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.     

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.     

Micellization and sol-gel transition of novel thermo- and pH-responsive ABC triblock copolymer synthesized by RAFT

A well-defined thermo- and pH-responsive ABC-type triblock copolymer monomethoxy poly(ethylene glycol)-b-poly(2-(2-methoxyethoxy) ethyl methacrylate-co-N-hydroxymethyl acrylamide)-b-poly(2-(diethylamino) ethyl methacrylate), mPEG-b-P(MEO₂MA-co-HMAM)-b-PDEAEMA, was synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT). The ABC-type triblock copolymer was endowed thermo- and pH-responsive, corresponding to the thermosensitive properties of P(MEO₂MA-co-HMAM) and pH-responsive properties PDEAEMA segments, respectively. The thermo- and pH-responsive properties of copolymer aqueous solutions were studied by UV transmittance measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM). The results showed that the N-hydroxymethyl acrylamide (HMAM) content in triblock copolymer affected the lower critical solution temperature (LCST) of the triblock copolymer aqueous solution. The copolymer self-assembled into core-shell micelles, with the thermoresponsive P(MEO₂MA-co-HMAM) block and the hydrophilic PEG block as the shell, the hydrophobic PDEAEMA block as the core, in alkaline solution at room temperature. While in acidic media, when the temperature above the lower critical solution temperature (LCST) of the triblock copolymer aqueous solution, the copolymer self-assembled into P(MEO₂MA-co-HMAM)-core micelles with mixed hydrophilic PEG and pH-responsive PDEAEMA coronas. Sol-gel transition temperature (T_sol-gel) for the triblock copolymer determined by vial inversion test further indicated that it is dependent on the concentration of the triblock copolymers and solution pH. Copolymer hydrogel loaded with bovine serum albumin (BSA) were used for the sustained release study. The results indicated that the hydrogel was a promising candidate for controlling protein drug delivery.     

Synthesis of sharply thermo and PH responsive PMA-b-PNIPAM-b-PEG-b-PNIPAM-b-PMA by RAFT radical polymerization and its schizophrenic micellization in aqueous solutions

Sharply thermo- and pH-responsive pentablock terpolymer with a core-shell-corona structure was prepared by RAFT polymerization of N-isopropylacrylamide and methacrylic acid monomers using PEG-based benzoate-type of RAFT agent. The PEG-based RAFT agent could be easily synthesized by dihydroxyl-capped PEG with 4-cyano-4-(thiobenzoyl) sulfanylpentanoic acids, using esterification reaction. This pentablock terpolymer was characterized by ¹H NMR, FT-IR, and GPC. The PDI was obtained by GPC, indicating that the molecular weight distribution was narrow and the polymerization was well controlled. The thermo- and pH-responsive micellization of the pentablock terpolymer in aqueous solution was investigated using ?uorescence spectroscopy technique, UV–vis transmittance, and TEM. The LCST of pentablock terpolymer increased (over 50 °C) compared to the NIPAM homopolymer (~32 °C), due to the incorporation of the hydrophilic PEG and PMA blocks in pentablock terpolymer (PNIPAM block as the core, PEG the block and the hydrophilic PMA block as the shell and the corona). Also, pH-dependent phase transition behavior shows at a pH value of about ~5.8, according to pKa of MAA. Thus, in acidic solution at room temperature, the pentablock terpolymer self-assembled to form core–shell–corona micelles, with the hydrophobic PMA block as the core, the PNIPAM block and the hydrophilic PEG block as the shell and the corona, respectively.     

Functionalization of amphiphilic coil-rod-coil triblock copolymer poly(2-vinylpyridine)-b-poly(n-hexyl isocyanate)-b-poly(2-vinylpyridine) with florescence moiety and C60

We recently achieved quantitative synthesis of an amphiphilic coil-rod-coil triblock copolymer, poly(2-vinylpyridine)-b-poly(n-hexyl isocyanate)-b-poly(2-vinylpyridine), by coupling in situ living diblock copolymer poly(2-vinylpyridine)-b-poly(n-hexyl isocyanate) (P2VP-b-PHIC) using malonyl chloride in the presence of pyridine. This led to the introduction of an active methylene group that is a site for further functionalization in the rod block. The Michael addition reaction of the triblock copolymer with 7-(4-trifluoromethyl) coumarin acrylamide led to copolymer bearing a fluorescent pendent in the rod block. The fluorescent labeled copolymers were isolated in ∼94% yields. Similarly C₆₀ pendent was introduced to the rod block by the Bingel reaction. The yields of C₆₀ functionalized copolymers were ∼54%. The precursor and functionalized amphiphilic coil-rod-coil copolymer show diverse morphologies, such as micelles and vesicles by simply changing the solvent. For the C₆₀ functionalized block copolymer, structural constraints in micelles and vesicles prevented C₆₀ pendents to aggregate.     

Synthesis and the effect of hydrophobic dodecyl end groups on pH-responsive micellization of poly(acrylic acid) and poly(ethylene glycol) triblock copolymer in aqueous solution

A pH-responsive triblock copolymer of poly(acrylic acid)-b-poly(ethylene glycol)-b-poly(acrylic acid) containing hydrophobic dodecyl end groups (C₁₂H₂₅-PAA-b-PEG-b-PAA-C₁₂H₂₅) with narrow molecular weight distribution (M _w/M _n?=?1.30) was synthesized via reversible addition-fragmentation chain transfer polymerization of acrylic acid (AA). Poly(ethylene glycol) (PEG) capped with S-1-dodecyl-S??-(??,????-dimethyl-????-acetic acid) trithiocarbonate (DDATC) end groups was used as the macro chain transfer agent (PEG macro-CTA) and 2,2??-azobisisobutyronitrile (AIBN) as initiator for monomer acrylic acid. The effect of the hydrophobic dodecyl end groups on pH-sensitive self-association of C₁₂H₂₅-PAA-b-PEG-b-PAA-C₁₂H₂₅ in aqueous solution was investigated by fluorescence spectroscopy, dynamic light scattering and atomic force microscope. At pH ??5.5, the solution behavior of C₁₂H₂₅-PAA-b-PEG-b-PAA-C₁₂H₂₅ is like polyelectrolyte in aqueous solution, and the effect of dodecyl end groups is negligible. At pH <5.0, the hydrophobic dodecyl end groups contribute dominantly to the pH-sensitive micellization and result in the formation of micelles with stronger hydrophobicity and larger size at low concentration (critical micelle concentration is 0.062?g/L). In the range of pH 2.5?C3.5, the steady (R _h????35.0?nm) and narrow size distributed micelles (polydispersity index, PDI?<?0.2) can be obtained. The micelles formed by C₁₂H₂₅-PAA-b-PEG-b-PAA-C₁₂H₂₅ triblock copolymer in acidic solution are expected to have a core?Cshell?Ccorona structure, where the hydrophobic dodecyl groups form the core, and weak hydrophobic PAA/PEG hydrogen-bonded complexes form the shell and the uncomplexed PAA, and PEG chain segments form the corona.     

Phase separation of polystyrene-b-(ethylene-co-butylene)-b-styrene (SEBS) deposited on polystyrene thin films

Phase separation of a triblock copolymer, polystyrene-b-(ethylene-co-butylene)-b-styrene (SEBS) on the thin films of a homopolymer, polystyrene (PS), was studied by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The final morphology after phase separation was found to be greatly dependent on the relation between the molecular weight of the PS block and homo-PS. Dispersed spherical and worm-like micelles of SEBS were observed when the molecular weight of homo-PS is smaller than the PS block in SEBS, while large structures with inner micro-phase separation of SEBS was found when the molecular weight of homo-PS was much higher than that of the PS block. The origin of such a change in morphology is attributed to the difference of structure and interfacial tension at the interface between the matrix homo-PS and the PS block in SEBS triblock copolymer assembly.     

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.     

Simple and facile synthesis of aryl benzoates from stabilized arenediazonium tetrafluoroborate using a recyclable polymer-supported benzoate ion

Temperature-responsive P(NIPAM-co-HMAM)-b-PEO-b-P(NIPAM-co-HMAM) triblock copolymers were synthesized by an atomic transfer radical polymerization (ATRP) method without freeze?Cpump?Cthaw cycles. The composition, structure, and molecular weight of the synthesized block copolymer were characterized by ¹?H NMR and GPC. The phase transitions induced by temperature for different copolymers in dilute aqueous solutions have been studied using transmittance measurements, laser particle size measurements, viscosity analysis, and surface tension measurement, which showed that the HMAM content and the PEO (or PEG) chain length in the synthesized triblock copolymer affects the copolymer??s lower critical solution temperature (LCST). The micellization behavior of each temperature-responsive triblock copolymer was investigated by fluorescence probe measurements and transmission electron microscopy (TEM), which showed that the triblock copolymers form stable micelles above the LCST. The introduction of the HMAM component and the formation of micelles represent the first steps in the development of an injectable gel that forms in situ through chemical and physical crosslinking.     

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.     

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.     

Biodegradable depsipeptide–PDO–PEG-based block copolymer micelles as nanocarriers for controlled release of doxorubicin

Nowadays, biodegradable amphiphilic block copolymers with stable performance and adjustable structure have attracted the interests of researchers in the field of drug delivery. In this work, the triblock copolymer, P(SBMD-co-PDO)-b-PEG-b-P(SBMD-co-PDO), was successfully synthesized by ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione (SBMD) and p-dioxanone (PDO) with poly(ethylene glycol) (PEG) as the initiator. In phosphate buffered solution (PBS), these copolymers could self-assemble into nano-sized micelles that have a hydrophobic P(SBMD-co-PDO) core surrounded by a hydrophilic PEG shell. Because of the strong hydrogen bonding and hydrophobic interactions, doxorubicin (DOX) was loaded into the micelles with high loading capacity (LC, up to 28.4%) and encapsulation efficiency (EE, up to 62.5%). The drug-loaded micelles showed sustained-release of DOX along with the hydrolytic degradation of the micelles in PBS. Therefore, these amphiphilic triblock copolymers have potential as drug matrix for controlled release.     

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.     

Self‐assembly and drug delivery behaviors of thermo‐sensitive poly(t‐butyl acrylate)‐b‐poly(N‐isopropylacrylamide) micelles

Self‐assembly of thermo‐sensitive poly (t‐butyl acrylate)‐b‐poly(N‐isopropylacrylamide) (PtBA‐ b‐PNIPAM) micelles in aqueous medium and its applications in controlled release of hydrophobic drugs were described. PtBA‐b‐PNIPAM was synthesized by atom transfer radical polymerization and aggregated into thermo‐sensitive core‐shell micelles with regular spheres in water, which was confirmed by ¹H‐NMR, fluorescence spectroscopy, transmission electron microscopic (TEM), and UV–vis spectroscopic techniques. The critical micelle concentration of micelles decreased with the increase of the hydrophobic components. The anti‐inflammation drug naproxen (NAP) was loaded as the model drug into polymeric micelles, which showed a dramatic thermo‐sensitive fast/slow switching behavior around the lower critical solution temperature (LCST). When the temperature was enhanced above LCST, release of NAP from core‐shell micelles was accelerated ascribed to the temperature‐induced deformation of micelles. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Thermoresponsive self‐assembled nanovesicles based on amphiphilic triblock copolymers and their potential applications as smart drug release carriers

A series of thermoresponsive triblock copolymers, methoxy poly(ethylene oxide)‐b‐poly(ε‐caprolactone)‐b‐poly(N‐isopropylacrylamide) (mPEO‐b‐PCL‐b‐PNIPAM), with different PCL and PNIPAM block lengths, were synthesized by a combination of ring opening polymerization and reversible addition‐fragmentation chain transfer polymerization techniques. The triblock copolymers undergo self‐assembly in aqueous solutions forming stable nanovesicles of various sizes with a lipid membrane structure similar to body cells as revealed by transmission electron microscopy. The nanovesicle is thermoresponsive, that is, its size is tunable using the temperature as a switch: shrinks at a temperature above the lower critical solution temperature (LCST) and expands at a temperature below the LCST. The corresponding LCST of the triblock copolymers is adjustable by varying the PNIAM segment length as well as the PCL segment length and covers a range from 33.9 to 41.0°C in water. The diameter of nanovesicles for mPEO_3k‐b‐PCL_5k‐b‐PNIPAM_13.2k is about 177.7 nm below the LCST and 138.9 nm above the LCST, as determined by dynamic light scattering. It was demonstrated using indomethacin, a popular anti‐inflammation medicine, that the triblock copolymers can effectively act as a drug release carrier under the right human physiological conditions, that is, store the drug at a lower temperature and release it at a higher temperature, possibly targeting at the lesion sites of human body. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41361.     

Multifunctional and thermoresponsive unimolecular micelles for tumor-targeted delivery and site-specifically release of anticancer drugs

Considering the fact that tumors have a lower pH value and a higher temperature than a normal tissue, a new type of thermoresponsive and biodegradable micelles, based on the H40-poly(?-caprolactone)-b-poly(N-isopropylacrylamide-co-acrylamide)-fluorescein methyl ester/b′-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate (i.e., H40-PCL-b-P(NIPAAm-co-AAm)-FL/b′-MPEG/PEG-FA (HPPNAP-FA)) with imaging and targeting moieties on the periphery were developed for the tumor-targeted delivery and temperature-induced site-specifically release of hydrophobic anticancer drugs. The amphiphilic HPPNAP-FA copolymer was able to self-assemble into unimolecular micelles in aqueous solution with an average diameter of 65 nm. The lower critical solution temperature (LCST) of micelles was around 39.5 °C. The anticancer drug, paclitaxel (PTX), was encapsulated into the multifunctional micelles. In vitro release studies demonstrated that the drug-loaded delivery system is relatively stable at physiologic conditions but susceptible to mild acidic environments and temperatures above LCST which would trigger the release of encapsulated drugs. Both flow cytometry and fluorescent microscopy showed that the cellular uptake of the PTX-loaded HPPNAP-FA micelles is higher than that of the PTX-loaded HPPNAP because of the folate receptor mediated endocytosis. The efficacy of this thermoresponsive drug delivery system was also evaluated at temperatures above the LCST (40 °C); the results demonstrated that the cellular uptake and the cytotoxicity of PTX-loaded micelles increase prominently. These results indicate that these multifunctional and thermoresponsive unimolecular micelles are promising biomaterials to improve the delivery efficiency and cancer specificity of hydrophobic chemotherapeutic drugs.     

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.     

Thermoresponsive behaviour in aqueous solution of poly(maleic acid‐alt‐vinyl acetate) grafted with poly(N‐isopropylacrylamide)

The synthesis of a thermoresponsive graft copolymer consisting of a maleic acid/vinyl acetate alternating copolymer backbone (MAc‐alt‐VA) and poly(N‐isopropylacrylamide) (PNIPAM) side chains is reported. Turbidimetric measurements in dilute aqueous solutions showed that no macroscopic phase separation takes place when the temperature is raised above the lower critical solution temperature (LCST) of PNIPAM, even at pH = 2. Moreover, in semi‐dilute aqueous solutions, a pronounced thermally induced viscosity increase (thermothickening) was observed. This thermoresponsive behaviour has been attributed to the interconnection of the hydrophilic MAc‐alt‐VA graft copolymer backbones by means of the hydrophobic PNIPAM side chain aggregates formed as the temperature increases above the LCST of this polymer. Copyright © 2004 Society of Chemical Industry