Chiral pH‐Responsive Amphiphilic Polymer Co‐networks: Preparation,Chiral Recognition,and Release Abilities

Novel amphiphilic polymer co‐networks (APCNs), poly(N‐acryloyl‐L ‐alanine)‐l‐polydimethylsiloxane (denoted as PNAA‐l‐PDMS), are prepared, and exhibit remarkable pH‐responsiveness, chiral‐recognition, and enantioselective‐release abilities. The APCNs are prepared by free‐radical copolymerization starting from N‐acryloyl‐L ‐alanine (NAA) and methacrylate‐terminated poly(dimethylsiloxane) (M‐PDMS) as co‐(macro)monomers. The APCNs show pronounced pH‐sensitivity, evidenced by a reversible swelling–deswelling transition upon a cyclicly altering pH. The chiral co‐networks are applied for enantioselective recognition and release. A maximum adsorption is achieved towards D ‐proline (61%), whereas for L ‐proline, it is only 10%. More interestingly, the release for the L ‐proline is 90%, whereas for the D ‐proline, only 70% is released.

     

Effects of Poly(N‐isopropylacrylamide) (PNIPAAm) on the Conformational Change of Poly(N 5‐hydroxyalkyl glutamine) (PHAG) in PHAG‐PNIPAAm Block Copolymer with Temperature

Diblock copolymers consisting of poly(N ⁵‐hydroxyalkylglutamine) (PHAG) and poly(N‐isopropylacrylamide) (PNIPAAm) were prepared by aminolysis with aminoalkanols of the side‐chain ester of poly(γ‐benzyl L ‐glutamate) (PBLG) as a part of PBLG‐PNIPAAm block copolymers. The molecular weight ratio of the initial PBLG to the resulting PHAG was nearly 0.35. The effect of PNIPAAm on the conformational change of PHAG in PHAG‐PNIPAAm block copolymers with temperature was investigated by circular dichroism. Poly[N ⁵‐(2‐hydroxyethyl)‐L ‐glutamine] (PHEG) and the PHEG‐PNIPAAm copolymer (GNE) stayed in a randomly coiled conformation whereas poly[N ⁵‐(3‐hydroxypropyl)‐L ‐glutamine] (PHPG), poly(N ⁵‐(4‐hydroxybutyl)‐L ‐glutamine) (PHBG), PHPG‐PNIPAAm copolymer (GNP), and PHBG‐PNIPAAm copolymer (GNB) underwent conformational transitions with temperature. The conformational change of the PHPG block in GNP copolymer occurred from an α‐helix to a random coil after the incorporation of PNIPAAm into the copolymer. The thermodynamic parameters of the thermally induced helix‐coil transition for PHBG and PHBG‐PNIPAAm in aqueous solution were calculated.     

Poly(L‐lactide) Nanoparticles via Ring‐Opening Polymerization in Non‐aqueous Emulsion

The preparation of poly(L ‐lactide) nanoparticles via ring‐opening polymerization (ROP) of L ‐lactide is conducted in non‐aqueous emulsion. In this process, acetonitrile is dispersed in either cyclohexane or n‐hexane as the continuous phase and stabilized by a PI‐b‐PEO, respectively, a PI‐b‐PS copolymer as emulsifier. The air and moisture sensitive N‐heterocyclic carbene 1,3‐bis(2,4,6‐trimethylphenyl)‐2‐ididazolidinylidene (SIMes) catalyzes the polymerization of L ‐lactide at ambient temperatures. Spherical poly(L ‐lactide) nanoparticles with an average diameter of 70 nm and a tunable molecular weight are generated. Hence, the non‐aqueous emulsion technique demonstrates its good applicability toward the generation of well‐defined poly(L ‐lactide) nanoparticles under very mild conditions.     

Nanoporous Gold Film Prepared by the Epoxidation of Poly(styrene‐b‐butadiene) Diblock Copolymer Templated Micelles

A new approach is developed for the preparation of nanoporous gold (Au) films using diblock copolymer micelles as templates. Stable Au nanoparticles (NPs) with a narrow distribution are prepared by modifying NPs functionalized with 4‐(dimethylamino)pyridine ligands (DMAP Au NPs) and a spherical micelle formed through the epoxidation of poly(styrene‐b‐butadiene) diblock copolymer to produce poly(styrene‐b‐vinyl oxirane) (PS‐b‐PBO) in tetrahydrofuran–acetonitrile solution. The exchange reaction of 4‐aminothiophenol of PS‐b‐PBO diblock copolymer micelles with DMAP Au NPs can produce block copolymer–Au NPs composite films. After the pyrolysis of the diblock copolymer templates at a specific temperature to avoid the collapse of the Au NPs, a nanoporous Au film is prepared.     

Assembled Structures and Chiroptical Properties of Amphiphilic Block Copolymers Synthesized by RAFT Polymerization of N‐Acryloyl‐L‐alanine

Amino acid‐based amphiphilic block copolymers involving poly(N‐acryloyl‐L ‐alanine), poly(A‐Ala‐OH), which exhibits a characteristic chiroptical property and pH‐dependent solubility, have been synthesized by reversible addition‐fragmentation chain transfer (RAFT) polymerization. The direct polymerization of A‐Ala‐OH without any protecting chemistry using the dithiocarbamate‐terminated polystyrene or poly(N‐acryloyl‐L ‐phenylalanine methyl ester) as a macrochain transfer agent produced well‐defined amphiphilic block copolymers. The self‐assembly behaviors and chiroptical properties of these amphiphilic block copolymers in selective solvents were investigated by dynamic light scattering, circular dichroism, and UV–Vis spectroscopic methods.

     

Tunable Arrangement of Gold Nanoparticles in Epoxidated Poly(styrene‐block‐butadiene) Diblock Copolymer Matrices

A new approach to synthesize block‐copolymer‐mediated/gold nanoparticle (Au NP) composites is developed. Stable and narrowly distributed Au NPs modified with a 2‐phenylethanethiol ligand are prepared by a two‐phase liquid–liquid method. A new epoxidation of a poly(styrene‐block‐butadiene) diblock copolymer, to form poly(styrene‐block‐vinyl oxirane) (PS‐b‐PBO), is achieved through chemical modification. It is found that the Au NPs disperse well in the PS block segment by partially crosslinking the PBO block segment with poly(ethylene oxide bisamine) (D230), a curing agent. The aggregation of Au NPs leads to a red‐shift of the plasmon absorption with the increase in the D230 content. However, without crosslinking the PBO block segment with D230, Au NPs distributes in both the PS and PBO segments.     

Synthesis and Aggregation Behaviors of Well‐Defined Thermoresponsive Pentablock Terpolymers With Tunable LCST

A series of thermoresponsive pentablock terpolymers, poly(N‐isopropylacrylamide)‐b‐poly(ethylene oxide)‐b‐poly(propylene oxide)‐b‐poly(ethylene oxide)‐b‐poly(N‐isopropylacrylamide), is prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization. The effect of NIPAM and PPO block lengths on lower critical solution temperature (LCST), critical micelle concentration (cmc), and aggregation number (N_agg) is investigated via UV–Vis spectroscopy and steady‐state fluorescence spectroscopy. The results show that upon increasing the block lengths, LCST and cmc decrease, while N_agg increases. TEM observation shows that associated spherical‐like particles are evidenced below the LCST of the terpolymers, and regular or irregular spherical micelles or even intermicellar aggregates are observed above the LCST.     

Temperature and pH dependence of the catalytic activity of colloidal platinum nanoparticles stabilized by poly[(vinylamine)‐co‐(N‐vinylisobutyramide)

Colloidal platinum nanoparticles in the size range of 5–35 Å have been successfully prepared in water at room temperature by NaBH₄ reduction of ionic platinum in the presence of poly[(vinylamine)‐co‐(N‐vinylisobutyramide)] (PVAm‐co‐PNVIBA). To our knowledge, the temperature‐ and pH‐responsive copolymer was used for the first time as the stabilizer of colloidal metal particles. Three PVAm‐co‐PNVIBA copolymers with PVAm contents of 4.1, 8.3, and 19.8 mol‐% were examined. The particle size and morphology of the platinum colloids varied with the copolymer composition, as confirmed by TEM measurements. The polymer‐stabilized Pt nanoparticles precipitated on heating above their critical flocculation temperatures (CFTs), which were strongly dependent on the solution pH and the copolymer composition. The CFTs were 0.2–1.6°C lower than the lower critical solution temperatures (LCSTs) of the copolymers free in water and the differences increased with increasing PVAm content. The catalytic activity of the Pt nanoparticles was investigated in the aqueous hydrogenation of allyl alcohol. It was found that the activity was regulated through temperature‐ and pH‐induced phase separation. The PVAm content also strongly effected the catalytic activity and the morphology of phase separated catalysts. With a PVAm content of 4.1 mol‐%, the colloidal platinum sol reversibly changed its catalytic activity with changes in temperature.     

Preparation and Characterization of Novel Temperature Sensitive Poly(N‐isopropylacrylamide‐co‐acryloyl beta‐cyclodextrin) Hydrogels with Fast Shrinking Kinetics

Summary: Novel temperature sensitive poly(N‐isopropylacrylamide‐co‐acryloyl beta‐cyclodextrin) (P(NIPA‐co‐A‐CD)) hydrogels with fast shrinking rates were prepared by radical polymerization of NIPA, A‐CD and crosslinker in a mixture of water/1,4‐dioxane as solvent. Because the mixed solvent was a poor solvent for the copolymers, phase separation occurred during the polymerization, which resulted in a heterogeneous, porous structure of the hydrogels. In contrast to the normal PNIPA hydrogel and the homo P(NIPA‐co‐A‐CD) gel prepared in water, the P(NIPA‐co‐A‐CD) hydrogels synthesized in water/1,4‐dioxane as solvent exhibited higher swelling ratios at the temperature below the lower critical solution temperature (LCST) and shrunk rapidly to equilibrium within shorter time when the temperature was increased above LCST. Increasing the acryloyl beta‐cyclodextrin content in the gels led to a slight decrease of the swelling ratio at lower temperature and had no marked influence on the shrinking kinetics. The gels prepared in water/1,4‐dioxane, at different v/v ratios of 1.0/0.2, 0.8/0.4 and 0.6/0.6, showed similar properties.

SEM photos of the heterogeneous P(NIPA‐co‐A‐CD) hydrogel prepared in water/1,4‐dioxane.     

Poly(N,N‐dimethylacrylamide)‐block‐Poly(L‐lysine) Hybrid Block Copolymers: Synthesis and Aqueous Solution Characterization

Four poly(N,N‐dimethylacrylamide)‐block‐poly(L ‐lysine) (PDMAM‐block‐PLL) hybrid diblock copolymers and two PLL homo‐polypeptides are prepared via ROP of ε‐trifluoroacetyl‐L ‐lysine N‐carboxyanhydride initiated by primary amino‐terminated PDMAM and n‐hexylamine respectively. The PLL blocks render the copolymers a multi‐responsive behavior in aqueous solution due to their conformational transitions from random coil to α‐helix with increasing pH, and from α‐helix to β‐sheet upon heating. The random coil‐to‐α‐helix transition is found to depend on the PLL length: the longer the peptide segment, the more readily the transition occurred. The same trend was observed for the α‐helix‐to‐β‐sheet transition, which was found to be inhibited for short polypeptides unless conjugated with the PDMAM block.

     

Block and Graft Copolymers Made of 16‐Membered Macrolactones and l‐Alanine: A Comparative Study

Block and graft poly(macrolactone)‐poly(α‐amino acid) copolymers made of l ‐alanine and pentadecalactone or globalide respectively, are prepared. A sequential ring‐opening polymerization (ROP) copolymerization route consisting of two stages, the first devoted to the preparation of the amino‐functionalized poly(macrolactone) and the second to the amino‐initiated polymerization of l ‐alanine N‐carboxyanhydride (Ala‐NCA), is followed for the synthesis of both types of copolymers. Poly(l ‐alanine) segment lengths are accurately controlled by adjusting the macroitiator/Ala‐NCA ratio used for reaction in the second stage. Block copolymers are semicrystalline with the poly(pentadecalactone) block crystallizes well in a separate phase and the poly(α‐amino acid) block arranged in either the α‐helical or β‐sheet structure in a ratio that is depending on composition and temperature. Graft copolymers are amorphous but with the poly(α‐amino acid) side chains arranged in a more or less regular conformation. Nanoparticles with a diameter of around 300 nm and moderate positive Z‐potential can be obtained from the block copolymers by self‐assembling in water whereas graft copolymers are unable to render recognizable objects of nanometer‐dimension under similar conditions.     

Gelation Behavior of Bioabsorbable Hydrogels Consisting of Enantiomeric Mixtures of A–B–A Tri‐block Copolymers of Polylactides (A) and Poly(ethylene glycol) (B)

A–B–A tri‐block copolymers of poly(L ‐lactide) (PLLA: A) and poly(ethylene glycol) (PEG: B) and those of poly(D ‐lactide) (PDLA: A) and PEG (B) were prepared and suspended in saline. Mixing suspensions consisting of the enantiomeric copolymers with identical block compositions induced a temperature‐dependent sol‐to‐gel transition. It was found that the composition window of the copolymers that allowed the spontaneous sol–gel transition around body temperature was considerably narrow, being affected by how easily the PLLA and PDLA blocks of the copolymers can form the stereocomplex in the mixed suspensions. The gelation rate and gel strength also depended on the copolymer composition and concentration at a constant gelation temperature of 37 °C.     

Folate‐Conjugated Poly(N‐(2‐hydroxypropyl) methacrylamide)‐block‐Poly(benzyl methacrylate): Synthesis,Self‐Assembly,and Drug Release

Well‐defined amphiphilic diblock copolymers of poly(N‐(2‐hydroxypropyl)methacrylamide)‐block‐poly(benzyl methacrylate) (PHPMA‐b‐PBnMA) are synthesized using reversible addition–fragmentation chain transfer polymerization. The terminal dithiobenzoate groups are converted into carboxylic acids. The copolymers self‐assemble into micelles with a PBnMA core and PHPMA shell. Their mean size is <30 nm, and can be regulated by the length of the hydrophilic chain. The compatibility between the hydrophobic segment and the drug doxorubicin (DOX) affords more interaction of the cores with DOX. Fluorescence spectra are used to determine the critical micelle concentration of the folate‐conjugated amphiphilic block copolymer. Dynamic light scattering measurements reveal the stability of the micelles with or without DOX. Drug release experiments show that the DOX‐loaded micelles are stable under simulated circulation conditions and the DOX can be quickly released under acidic endosome pH.     

Temperature and pH Dual‐Responsive Behavior of Dendritic Poly(N‐isopropylacrylamide) with a Polyoligomeric Silsesquioxane Core and Poly(2‐hydroxyethyl methacrylate) Shell

Novel temperature and pH dual‐responsive dendritic polyoligomeric silsesquioxane (POSS)–poly(N‐isopropylacrylamide) (PNIPAm)–poly(2‐hydroxyethyl methacrylate) (PHEMA) copolymers are prepared via atom transfer radical polymerization and click reactions. The cloud points (T_c) decrease with decreasing pH from 10.0 to 5.0 due to the weakened inter‐molecular interactions and enhanced intra‐molecular hydrogen bonding, whereas the T_c exhibits a small increase from pH 5.0 to 4.0 because of the better solvation of PHEMA at highly acidic conditions. The above findings are corroborated by the different sizes of aggregates observed by dynamic light scattering. The encapsulation of a fluorescent dye and stimulated release by temperature and pH changes are also demonstrated.     

Aggregation and Crosslinking of Poly(N,N‐dimethylacrylamide)‐b‐pullulan Double Hydrophilic Block Copolymers

The self‐assembly of polymers is a major topic in current polymer chemistry. In here, the self‐assembly of a pullulan based double hydrophilic block copolymer, namely pullulan‐b‐poly(N,N‐dimethylacrylamide)‐co‐poly(diacetone acrylamide) (Pull‐b‐(PDMA‐co‐PDAAM)) is described. The hydrophilic block copolymer induces phase separation at high concentration in aqueous solution. Additionally, the block copolymer displays aggregates at lower concentration, which show a size dependence on concentration. In order to stabilize the aggregates, crosslinking via oxime formation is described, which enables preservation of aggregates at high dilution, in dialysis and in organic solvents. With adequate stability by crosslinking, double hydrophilic block copolymer (DHBC) aggregates open pathways for potential biomedical applications in the future.     

Pyrene End‐Labeled Diblock Glycopolymers: Synthesis and Aggregation

Summary: A pyrene end‐labeled amphiphilic block copolymer, poly(ε‐caprolactone)‐block‐poly[6‐O‐(4‐vinylbenzyl)‐D ‐galactose] (Py‐PCL‐b‐PVBG), was synthesized by a four‐step method. The aggregation behavior of the diblock copolymer in solution was studied by monitoring the fluorescence of pyrene. TEM measurements revealed that the aggregates obtained by first dissolving the copolymer in N,N‐dimethylformamide (DMF), followed by the addition of water, were primarily spheres with the PCL blocks in the core. The PVBG corona was then crosslinked with glutaraldehyde. Final removal of the PCL core was accomplished by degradation under basic conditions, which resulted in the formation of hollow glycopolymer nanospheres.

Structure of poly(ε‐caprolactone)‐block‐poly[6‐O‐(4‐vinylbenzyl)‐D ‐galactose].     

Synthesis of Poly(N‐isopropylacrylamide)‐Block‐Poly(tert‐Butyl Methacrylate) Block Copolymer by Visible Light–Induced Metal‐Free Atom Transfer Polymerization

Atom transfer radical polymerization (ATRP) is one of the most powerful methodologies for polymerization. Well‐controlled ATRP of N‐isopropylacrylamide (NIPAAm) could be obtained in organic‐water mixture solvent with conventional metal catalyst/ligand catalyst system. However, the mixture solvent is not suitable for copolymerization of NIPAAm with hydrophobic monomers. Moreover, further purification of metal was required for biomedical polymerization. Here, poly(N‐isopropylacrylamide) (PNIPAAm) is synthesized by visible light–induced metal‐free ATRP using a photoredox catalyst. PNIPAAm is obtained with high conversion and controlled molecular weight with low dispersity. Moreover, poly(N‐isopropylacrylamide)‐block‐poly(tert‐butyl methacrylate) (PNIPAAm‐b‐PMAA) block copolymer can be synthesized by such metal‐free ATRP. PNIPAAm‐b‐PMAA can be obtained by following hydrolysis.     

Preparation and Characterization of Novel Low‐Temperature/pH Dual‐Responsive Poly(N‐isopropylacrylamide‐co‐1H‐benzimidazolyl‐ethyl acrylate) Copolymers

Stimuli‐responsive polymers in response to both low temperature and pH are of great potential for designing drug carriers to obtain a better therapeutic effect during cryotherapy of tumors. In this work, novel low‐temperature and pH dual‐responsive poly(N‐isopropylacrylamide‐co‐1H‐benzimidazolyl‐ethyl acrylate) (PNBM) linear copolymers are developed, which can undergo stretching/shrinking conformational transition at low temperature and mildly acidic conditions. The dual‐responsive properties of PNBM copolymers can be affected and regulated by the host–guest inclusion action between benzimidazole and hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) molecules. The critical response temperature of the copolymers can be flexibly adjusted when the benzimidazole groups in copolymer chains are captured by HP‐β‐CD. And the PNBM copolymers present a pH‐responsive stretching‐to‐shrinking‐to‐stretching conformational transition in a narrow pH range in HP‐β‐CD solution. The results provide valuable guidance for designing and applying PNBM‐based smart materials in biomedical applications.     

Amphiphilic Polyoxazoline‐block‐Polypeptoid Copolymers by Sequential One‐Pot Ring‐Opening Polymerizations

Amphiphilic block copolymers possess great potential as biomaterials in drug delivery and gene therapy. Herein, pseudopeptidic‐type diblock copolymer of poly(2‐oxazoline)‐block‐polypeptoid (POx‐b‐POI) is presented and synthesized. Poly[2‐(3‐butenyl)‐2‐oxazoline]‐block‐poly(sarcosine) (PBuOx‐b‐PSar) comprising hydrophobic POx segment bearing alkenyl side chain and hydrophilic POI segment of N‐methyl glycine, viz., sarcosine, is prepared by ring‐opening polymerization (ROP) through a one‐pot and three‐step route. Diphenyl phosphate initiates ROP of BuOx, and then the living chain end of PBuOx is quenched by ammonia to obtain PBuOx‐ammonium phosphate in situ, the active ammonium group initiates ROP of sarcosine N‐carboxy anhydride. PBuOx‐b‐PSar with controlled molecular weights (4.7–10.8 kg mol⁻¹) and narrow dispersities (Ð _M 1.15–1.21) are characterized by ¹H NMR, ¹³C NMR, and size‐exclusion chromatography. Dynamic light scattering and transmission electron microscopy analysis reveal that PBuOx‐b‐PSar self‐assembles into nanostructures of average diameter D _H of 37–109 nm in aqueous solution. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide test demonstrates the cytocompatibility (relative cell viability > 80%) of the PBuOx‐b‐PSar. In view of the self‐assembly and biocompatibility, the readily prepared diblock copolymers may hopefully be used in biomedical applications.

     

Poly(N‐isopropylacrylamide‐co‐N‐isopropylmethacrylamide) Thermo‐Responsive Microgels as Self‐Regulated Drug Delivery System

Poly(N‐isopropylacrylamide‐co‐N‐isopropylmethacrylamide) (poly(NIPAAm‐co‐NIPMAAm)) is synthesized as an attractive thermo‐responsive copolymer by an original procedure. Due to the similar structure of the two co‐monomers, the poly(NIPAAm‐co‐NIPMAAm) copolymer displays a very sharp phase transition, under physiological conditions (phosphate buffer solution at pH = 7.4). The copolymer, showing the 51/49 co‐monomer NIPAAm/NIPMAAm molar ratio, displays a lower critical solution temperature (LCST) close to that of the human body temperature (36.8 °C). The poly(NIPAAm‐co‐NIPMAAm) microgels obtained at the 51:49 co‐monomer ratio displays a volume phase transition temperature (VPTT) slightly smaller than LCST. The deswelling rate of the microgels is very high (k = 0.019 s^?1), the shrinkage occurring almost instantaneously, whereas the swelling rate is slightly lower (k = 0.0077 s^?1). The microgels are loaded with the model drug dexamethasone and the drug release is investigated at different temperatures, below and above the VPTT. Under thermal cycling operation between 32 and 38 °C, the pulsatile release of dexamethasone is observed.