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.     

Complex micelles with a responsive shell for controlling of enzymatic degradation

Complex polymeric micelles with a PLA core and a mixed PEG/PNIPAM shell were prepared by self-assembly of two block copolymers: poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) and poly(N-isopropylacrylamide)-b-poly(lactic acid) (PNIPAM-b-PLA). Using ¹H NMR spectroscopy and dynamic light scattering, the micellization and the enzymatic degradation status were characterized. At 25 °C, the PNIPAM block is hydrophilic and the PLA core is prone to the enzymatic degradation, resulting in the disassembly of the micelles. While increasing the temperature to 45 °C, the PNIPAM collapsed onto the PLA core, protecting the PLA core from the attack by the enzyme, and the micelles exhibit a resistance to the enzymatic degradation. Furthermore, the enzymatic degradation rate of the micelles can also be tuned by changing the ratio of PEG to PNIPAM. With increasing content of PNIPAM, the conformation of the collapsed PNIPAM changes from patchy domains to a continuous and dense layer, and the enzyme accessibility to the PLA core is changed.     

Double-responsive core-shell-corona micelles from self-assembly of diblock copolymer of poly(t-butyl acrylate-co-acrylic acid)-b-poly(N-isopropylacrylamide)

Self-assembly of poly(t-butyl acrylate-co-acrylic acid)-b-poly(N-isopropylacrylamide) [P(tBA-co-AA)-b-PNIPAM], which was obtained from part hydrolysis of PtBA-b-PNIPAM synthesized by sequential atom transfer radical polymerization (ATRP) was studied. Thermo- and pH-responsive core-shell-corona (CSC) micelles with different structures were formed from (PtBA-co-PAA)-b-PNIPAM in aqueous solution. At pH 5.8 and 25 °C, the block copolymer self-assembled into spherical core-shell micelles with hydrophobic PtBA segments as the core, hydrophilic PAA/PNIPAM segments as the mixed shell. Increasing temperatures, core-shell micelles converted into CSC micelles with PtBA as the core, collapsed PNIPAM as the shell and soluble PAA as the corona. Moreover, decreasing pH at 25 °C, PAA chains collapsed onto the core resulting in CSC micelles with PtBA as the core, PAA as the shell and PNIPAM as the corona.     

Synthesis and characterization of thermo-responsive supramolecular diblock copolymers

In this paper, we report the synthesis and characterization of a new thermo-responsive supramolecular amphiphiles diblock copolymer, methoxy poly (ethylene glycol)-block-Poly(N-isopropylacrylamide) (mPEG-b-PNIPAM). The mPEG with β-cyclodextrin (β-CD) group and the PNIPAM with adamantine (AD) group were synthesized, respectively, and mPEG-b-PNIPAM was then obtained by the host-guest inclusion between AD and β-CD. The structure and molecular weight of mPEG-b-PNIPAM was confirmed by ¹H NMR and GPC measurements. At low temperature (T?<?33 °C), the PNIPAM block is hydrophilic. With increasing temperature, the hydrophobicity the of PNIPAM block increases. This molecular feature leads to interesting aggregation behavior of micelles in aqueous solutions at different temperatures. The self-assembly was revealed by UV, DLS measurements, and TEM observations.     

Phenylboronic acid as a sugar- and pH-responsive trigger to tune the multiple micellization of thermo-responsive block copolymer

Phenylboronic acid-containing thermo-responsive block copolymer, poly(ethylene oxide)-b-poly(methoxydi(ethylene glycol) methacrylate-co- aminophenylboronic acid ethyl methacrylate) (PEO-b-P(DEGMMA-co-PBAMA)), was employed to investigate the multiple micellization and dissociation transitions. The unique sugar- and pH-responsive properties of phenylboronic acid were interesting to provide two parallel approaches to tune the critical micellization temperature (CMT) and multiple micellization of thermo-responsive block copolymer. The block copolymers were molecularly soluble below 21 °C and underwent micellization above 21 °C at pH 8.7. After glucose was added at 24 °C, hydrophobic phenylboronic acid was changed to hydrophilic boronate-glucose complex and the CMT of the thermo-sensitive block was increased which caused the dissociation of micelles. In parallel, if the solution pH was increased from 8.7 to 11 at 25 °C, micelles were disrupted because of the formation of hydrophilic phenylboronate anion, which elevated the CMT of the thermo-sensitive block polymer. The introduction of phenylboronic acid groups into the thermo-responsive block copolymers provides a novel approach to tune the multiple micellization and dissociation transitions that might have great potentials in biomedical applications.     

Dissipative particle dynamics study on the multicompartment micelles self-assembled from the mixture of diblock copolymer poly(ethyl ethylene)-block-poly(ethylene oxide) and homopolymer poly(propylene oxide) in aqueous solution

Dissipative particle dynamics (DPD) method is applied to model the self-assembly of diblock copolymer poly(ethyl ethylene)-block-poly(ethylene oxide) (PEE-b-PEO) and homopolymer poly(propylene oxide) (PPO) in aqueous solution. In this study, several segments are coarse-grained into a single simulation bead based on the experimental density. For the self-assembly of pure diblock copolymer PEE-b-PEO in dilute solution, the DPD simulation results are in good agreement with experimental data of micelle morphologies and sizes. The chain lengths of the block copolymers and the volume ratios between PPO and PEE-b-PEO are varied to find the conditions of forming multicompartment micelles. The micelles with core-shell-corona structure and the micelles with two compartments are both formed from the mixture of PEE-b-PEO and PPO in aqueous solution.     

Structural effect of a series of block copolymers consisting of poly(N-isopropylacrylamide) and poly(N-hydroxyethylacrylamide) on thermoresponsive behavior

Well-defined diblock and triblock copolymers consisting of poly(N-isopropylacrylamide) (PNIPAM) and poly(N-hydroxyethylacrylamide) (PHEAA) were prepared using the atom transfer radical polymerization (ATRP) method. The number-average molecular weight and fraction of each segment were precisely controllable by adjusting the monomer/initiator ratio in feed. The lower critical solution temperature (LCST) of a series of block copolymers with different compositions was examined using a turbidimetry analysis. The copolymers with a relatively lower molar fraction of HEAA units in the polymer chain exhibited phase transition phenomenon, in which the LCST depended on the fraction in the copolymer. On the other hand, the LCST disappeared for the copolymers with higher HEAA unit molar fractions. The ¹H NMR measurement clarified that the disappearance of the LCST was attributed to the formation of the water-soluble micelle. Furthermore, the thermoresponsive property of the series of block copolymers was elucidated on the basis of the structural effect of the copolymer, which includes the order and length of the block segments.     

Supramolecular self-assembly through inclusion complex formation between poly(ethylene oxide-b-N-isopropylacrylamide) block copolymer and α-cyclodextrin

A well-defined poly(ethylene oxide-block-N-isopropylacrylamide) (PEO-b-PNIPAM) diblock copolymer was synthesized by atom transfer radical polymerization and formed the inclusion complexes (ICs) after selective threading of the PEO segment of the block copolymer through the cavities of α-cyclodextrin (α-CD) units. The formation of the α-CD/PEO ICs between α-CD and PEO segment of the PEO-b-PNIPAM transformed the system from its original random coil conformation into a rod/coil-like structure. The stacking of the α-CD/PEO ICs and phase separation within the α-CD/PEO-b-PNIPAM IC resulted in the self-assembly of long-range-ordered lamellar structure exhibiting alternating layers of (i) α-CD/PEO ICs with hexagonally packed plates and (ii) amorphous phase of unincluded PEO/PNIPAM with brush conformation.     

α‐cyclodextrin assisted self‐assembly of poly(ethylene glycol)‐block‐poly(N‐isopropylacrylamide) in aqueous media

Poly(ethylene glycol)‐block‐poly(N‐isopropylacrylamide) (PEG‐b‐PNIPAM) block copolymers were synthesized by atom transfer radical polymerization, and the α‐cyclodextrin (α‐CD) induced self‐assembly characteristics of the system were elucidated. Below the lower critical solution temperature (LCST) of PNIPAM, CD threaded onto the PEG segments and induced micellization to form rod‐shaped nanostructures comprising of a PEG/α‐CD condensed phase and a PNIPAM shell. Increasing the temperature of system above the LCST caused the PNIPAM segments to collapse, which resulted in the dethreading of the CD. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Synthesis and Self-Assembly of β-Cyclodextrin Terminated DMA/NIPAM Diblock Copolymers

A series of β-cyclodextrin (β-CD) terminated diblock copolymers has been prepared via click reaction. The Huisgen cycloaddition between alkyne decorated copolymer and azide functionalized β-CD was performed in organic solvent in the presence of a Cu(I) catalyst, resulting in the formation of β-CD terminated diblock copolymers, which contain thermally responsive poly(N-isopropylacrylamide) (PNIPAM) block and hydrophilic poly(N,N-dimethylacrylamide) (PDMA) block. Using dynamic light scattering and fluorescence spectroscopy measurements, it is demonstrated that these β-CD functionalized block copolymers are capable of reversibly forming micelles in response to changes in solution temperature and that the critical micelle concentration, micellar size, and transition temperature are dependent on both the NIPAM block length and the polymer functionalization.     

Regular and irregular micelles formed by A LEL triblock copolymer in aqueous solution

Laser light scattering (LLS) techniques were used to characterize the micellization of poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (LEL) triblock copolymer (MW 1K-2K-1K) in aqueous solution. We observed the existence of both thermodynamically stable flower-like micelles (regular micelles) and large, less soluble nanoparticles (irregular micelles) in dilute aqueous solutions with the same preparation procedure. Both kinds of micelles were found to co-exist with single copolymer chains. The initial copolymer concentration determines the nature of the micelles. The regular core-shell micelle formation follows a closed association mechanism, resulting in flower-like micelles. The hydrophobicity of a L unit is estimated as ∼0.5-0.6 B (polyoxybutylene) units from the micellization parameters, which is quite consistent with earlier estimations obtained from EL diblock copolymers.     

Synthesis and micellization of thermo- and pH-responsive block copolymer of poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine)

A novel double-hydrophilic block copolymer poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine) (PNIPAM-b-P4VP) with low polydispersity which could respond to both temperature and pH stimuli in aqueous solution was synthesized by atom transfer radical polymerization. Micellization of the copolymer in aqueous solution was characterized by dynamic and static laser scattering, ¹H NMR and transmission electron microscopy. In aqueous solution, the copolymer existed as unimer at pH 2.8 at 25 °C. When the temperature was raised to 50 °C at pH 2.8, the copolymer associated into spherical core-shell micelles with the PNIPAM block forming the core and the P4VP block forming the shell. On the other hand, when pH was increased from 2.8 to 6.5 at 25 °C, the copolymer associated into spherical core-shell micelles with the core formed by the P4VP block and the shell formed by the PNIPAM block. The process was reversible. The critical aggregation temperature of the block copolymer is 36 °C, and the critical aggregation pH value is 4.7.     

Thermosensitive nanospheres of low-density core - An approach to hollow nanoparticles

A novel strategy for the preparation of hollow core-shell nano- and microparticle is reported. Nanoparticle cores were created from poly(N-isopropylacrylamide) (PNIPAM) by controlled heating above the LCST of this polymer in the presence of a small amount of sodium dodecyl sulfate. Shells were formed by radical copolymerization of 2-hydroxyethyl methacrylate (HEMA) and poly(ethylene glycol) dimethacrylate (PEG-DMA) as cross-linking agent. The PNIPAM particles were acting as nucleating agents so that core-shell colloidal particles of PNIPAM covered with cross-linked PHEMA resulted. Subsequent release of a part of the PNIPAM chains from the interior of the particles was obtained by dialysis. The sizes and the temperature behavior of obtained particles were measured by DLS, TEM and SEM. The semi-hollow particles showed reversible volume response to cyclic temperature changes.     

“Reservoir” and “barrier” effects of ABC block copolymer micelle in hydroxyapatite mineralization control

An amphiphilic triblock poly (ethylene glycol)-block-poly (acrylate acid)-block-poly (ε-caprolactone) (PEG-PAA-PCL) copolymer was synthesized by sequential anionic polymerization. By comparing with diblock copolymer poly (acrylic acid)-block-poly (ε-caprolactone) (PAA-PCL), the triblock copolymer (PEG-PAA-PCL) micelle has core-shell-corona structure, which possesses better dispersion, could be a good candidate as structure template for the controlled mineralization of hydroxyapatite (HA). The interactions between inorganic ions and polymers were studied by using Ca²⁺ ion selective electrode and zeta potential, which indicated the “reservoir” effect of micelles and the “barrier” effect of PEG segments during mineralization process. Ca²⁺ ions can penetrate through the corona and interact with PAA segments. When PO₄³⁻ ions were added, Ca²⁺ ions diffuse out, and react with PO₄³⁻ ions to form the new apatite layer. Thus the supersaturation could be well tuned by the triblock copolymer micelles, and the nucleation and crystal growth in nano scale could be controlled by appropriate usage of this template system.     

Synthesis and characterization of dual stimuli-responsive block copolymers based on poly(N-isopropylacrylamide)-b-poly(pseudoamino acid)

The current study synthesized amphiphilic thermal/pH-sensitive block copolymers PNiPAAm-b-PHpr by condensation polymerization of trans-4-hydroxy-l-proline (Hpr) initiated from hydroxy-terminated poly(N-isopropylacrylamide) (PNiPAAm) as the macroinitiator in the presence of the catalyst, SnOct₂. ¹H NMR, FTIR, and gel permeation chromatography (GPC) characterized these copolymers. Their solutions showed reversible changes in optical properties: transparent below a lower critical solution temperature (LCST) and opaque above the LCST. The LCST values depended on the polymer composition and the media. With critical micelle concentrations (CMCs) in the range of 1.23-3.73 mg L⁻¹, the block copolymers formed micelles in the aqueous phase owing to their amphiphilic characteristics. Increased hydrophobic segment length or decreased hydrophilic segment length in an amphiphilic diblock copolymer produced lower CMC values. The current work proved the core-shell structure of micelles by ¹H NMR analyses of the micelles in D₂O. Transmission electron microscopy analyzed micelle morphology, showing a spherical core-shell structure. The micelles had an average size in the range of 170˜210 nm (blank), and 195˜280 nm (with drug). Observations showed high drug entrapment efficiency and drug-loading content for the drug micelles.     

Block copolymer micelles as carriers of transition metal ions Y(III) and Cu(II) and gelation thereof

Poly(ethylene oxide)-block-poly(2-(diethylamino)ethyl methacrylate) (PEO-b-PDEAEMA) diblock copolymer was synthesized by anionic polymerization, whose molecular structure was characterized by ¹H NMR and size exclusion chromatography (SEC). The diblock copolymer self-assembled into micelles in nonacid aqueous solution with PEO and PDEAEMA as corona and core respectively. By virtue of the coordinating property of PDEAEMA block to metal ions, the resultant micelles were then used as carriers to load metal ions Y(III) and Cu(II) in the micellar core. The morphology and stability of the metal loaded micelles were characterized by dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM). The metal loading amounts were determined by elemental analyses, UV spectrometry and titrimetric analysis. In addition, the Y(III) loaded micelles were demonstrated to complex with α-cyclodextrins and form supramolecular hydrogels in-situ. The metal loaded micelles and the resultant supramolecular hydrogels will have potential application for cancer internal radiotherapy.     

Preparation of block-brush PEG-b-P(NIPAM-g-DMAEMA) and its dual stimulus-response

Well-defined dually responsive block-brush copolymer of poly(ethylene glycol)-b-[poly(N-isopropylacrylamide)-g-poly(N,N-dimethylamino-ethylmethacrylate)], [PEG-b-P(NIPAM-g-PDMAEMA)] was successfully prepared by the combination of atom transfer radical polymerization (ATRP) and click chemistry based on azide-capped PDMAEMA and alkyne-pending PEG-b-PNIPAM copolymer. Azide-capped PDMAEMA was synthesized through ATRP of DMAEMA monomer using an azide-functionalized initiator of β-azidoethyl-2-bromoisobutyrate. Alkyne-pending PEG-b-PNIPAM copolymer was obtained through ATRP copolymerization of NIPAM with propargyl acrylate. The final block-brush copolymer was synthesized by the click reaction between these two polymer precursors. Because of characteristics of three different blocks, the copolymer exhibited dually thermo- and pH-responsive behavior. The responsive behaviors of block-brush copolymer were studied by laser light scattering, temperature-dependent turbidity measurement and micro differential scanning calorimetry. The phase transition temperature of block-brush copolymer increased with the decrease of pH value. At pH = 5.0, the copolymer displayed weak thermo-responsive behavior and might form uni-molecular micelles upon heating. At higher pH values, the block-brush copolymer aggregated intermolecularly into the micelles during the phase transition.     

Catalytic activity of a thermosensitive hydrophilic diblock copolymer-supported 4-N,N-dialkylaminopyridine in hydrolysis of p-nitrophenyl acetate in aqueous buffers

This article reports on the synthesis of a thermosensitive hydrophilic diblock copolymer with the thermosensitive block containing a catalytic 4-N,N-dialkylaminopyridine and the study of the effect of thermo-induced micellization on its catalytic activity in the hydrolysis of p-nitrophenyl acetate (NPA). The block copolymer, poly(ethylene oxide)-b-poly(methoxydi(ethylene glycol) methacrylate-co-2-(N-methyl-N-(4-pyridyl)amino)ethyl methacrylate), was synthesized by ATRP. The critical micellization temperatures (CMTs) of this block copolymer in the pH 7.06 and 7.56 buffers were 40 and 37 °C, respectively. The polymer was used as the catalyst for the hydrolysis of NPA. We found that below CMT, the logarithm of initial hydrolysis rate changed linearly with inverse temperature. With the increase of temperature above CMT, the plot of logarithm of reaction rate versus 1/T leveled off, i.e., the hydrolysis rate did not increase as much as anticipated from the Arrhenius equation. This is likely because the reaction rate at temperatures above CMT was controlled by mass transport of NPA from bulk water phase to the core of micelles where the catalytic sites were located.     

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.