These PNIPAM‐b‐PLL copolymers can self‐assemble into micelle‐like aggregates with PNIPAM as the hydrophobic block at acidic pH and high temperatures; and at alkaline pH and low temperatures, they can self‐assemble into particles with PLL as the hydrophobic block. The copolymers may have potential applications in biotechnological and biomedical areas as drug release carriers.

     

Synthesis of Thermo‐ and pH‐Sensitive Polyion Complex Micelles for Fluorescent Imaging

Two thermo‐ and pH‐sensitive polypeptide‐based copolymers, poly(N‐isopropylacrylamide‐co‐N‐hydroxymethylacrylamide)‐b‐poly(L ‐lysine) (P(NIPAAm‐co‐HMAAm)‐b‐PLL, P1 ) and poly(N‐isopropylacrylamide‐co‐N‐hydroxymethylacrylamide)‐b‐poly(glutamic acid) (P(NIPAAm‐co‐HMAAm)‐b‐PGA, P2 ), have been designed and synthesized by the ring‐opening anionic polymerization of N‐carboxyanhydrides (NCA) with amino‐terminated P(NIPAAm‐co‐HMAAm). It was found that the block copolymers exhibit good biocompatibility and low toxicity. As a result of electrostatic interactions between the positively charged PLL and negatively charged PGA, P1 and P2 formed polyion complex (PIC) micelles consisting of polyelectrolyte complex cores and P(NIPAAm‐co‐HMAAm) shells in aqueous solution. The thermo‐ and pH‐sensitivity of the PIC micelles were studied by UV/Vis spectrophotometry, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Moreover, fluorescent PIC micelles were achieved by introducing two fluorescent molecules with different colors. Photographs and confocal laser scanning microscopy (CLSM) showed that the fluorescence‐labeled PIC micelles exhibit thermo‐ and pH‐dependent fluorescence, which may find wide applications in bioimaging in complicated microenvironments.     

Synthesis of 3‐(tert‐Butoxycarbonylmethyl)‐N‐vinyl‐2‐caprolactam and Homologous Copolymerization Toward Biocompatible Carboxylated Poly(N‐vinyl‐2‐caprolactam) Responsive to pH and Temperature

A new monomer derivative of N‐vinyl‐2‐caprolactam (VCL), namely 3‐(tert‐butoxycarbonylmethyl)‐N‐vinyl‐2‐caprolactam (TBMVCL), was synthesized via nucleophilic substitution at the α‐carbon to the lactam carbonyl group. The monomer was copolymerized radically with VCL and the copolymer compositions were controlled through varying the molar feeding percentages of TBMVCL. The resulting copolymers exhibited temperature‐responsive properties in water, with cloud points decreasing from 33 °C to 13 °C when the TBMVCL composition increased from 2.2 mol % to 18.6 mol %. Removal of the tert‐butyl protecting groups via acid hydrolysis exposed the carboxyl groups, which conferred pH sensitivity to the thermoresponsive properties of the resulting deprotected copolymers. The cloud point was found to increase with the increase of solution pH from 2.0 to 7.4, due to the ionization of the carboxyl groups. The influence of pH was most drastic for the 18.6 mol % copolymer composition. Furthermore, the phase transition temperature of the deprotected copolymers was found to be dependent on the polymer solution concentration, exemplifying classical Flory–Huggins miscibility behavior. Comparison of responsiveness was also made with another type of carboxyl functionalized poly(N‐vinyl‐2‐caprolactam) copolymer reported in our prior study, to examine the influence of the chemical structure of the carboxyl substitution group. Finally, the deprotected copolymer was demonstrated to be biocompatible using a fibroblast cell culture. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 112–120