Synthesis and self-association in aqueous media of poly(ethylene oxide)/poly(ethyl glycidyl carbamate) amphiphilic block copolymers

New temperature sensitive AB, ABA, and BAB amphiphilic block copolymers consisting of hydrophilic poly(ethylene oxide) and hydrophobic poly(ethyl glycidyl carbamate) blocks were synthesized by anionic polymerization followed by chemical modification reactions. The self-association of the block copolymers in aqueous media was studied by UV-vis spectroscopy and dynamic and static light scattering. The obtained block copolymers spontaneously form micelles in aqueous media. The critical micellization concentration varied from 0.5 to 4 g/L depending on the copolymer architecture and composition. The influence of the temperature upon the self-association of the block copolymers was investigated. The increase of temperature did not affect the value of the critical micellization concentration, but led to the formation of better defined micelles with narrow size distribution.     

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.     

Doubly thermo-responsive brush-linear diblock copolymers and formation of core-shell-corona micelles

Doubly thermo-responsive brush-linear diblock copolymer of poly[poly(ethylene glycol) methyl ether vinylphenyl]-block-poly(N-isopropylacrylamide) (PmPEGV-b-PNIPAM) is prepared by RAFT polymerization. The obtained brush-linear diblock copolymer exhibits two lower critical solution temperatures (LCSTs) corresponding to the linear poly(N-isopropylacrylamide) (PNIPAM) block and the brush poly[poly(ethylene glycol) methyl ether vinylphenyl] (PmPEGV) block in water. This brush-linear diblock copolymer undergoes a two-step temperature sensitive micellization. At temperature above the first LCST, the brush-linear diblock copolymer self-assembles into core-corona micelles with the dehydrated PNIPAM block forming the core and the solvated brush PmPEGV block forming the corona. When temperature increases above the second LCST, the polystyrene backbone in the brush PmPEGV block collapses onto the dehydrated PNIPAM core to form core-shell-corona micelles, in which the dehydrated PNIPAM block forms the core, the collapsed polystyrene backbone in the brush PmPEGV block forms the shell and the solvated poly(ethylene glycol) side-chains forms the corona. The effect of the length of the PNIPAM block and the length of the poly(ethylene glycol) side-chains on the thermo-responsive micellization and the size of core-shell-corona micelles is investigated.     

Nanostructured silica templated by double hydrophilic block copolymers with a comb-like architecture

An original way to synthesize nanostructured materials is to use new structuring agents constituted of double hydrophilic block copolymers (DHBC). The originality of these structuring agents is multiple: in water, the hydrosoluble DHBC copolymers can become amphiphilic and form micelles in specific conditions, i.e. after addition of other molecules or after a change of a physicochemical parameter (pH), which selectively makes one of the blocks insoluble in water. The addition of a silica precursor to a micelle suspension can lead to the formation of hybrid mesostructured materials, precursors for mesoporous silica. The micellization process may be reversible and the micelles can then be removed from the silica materials in an aqueous solution at room temperature after application of a dissociation stimulus, leading to the mesoporous materials. A new original DHBC is used here for silica structuring: instead of a classical linear diblock copolymer, it is a diblock copolymer with a linear polyacid block (PAA) and a poly(ethylene oxide) based neutral block (PAMPEO) with a comb-type architecture. It is synthesized by controlled radical polymerization (RAFT method) which permits a control of the block lengths. It is shown here that these new DHBC polymers can form polyion complex micelles by complexation with a natural polyamine and that the micellization is reversible as a function of the pH. It is also shown that the new pH sensitive micelles can act as structuring agents in the preparation of mesoporous silica materials.     

Synthesis and pH-dependent micellization of 2-(diisopropylamino)ethyl methacrylate based amphiphilic diblock copolymers via RAFT polymerization

The polymerization of 2-(diisopropylamino)ethyl methacrylate (DPA) by RAFT mechanism in the presence of 4-cyanopentanoic acid dithiobenzoate in 1,4-dioxane was studied. The DPA homopolymer was employed as a macro chain transfer agent to synthesize pH-sensitive amphiphilic block copolymers using poly(ethylene glycol) methyl ether methacrylate (PEGMA) as the hydrophilic block. ¹H NMR and GPC measurements confirmed the successful synthesis of these copolymers. Potentiometric titrations and fluorescence experiments proved that the copolymers underwent a sharp transition from unimers to micelles at a pH of ∼6.7 in phosphate buffered saline solutions. It was found that the hydrophilic/hydrophobic balance of these block copolymers had no apparent effect on their pH-induced micellization behaviors. The DLS investigation revealed that the micelles have a mean hydrodynamic diameter below 60 nm with a narrow size distribution.     

pH/temperature sensitive poly(ethylene glycol)-based biodegradable polyester block copolymer hydrogels

Novel pH and temperature sensitive biodegradable block copolymers composed of poly(ethylene glycol) (PEG), polyglycolide (GA), ?-caprolactone (CL) and sulfamethazine oligomers (OSMs) were synthesized by ring opening polymerization and 1,3-dicyclohexyl-carbodiimide (DCC) mediated coupling reactions. Their physicochemical properties in aqueous media were characterized by ¹H NMR spectroscopy and gel permeation spectroscopy. The sol-gel phase transition behavior of OSM-PCGA-PEG-PCGA-OSM block copolymers was investigated both in solution and injection to PBS buffer at pH 7.4 and 37 °C. Aqueous solutions of OSM-PCGA-PEG-PCGA-OSM changed from a sol to a gel phase with increasing temperature and decreasing pH. The sol-gel transition properties of these block copolymers are influenced by the hydrophobic/hydrophilic balance of the copolymers, block length, hydrophobicity, stereoregularity of the hydrophobic components within the block copolymer, and the ionization of the pH functional groups in the copolymer, which depends on the environmental pH. Degradation of the triblock and pentablock copolymers at 37 °C (pH 7.4), and at 0 °C and 5 °C both at pH 8.0, was investigated. It was demonstrated here using the in vitro test method, that the anticancer agent paclitaxel (PTX) could be loaded and released by the pH and temperature sensitive OSM-PCGA-PEG-PCGA-OSM block copolymer, such that this could be used as a suitable matrix for subcutaneous injection in drug delivery systems.     

Fabrication of core or shell reversibly photo cross-linked micelles and nanogels from double responsive water-soluble block copolymers

Poly(butanedioic acid, 1-[3-[(2-methyl-1-oxo-2-propen-1-yl)oxy]propyl] ester)-b-poly(methoxydi(ethylene glycol) methacrylate-co-4-methyl-[7-(methacryloyl)oxyethyloxy] coumarin) (PSPMA-b-P(DEGMMA-co-CMA)) block copolymer was synthesized via atom transfer radical polymerization (ATRP). The temperature and pH responsive micellization behaviors of PSPMA-b-P(DEGMMA-co-CMA) were investigated to obtain P(DEGMMA-co-CMA)-core and PSPMA-core micelles. After the two types of micelles were exposed to 365 nm UV light, core cross-linked (CCL) micelles and shell cross-linked (SCL) micelles were facilely prepared. The photo cross-linking was proved to be reversibly controlled under alternative irradiation of 365 nm and 254 nm UV light. More interestingly, block copolymer nanogels were fabricated by translating the hydrophobic core of the CCL and SCL micelles into hydrophilic via adjusting the temperature and pH. The sizes of the block copolymer nanogels can be facilely controlled by UV light irradiation. The introduction of reversibly photo cross-linkable groups into the double responsive block copolymers provides a novel approach to develop more sophisticated, controllable, and smarter nanocarriers that might have great potentials in biomedical applications.     

A tumor-targeting nano doxorubicin delivery system built from amphiphilic polyrotaxane-based block copolymers

Amphiphilic polyrotaxane (PR)-based block copolymers are synthesized by end-capping polypseudorotaxanes (PPRs) formed from distal 2-bromopropionyl terminated Pluronic F68 and a varying amount of β-cyclodextrins (β-CDs) using hydrophilic polymeric blocks of poly(ethylene glycol) methyl ether methacrylate (PEGMA) yielded via the in situ ATRP. To gain a tumor-targeting nano doxorubicin (DOX) delivery system for cancer chemotherapy, an active tumor-targeting ligand, folic acid (FA), is conjugated to the two ends of the resulting copolymers through “azide-ethylene click chemistry”. The conjugated copolymers enable to self-assemble into unique core–shell structured micelles in aqueous solution and to load DOX into the hydrophobic core. The drug loading content is increased from 2.0 wt% to 25.5 wt% with respect to the blank block copolymer most likely due to the hydrogen bond interaction between DOX and β-CDs threaded. After drug loading, the size of the micelles is enlarged from 120 nm to 220 nm in diameter as determined by dynamic light scattering (DLS) analysis. Moreover, these tumor-targeted polymeric micelles exhibit a slower and sustained DOX release behavior. The cell uptake and distribution, as well as the cytotoxicity of the polymeric micelles are also evaluated toward the MDA-MB-231 cells. The FA-conjugated PR-based block copolymer micelles appear to be internalized by the cancer cells via FA receptor mediated endocytosis; thus, they present enhanced cytotoxicity to the selected breast cancer cells.     

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.     

RAFT polymerization of temperature- and salt-responsive block copolymers as reversible hydrogels

Reversible-addition fragmentation chain transfer (RAFT) polymerization enabled the synthesis of novel, stimuli-responsive, AB and ABA block copolymers. The B block contained oligo(ethylene glycol) methyl ether methacrylate (OEG) and was permanently hydrophilic in the conditions examined. The A block consisted of diethylene glycol methyl ether methacrylate (DEG) and [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMA). The A block displayed both salt- and temperature-response with lower critical solution temperatures (LCSTs) dependent on the molar content of TMA and the presence of salt. Higher TMA content in the AB diblock copolymers increased the critical micelle temperatures (CMT) in HPLC-grade water due to an increased hydrophilicity of the A block. Upon addition of 0.9 wt% NaCl, the CMTs of poly(OEG-b-DEG₉₅TMA₅) decreased from 50 °C to 36 °C due to screening of electrostatic repulsion between the TMA units. ABA triblock copolymers displayed excellent hydrogel properties with salt- and temperature-dependent gel points. TMA incorporation in the A block increased the gel points for all triblock copolymers, and salt-response increased with higher TMA composition in the A block. For example, poly(DEG₉₈TMA₂-b-OEG-b-DEG₉₈TMA₂) formed a hydrogel at 40 °C in HPLC-grade water and 26 °C in 0.9 wt% NaCl aqueous solution. These salt- and temperature-responsive AB diblock and ABA triblock copolymers find applications as drug delivery vehicles, adhesives, and hydrogels.     

Amphiphilic mPEG-block-poly (profen amide-co-esters) copolymers: One pot biocatalytic synthesis, self-assembly in water and drug release

We developed a three-component, one pot biocatalytic polymerization to prepare amphiphilic diblock methoxy poly(ethylene glycol)-b-poly(profen amide -co- esters) (mPEG-PPAE) copolymers under the catalysis of Novozym-435 performed in diphenyl ether at 85 °C in vacuum for 48 h. Thirteen mPEG-PPAE copolymers with different profens, dicarboxylates, or PEG were designed and prepared as carriers for the sustained release of the ketoprofen, naproxen and ibuprofen amides. Their structure was characterized by FT-IR, ¹H NMR and GPC measurements. These copolymers can readily self-assemble into nanosized micelles with the well dispersed sphere in aqueous solution, which were confirmed by DLS and TEM. The size of the micelles was influenced by the copolymer concentrations, and the higher copolymer concentration lead to the smaller size. The in vitro ibuprofen amide sustained release behavior indicated that the copolymer is highly sensitive to acid environment, and the release of ibuprofen amide can be effectively controlled.     

Effect of PEO-PPO-PEO structure on the compressed ethylene-induced reverse micelle formation and water solubilization

Some of the poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymers aggregate in p-xylene upon addition of ethylene and form reverse micelles at higher temperature at which the reverse micelles cannot be formed without addition of compressed ethylene. An abrupt increase of water solubilization is observed at a certain ethylene pressure. The effects of surfactant structure, such as the ratio of EO (EO weight percent) and the molecular mass, on the copolymer micellization and the solubilization of water in such systems are studied. For the copolymers with the same length of PO block, higher EO ratios facilitate the reverse micelle formation. However, as the EO ratio reaches 70%, it cannot form reverse micelles because the hydrophilicity is too high. For the copolymers with same composition, higher molecular weight is favorable to forming the reverse micelle due to the hydrophilic and folding effects, respectively. The reverse micelle solution can solubilize water with W₀ (molar ratio of water to EO segment) up to 4.1.     

Vesicle formation of polystyrene-block-poly (ethylene oxide) block copolymers induced by supercritical CO2 treatment

A novel route for a preparation of polystyrene-block-poly(ethylene oxide) (PS-b-PEO) block copolymer vesicles induced by supercritical carbon dioxide (scCO₂) is demonstrated. When PS-b-PEO block copolymer solutions in tetrahydrofuran (THF) are treated with scCO₂ at 70 °C for different times, PS-b-PEO copolymers first assemble into aggregated spheres; then aggregated spheres change into large compound micelles and finally evolve into vesicles. The possible formation mechanism of the vesicles is discussed.     

Polymeric micelles based on photocleavable linkers tethered with a model drug

An amphiphilic block copolymer with photocleavable nitrobenzyl moieties in the side chain of the hydrophobic block was successfully synthesized by a combination of atom transfer radical polymerization (ATRP) and the Cu(I)-catalyzed 1,3-dipolar cycloaddition of azide and alkynes. 2-(Trimethylsilyloxy)ethyl methacrylate (HEMATMS) was polymerized from a poly(ethylene oxide) (PEO) macroinitiator via ATRP, leading to a well-defined block copolymer of PEO₁₁₃-b-PHEMATMS₄₅ with low polydispersity index (PDI = 1.09). After the polymerization, trimethylsilyl (TMS) groups were deprotected and then functionalized in-situ with 3-azidopropionic chloride to yield PEO-b-[2-(1-azidobutyryloxy)ethyl methacrylate] (PEO-b-PAzHEMA). Alkyne-functionalized pyrene with a photocleavable 2-nitrobenzyl moiety was added to the PEO-b-PAzHEMA backbone via click chemistry to produce the desired block copolymer with high fidelity. The resulting block copolymer was self-assembled in water to yield spherical micelles with an average diameter of 60 nm. Upon UV irradiation, 2-nitrobenzyl moieties were selectively cleaved, leading to the release of a model drug, 1-pyrenebutyric acid. Coumarin 102, another model drug that was physically encapsulated in the core of micelles during micellization in water, was also released at the same time. The general strategy presented herein can potentially be utilized for the preparation of polymeric vehicles that are capable of delivering multiple therapeutics under controlled individual release kinetics.     

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.     

The Synergism Effect Between Sodium Dodecylbenzene Sulfonate and a Block Copolymer in Aqueous Solution

The synergistic behavior of sodium dodecylbenzene sulfonate (SDBS) with poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) block copolymer was studied using surface tension measurements. The surface tension of single and mixed solutions of SDBS and the block copolymer in this study was measured at different concentrations and at 25 °C. The critical micelle concentration (CMC) of these solutions was determined from the surface tension measurements. The SDBS gives higher CMC values than those of the block copolymer. The results show that the CMC value of SDBS decreases as the molar ratio of SDBS increases in the mixture solution with the block copolymer. The surface parameters of adsorption and micellization for single and mixed solutions were investigated. The results show that the surface and micellization properties of SDBS were improved as a result of mixing with the block copolymer. The mole fractions in the micelles and interaction parameters of the mixed solutions were calculated. The foam stability of single and mixed solutions at 25 °C was determined. The results show that the SDBS has more foam stability than the block copolymer and the foam stability increases as the molar ratio of SDBS increase in mixed solution of it with block copolymer.

Synthesis and physicochemical characterization of amphiphilic block copolymers bearing acid-sensitive orthoester linkage as the drug carrier

Amphiphilic block copolymers bearing an acid-sensitive orthoester linkage, composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(γ-benzyl L-glutamate) (PBLG), were prepared as the carrier capable of selectively releasing the hydrophobic drug at the mildly acidic condition. Diblock copolymers with various lengths of PBLG were synthesized via ring opening polymerization of benzyl glutamate NCA in the presence of the acid-labile PEG as a macroinitiator. Owing to their amphiphilicities, the copolymers formed spherical micelles in aqueous conditions, and their particle sizes (22-106 nm in diameter) were dependent on the block length of PBLG. These nanoparticles were stable in the physiological buffer (pH 7.4), whereas they were readily decomposed under the acidic condition. In particular, the block copolymer with a smaller hydrophobic portion was rapidly disassembled under the acidic condition. Doxorubicin (DOX), chosen as the model anti-cancer drug, was effectively encapsulated into the hydrophobic core of the micelles using the solvent casting method. The loading efficiency depended on the hydrophobic block length of the copolymer; i.e., the longer hydrophobic block allowed for loading of larger amounts of the drug. In vitro release studies demonstrated that DOX was slowly released from the pH-sensitive micelles in the physiological buffer (pH 7.4), whereas the release rate of DOX significantly increased under the acidic condition (pH 5.0). From the in vitro cytotoxicity test, it was found that DOX-loaded pH-sensitive micelles showed higher toxicity to SCC7 cancer cells than DOX-loaded micelles without the orthoester linker. These results suggest that the amphiphilic block copolymer bearing the orthoester linkage is useful for pH-triggered delivery of the hydrophobic drug.     

pH-Sensitive Micelles Based on Double-Hydrophilic Poly(methylacrylic acid)-Poly(ethylene glycol)-Poly(methylacrylic acid) Triblock Copolymer

pH-sensitive micelles with hydrophilic core and hydrophilic corona were fabricated by self-assembling of triblock copolymer of poly(methylacrylic acid)-poly(ethylene glycol)-poly(methylacrylic acid) at lower solution pH. Transmission electron microscopy and laser light scattering studies showed micelles were in nano-scale with narrow size distribution. Solution pH value and the micelles concentration strongly influenced the hydrodynamic radius of the spherical micelles (48–310 nm). A possible mechanism for the formation of micelles was proposed. The obtained polymeric micelle should be useful for biomedical materials such as carrier of hydrophilic drug.     

Sustained release of ibuprofen from polymeric micelles with a high loading capacity of ibuprofen in media simulating gastrointestinal tract fluids

Amphiphilic diblock copolymers with poly(ethylene glycol) as the hydrophilic block and a random copolymer of n-butyl methacrylate or styrene and (N,N-diethylamino)ethyl methacrylate as the hydrophobic block were prepared by atom transfer radical polymerization (ATRP). Ibuprofen, a model drug that contains a carboxylic group and hydrophobic moiety, was loaded into micelles formed from the amphiphilic diblock copolymers by a combination of ionic interaction and hydrophobic effect. The loading capacity of ibuprofen in the micelles reached 60%. Loaded ibuprofen was released in a sustained fashion into media simulating gastric fluid (pH 1.6, 2 h), small intestinal fluid (pH 7.4, 4 h), and colon fluid (pH 6.7, 18 h). Simulating the case of oral administration at 2 doses per day, loaded ibuprofen was released almost linearly against time after the second dose in media simulating human gastrointestinal tract fluids.     

Association behavior of thermo-responsive block copolymers based on poly(vinyl ethers)

Thermo-sensitive nanosized structures have been prepared in water from poly(methyl vinyl ether)-block-poly(isobutyl vinyl ether) (PMVE-b-PIBVE) block copolymers. The composition and the architecture (diblock and triblock architectures) of the PMVE-b-PIBVE copolymers have been varied. The investigated copolymers had an asymmetric composition with a major PMVE block. While the PIBVE blocks are hydrophobic, the PMVE blocks are hydrophilic at room temperature and become hydrophobic above their demixing temperature (around 36 °C) as a result of the lower critical solution temperature (LCST) behavior. At room temperature, the amphiphilic copolymers aggregate in water above a critical micelle concentration, which has been experimentally measured by hydrophobic dye solubilization. The hydrodynamic diameter of the structures formed above the cmc has been measured by dynamic light scattering (DLS) while their morphology has been studied by transmission electron microscopy (TEM). ¹H NMR measurements in D₂O at room temperature reveal that the aggregates contain PIBVE insoluble regions surrounded by solvated PMVE chains. These investigations have shown that polydisperse spherical micelles are formed for asymmetric PMVE-b-PIBVE copolymers containing at least 9 IBVE units. For copolymers containing less IBVE units, loose aggregates are formed.Finally, the thermo-responsive, reversible properties of these structures have been investigated. Above the cloud point of the copolymers, the loose aggregates precipitate while the micelles form large spherical structures.