Critical Micelle Temperature Research Articles

A quantitative recipe for engineering protein polymer nanoparticles

Protein polymers can assemble switchable nanostructures with emerging applications as biomaterials and nanomedicines. For example, above a critical micelle temperature (CMT) some elastin-like polypeptide (ELP) diblock copolymers assemble spherical nanoparticles, which may modulate cellular internalization and in vivo biodistribution. To achieve engineering-level control over their properties, this report explores a comprehensive library of ELP monoblock and diblock polymers. For the first time, we report that a surprisingly high core molecular weight is required for stable nanoparticle formation; furthermore, nanoparticle size depends on polymer molecular weight. A mathematical model was developed to characterize four ELP monoblock libraries and to predict the phase behavior of corresponding diblock copolymers. The CMT was almost entirely dependent on the hydrophobic core ELP, while the bulk phase transition temperature (Tt,bulk ) depends predominantly on the hydrophilic block. Nanoparticle assembly was accompanied by a conversion in secondary structure of the hydrophobic block from random coil and beta-sheets to type-2 β turns. For the first time, this report enables the rational design of ELP protein polymer nanoparticles with physico-chemico properties that will be suitable for biological applications.

Self-Assembled Glucose and Thermo Dual-Responsive Micelles of an Amphiphilic Graft Copolymer

Amphiphilic copolymers P(PBA)-g-P(PEG) containing poly(phenylboronic acid) (PPBA) and poly(ethylene glycol) (PEG) side chains were synthesized by copolymerization of 4-vinylphenylboronic acid (PBA) and poly(ethylene glycol) methyl ether methacrylate. The surface tension results showed that the critical micelle concentration (CMC) of P(PBA)-g-P(PEG) was 0.09 g/L. TEM revealed that these copolymers self-assembled into regular sphere micelles above CMC. The photon correlation spectroscopy suggested that they had unique performance of thermo-induced self-assembly. Above critical micelle temperature, they self-assembled into monodisperse micelles with thermosensitivity. Hydrodynamic diameters of these micelles increased dramatically in the presence of glucose. The glucose-regulated drug release behavior was observed through UV-vis spectroscopy.

Dual pH‐ and Temperature‐Responsive Metallosupramolecular Block Copolymers with Tunable Critical Micelle Temperature by Modulation of the Self‐Assembly of NIR‐Emissive Alkynylplatinum(II) Complexes Induced by Changes in Hydrophilicity and Electrostatic Effects

Terpyridylplatinum(II)-based metallosupramolecular triblock copolymers with hydrophilic alkynyl ligands have been synthesised and characterised. As a result of the intrinsic properties of Pluronics, reversible temperature-induced micellisation occurred at high temperature leading to aggregation of the platinum(II) complex moieties through Pt⋅⋅⋅Pt and π-π interactions, resulting in significant UV/Vis absorption and near-infrared (NIR) emission spectral changes. The critical micelle temperatures of the complexes were found to vary from 21 to 30 °C due to differences in the hydrophilicity of the alkynyl ligands and the electrostatic repulsions between the positively charged platinum(II) complex moieties. One of the complexes with pH-responsive CH2NMe2 groups on the alkynyl ligand was found to show NIR emission that is sensitive to both pH and temperature. Such dual-responsive behaviour has been ascribed to the modulation of the self-assembly of the complex moieties by temperature-induced micellisation and the changes in the hydrophilicity as well as electrostatic interactions upon protonation/deprotonation of the CH2NMe2 groups on the alkynyl ligand.

Effect of Chain Length of PEO on the Gelation and Micellization of the Pluronic F127 Copolymer Aqueous System

The effect of adding homopolymer poly(ethylene oxide) (PEO) on the sol/gel behavior of amphiphilic triblock copolymer Pluronic F127 ((EO)98(PO)67(EO)98) in aqueous media is explored. Emphasis is placed on the influence of the PEO molecular weight and concentration on micellization and gelation and the exploration of their correlation. PEO is always found to lower the critical micellization temperature modestly. However, short PEO chains promote the gelation of F127, and long chains delay or even curb gel formation. Micelle size measurements and cryo-TEM micrographs provide evidence for micellar aggregation via the bridging of long PEO chains or depletion flocculation, thereby impeding the ordering of micelles for gel formation.

Simultaneous Determination of Critical Micelle Temperature and Micelle Core Glass Transition Temperature of Block Copolymer–Solvent Systems via Pyrene-Label Fluorescence

The critical micelle temperature (CMT) and micelle core glass transition temperature (Tg) for a poly(methyl methacrylate) (PMMA)-poly(tert-butyl methacrylate) (PtBMA) diblock copolymer system were measured by fluorescence via single temperature (T) ramps. Synthesis yielded identical block lengths in unlabeled and pyrene-labeled diblocks, the latter with dye at the PMMA block terminus. Studies were conducted at 5–18 wt % diblock in 2-ethylhexanol (2EH) with a trace of labeled diblock (0.2 wt % of total copolymer). The T dependence of pyrene-label fluorescence intensity yielded the CMT and micelle core Tg in systems where the PMMA-block and the 2EH within the cores constituted 1.9–7.8% of sample mass. While the CMT can be measured by many methods, this is the first direct measurement of micelle core Tg at low core content (e.g., 1.9 wt %) in a block copolymer/solvent system. Differential scanning calorimetry was done on diblock samples, showing severe limitations for sensing and characterizing core Tg. Fluorescence from trace levels of labeled diblock was used with 5–20 wt % PMMA–poly(n-butyl acrylate)–PMMA triblocks in 2EH. The micelle core Tg is important in triblock systems that form thermoreversible gels because it fundamentally underlies the viscoelastic to elastic gel transition. Fluorescence results demonstrated the dependence of the CMT and the near invariance of the micelle core Tg on core-block molecular weight in these diblock and triblock systems for PMMA blocks with Mn = 15–25 kg/mol and solvent in the micelle core.

Π–Π Stacking Increases the Stability and Loading Capacity of Thermosensitive Polymeric Micelles for Chemotherapeutic Drugs

Thermosensitive amphiphilic block copolymers self-assemble into micelles above their lower critical solution temperature in water, however, the micelles generally display mediocre physical stability. To stabilize such micelles and increase their loading capacity for chemotherapeutic drugs, block copolymers with novel aromatic monomers were synthesized by free radical polymerization of N-(2-benzoyloxypropyl methacrylamide (HPMAm-Bz) or the corresponding naphthoyl analogue (HPMAm-Nt), with N-(2-hydroxypropyl) methacrylamide monolactate, using a polyethylene glycol based macroinitiator. The critical micelle temperatures and critical micelle concentrations decreased with increasing the HPMAm-Bz/Nt content. The micelles of 30-50 nm were prepared by heating the polymer aqueous solutions from 0 to 50 °C and were colloidally stable for at least 48 h at pH 7.4 and 37 °C. Paclitaxel and docetaxel encapsulation was performed by mixing drug solutions in ethanol with polymer aqueous solutions and heating from 0 to 50 °C. The micelles had a drug loading capacity up to 34 wt % for docetaxel, which is among the highest loadings reported for polymeric micelles, with loaded micelle sizes ranging from 60 to 80 nm. The micelles without aromatic groups almost completely released loaded paclitaxel in 10 days, whereas the HPMAm-Bz/Nt containing micelles released 50% of the paclitaxel at the same time, which showed a better retention for the drug of the latter micelles. (1)H solid-state NMR spectroscopy data are compatible with π-π stacking between aromatic groups. The empty micelles demonstrated good cytocompatibility, and paclitaxel-loaded micelles showed high cytotoxicity to tumor cells. In conclusion, the π-π stacking effect introduced by aromatic groups increases the stability and loading capacity of polymeric micelles.

Reversible Addition-Fragmentation Chain Transfer Synthesis of a Micelle-Forming, Structure Reversible Thermosensitive Diblock Copolymer Based on the N-(2-Hydroxy propyl) Methacrylamide Backbone.

A diblock copolymer composed of N-(2-hydroxy propyl) methacrylamide (HPMAm) as hydrophilic block and N-(2-hydroxy propyl) methacrylamide dilactate (HPMAm-Lac2) as thermosensitive block was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. To this end, HPMAm was first polymerized with 4-cyano-4-[(dodecylsulfanylthiocarbonyl)-sulfanyl]pentanoic acid as the chain transfer agent and azobisisobutyronitrile (AIBN) as the initiator. The polymerization showed a linear increase in Mn as a function of monomer conversion. The living p(HPMAm) chain (7 kDa) was subsequently extended with HPMAm-Lac2 yielding a diblock copolymer (total Mn of 22 kDa). The copolymer showed reversible thermosensitivity in aqueous solution and self-assembled into micelles with a size of 58 nm (PDI 0.13) above its critical micelle temperature (CMT, 2.1 °C) and concentration (CMC, 0.044 mg/mL) and was soluble below the CMT. Paclitaxel, a hydrophobic chemotherapeutic drug, was encapsulated in the micelles with a loading capacity of 16.1 ± 1.2%. Hydrolysis of the dilactate side groups of the p(HPMAm-Lac2) block converted the copolymer to the fully hydrophilic p(HPMAm) homopolymer, resulting in dissociation of the micelles. In conclusion, the livingness and versatility of RAFT polymerization provide possibilities to synthesize block copolymers with HPMAm and derivatives thereof.

Encapsulation of Hydrophobic Drugs in Pluronic F127 Micelles: Effects of Drug Hydrophobicity, Solution Temperature, and pH

Three drugs, ibuprofen, aspirin, and erythromycin, are encapsulated in spherical Pluronic F127 micelles. The shapes and the size distributions of the micelles in dilute, aqueous solutions, with and without drugs, are ascertained using cryo-scanning electron microscopy and dynamic light scattering (DLS) experiments, respectively. Uptake of drugs above a threshold concentration is seen to reduce the critical micellization temperature of the solution. The mean hydrodynamic radii and polydispersities of the micelles are found to increase with decrease in temperature and in the presence of drug molecules. The hydration of the micellar core at lower temperatures is verified using fluorescence measurements. Increasing solution pH leads to the ionization of the drugs incorporated in the micellar cores. This causes rupture of the micelles and release of the drugs into the solution at the highest solution pH value of 11.36 investigated here and is studied using DLS and fluorescence spectrocopy.

Thermo- and Light-Regulated Formation and Disintegration of Double Hydrophilic Block Copolymer Assemblies with Tunable Fluorescence Emissions

We report on thermo- and light-regulated formation and disintegration of double hydrophilic block copolymer (DHBC) micelles associated with tunable fluorescence emissions by employing two types of DHBCs covalently labeled with fluorescence resonance energy transfer (FRET) donor and acceptor moieties, respectively, within the light and temperature dually responsive block. Both DHBCs are molecularly soluble at room temperature in their aqueous mixture, whereas, upon heating to above the critical micellization temperature (CMT, ~31 °C), they coassemble into mixed micelles possessing hydrophilic coronas and mixed cores containing FRET donors and acceptors. Accordingly, the closer spatial proximity between the FRET pair (NBDAE and RhBEA moieties) within micellar cores leads to substantially enhanced FRET efficiency, compared to that in the non-aggregated unimer state. Moreover, upon UV irradiation, the light-reactive moieties undergo light-cleavage reaction and transform into negatively charged carboxylate residues, leading to elevated CMT (∼46 °C). Thus, thermo-induced mixed micelles in the intermediate temperature range (31 °C < T < 46 °C) undergo light-triggered disintegration into unimers, accompanied with the decrease of FRET efficiency. Overall, the coassembly and disassembly occurring in the mixed DHBC solution can be dually regulated by temperature and UV irradiation, and most importantly, these processes can be facilely monitored via changes in FRET efficiency and distinct emission colors.

Micelles, mixed micelles, and applications of polyoxypropylene (PPO)-polyoxyethylene (PEO)-polyoxypropylene (PPO) triblock polymers

Abstract This review gives a brief outline of various micellar properties of triblock polymers such as critical micellization concentration, critical micellization temperature, and microviscosity. Detailed discussion of the effect of temperature on micellar properties of various triblock polymer mixtures is given. Applications of triblock polymers in solubilization as drug delivery agents, as nano drug, for the synthesis of gold nanoparticles, for cobalt determination, etc. are discussed.

Solubilization and Release of a Model Drug Nimesulide from PEO–PPO–PEO Block Copolymer Core–Shell Micelles: Effect of Size of PEO Blocks

The commercially available polypropylene oxide (PPO)–polyethylene oxide (PEO) symmetrical triblock copolymers (Pluronics®) have been recognized as pharmaceutical excipients and used in a variety of applications. This paper reports studies on micellar and solubilization behavior of three PEO–PPO–PEO block copolymers, viz. P103, P104 and P105 (same PPO mol. wt = 3250 g·mol−1 but different % PEO = 30, 40 and 50 %, respectively) in aqueous solutions. Critical micellization concentrations (CMCs), critical micellization temperatures (CMTs), and micelle size/polydispersity for copolymers with and without the drug, nimesulide (NIM), are reported. The solubilization of NIM is significantly enhanced with increasing hydrophobicity (P103 > P104 > P105), concentration, temperature and in the presence of added salt. The copolymer hydrophobicity, temperature and the drug loading strongly affect micelle behavior. The micelle–water partition coefficient (P) and thermodynamic parameters of solubilization, viz. Gibbs energy (\( \Updelta G_{s}^{\text{o}} \)), enthalpy (\( \Updelta H_{s}^{\text{o}} \)) and entropy (\( T\Updelta S_{s}^{\text{o}} \)), were calculated. The solubilization site of the drug in different micellar solutions and its release from Pluronics® micelles in phosphate buffer saline (PBS) solution at 37 °C were examined. The kinetics of NIM exhibits burst release characteristics, which are believed to be controlled by degradation of the copolymers. These studies were carried out to investigate the feasibility of using Pluronics® as a release vehicle of nimesulide in vitro. From the results, it was concluded that Pluronic® based formulations might be practical for drug delivery.

Effect of Temperature, Cosolvent, and Added Drug on Pluronic–Flurbiprofen Micellization

Structural changes in the micellization of Pluronics P103 and P123, as a function of temperature, cosolvent (ethanol, 10 v/v %), and the addition of the hydrophobic drug flurbiprofen, were investigated by SANS and tensiometry. Addition of ethanol increases the critical micellization concentration of the Pluronics (making the polymer more soluble), while increasing the repulsive interactions between the flurbiprofen-Pluronic spherical complexes. However, increasing temperature and addition of drug increases both the aggregation number and core radius and leads to a more dehydrated core. The addition of flurbiprofen to Pluronic P103 was also found to reduce the critical micellization temperature from between 15 and 20 °C to below 10 °C and at higher drug concentrations leads to an attractive interaction between micelles and eventually phase separation.

Alkanol‐Induced Micelles of a Very Hydrophilic EO–PO–EO Block Copolymer: Characterization by Spectral and Scattering Methods

AbstractThe aqueous solution behavior of a PEO–PPO–PEO block copolymer (EO103PO39EO103), was investigated in the presence of aliphatic alkanols (C2, C4, C6 and C8). The non‐associated polymer chains remain extremely hydrated in water, but aggregation in the form of spherical micelles was evidenced, triggered by the interaction of polymer chains with hydrophobic alkanol. We assume that the hydrophobic interaction between the PPO block of the copolymer and alkanol promotes micellization, which increases further with the introduction of higher chain length species. The critical micellization temperature (CMT), as measured by UV–visible spectroscopy, indicates an interaction of polymer chains with the alkanol bearing a higher chain length, which triggers aggregation. The micelles were characterized by small angle neutron scattering to elucidate the size and related micellar parameters. The gradual increase in the alkanol content increases the aggregation number, though the micelles were spherical in shape. We conclude that ethanol, due to its preferential solubility in the aqueous phase, does not affect the aggregation. The alkanols with chain lengths of C4–C8 chain, interact with the PPO block through hydrophobic interaction and shifts the CMTs to lower values. The combined effect of inorganic salt (NaCl) and alkanols show enhanced micellar properties.

Solution Behavior of Normal and Reverse Triblock Copolymers (Pluronic L44 and 10R5) Individually and in Binary Mixture

Solution properties of pluronics L44 or L [(PEO)(10)(PPO)(23)(PEO)(10)] and 10R5 or R [(PPO)(8)(PEO)(22)(PPO)(8)] were studied individually as well in their binary mixtures in aqueous medium. The critical micelle concentration (CMC), critical micelle temperature, and cloud point (CP) were determined. Ideal and nonideal behaviors of their mixtures in the formation of CMC and CP were observed; the energetics of the studied processes were determined. Spectrophotometry, isothermal titration calorimetry and dynamic light scattering (DLS) methods were used for evaluations. Morphologies of the dispersed L, R, and their mixtures along with their polydispersities were determined from DLS measurements. Atomic force microscopy was also employed. The interfacial properties of L and R were investigated forming Langmuir monolayers in a surface balance. The surface pressures (π) generated by the compounds were moderate, the area per molecule was higher for R than L. R has shown antibacterial activity against both gram positive and gram negative bacteria whereas L was inactive in this respect.

Nanocomposite thermogel for controlled release of small proteins

A nanocomposite thermogel composed of Pluronic®-based multiblock copolymer and laponite nanoclay was developed to sustain delivery of low-molecular-weight proteins. The rapid release of low-molecular-weight proteins from multiblock copolymer thermogels has been a problem for sustained delivery but was solved by using nanocomposite thermogel. Lysozyme (Mw = 14,700), a relatively low-molecular-weight protein, was successfully loaded into and released from nanocomposite thermogel. In addition, interactions among multiblock copolymer, laponite, and lysozyme were studied in terms of gelation, micellization, particle size, and zeta potential. Critical micellization temperatures and sol–gel transition temperatures of multiblock copolymer solutions were lowered with laponite addition. Positively charged lysozyme was adsorbed onto anionic surface of laponite, which increased with an increase in the lysozyme concentration. Particle size and zeta potential of the laponite–lysozyme complex were also dependent on the lysozyme concentration. The nanocomposite thermogel sustained lysozyme release to 40 days, whereas lysozyme release from multiblock copolymer thermogel lasted for only 18 days. The structural stability of released lysozyme was confirmed by circular dichroism spectroscopy and differential scanning calorimetry.

Solubilization and location of phenol and benzene in a nonlinear amphiphilic EO–PO block copolymer micelles: 1H NMR and SANS studies

The aqueous solution behavior of a poly(ethylene oxide)–poly(propylene oxide), PEO–PPO, star block copolymer Tetronic® T904 with solubilized phenol and benzene was examined by cloud point (CP), viscosity measurements, 1D and 2D NMR experiments, dynamic light scattering(DLS), and small angle neutron scattering (SANS) techniques. Both the solubilizates decreased the CP and the critical micelle temperature (CMT) of T904. This behavior is explained in terms of the free energy of hydration of the phenol/benzene and the replacement of water molecules from the PPO and PEO blocks by the formation of hydrogen bonds which induced micellization and phase separation at lower temperature. The effect of solubilizates on micellar growth was investigated by viscosity and DLS. Benzene molecules solubilized in T904 micelles are found in intimate contact with the PEO chain while we find that the phenol molecules are located within micelle palisade layer as well as at the micelle–water interface. The SANS data indicate that these solubilizates significantly influence the solution behavior of the copolymer; the structure of micelles stays essentially constant as a function of solubilizate concentration. On the other hand, the shell thickness changes rapidly with phenol concentration. The results showed that phenol decreased CP/CMT and had a more pronounced effect on micellar growth as compared to benzene.

Preparation and optimization of media using Pluronic® micelles for solubilization of sirolimus and release from the drug eluting stents

Understanding the in-vitro release profile of drugs from drug eluting devices such as cardiac stent is crucial in designing and optimizing the drug embedded matrices. Sirolimus (SRL), a widely used anti-inflammatory/antiproliferative/immunosuppressive hydrophobic drug undergoes irreversible changes such as hydrolysis leading to erroneous assessment of the release profile. The release profile mainly depends on the drug release medium. The present study aims to develop and optimize the aqueous medium for the solubilization of SRL and in-vitro release method from drug eluting stent (DES). In the first stage of study several release media containing different buffer compositions, pH, and a series of micelle forming PEO–PPO–PEO block copolymers (known as Pluronic®) were examined for solubility and stability of SRL by reversed phase high performance liquid chromatography (RP-HPLC). SRL showed good solubility and stability at pH 4.0 (both in acetate buffer as well in phosphate buffer) in the presence of block copolymers. Solubilization of SRL was remarkably higher in P103 and P123 micelles than more hydrophilic F68 and F127. To get further insight into the underlying drug dissolution mechanisms, critical micellization temperature (CMT), and hydrodynamic size of micelles with and without drug incorporation were determined by UV–visible spectroscopy and dynamic light scattering (DLS) respectively. The micelle–water partition coefficient (P) and location of solubilized drug were also evaluated from a thermodynamics viewpoint. Finally, the optimized media were examined for the release of SRL from drug eluting stent; the data suggest that a release medium consisting of 0.1% P123 in phosphate buffer pH 4.0 is most suitable for evaluation of in-vitro release of SRL from DES.

Thermal Gelation and Stability of Pectin Grafted with PEPE

ABSTRACTStimuli-sensitive materials can change properties upon exposure to an external stimulus. Thermoreversible gelation upon heating is one example for such a stimuli sensitivity. Here, it is of significance to tailor the transition temperature and to achieve large changes of G’ and the viscosity. Grafting of the thermosensitive poly(ethylene glycol-b-propylene glycol-b-ethylene glycol)s (PEPEs) to pectin was performed in order to investigate if tailoring of the sol-gel-transition temperature can be achieved by adjusting the grafting ratio. PEPEs were aminated and grafted to the polysaccharide via EDC coupling as shown by FTIR. The sol-gel transition of the pectin, PEPE, and the grafted system (PGP) was investigated by rheology. The gelation temperature (Tgel) of the system could be adjusted by varying the grafting density of PEPE onto pectin as well as by the concentration of the thermosensitive polymer in aqueous solution. A concentration of 15 – 20 wt% of the grafted system in water led to gelation temperatures in the range of 25 – 33 °C and the critical micelle concentration (CMC) and critical micelle temperature (CMT) of the grafted systems were determined by UV spectroscopy. The viscosity and the G’ increased by four orders of magnitudes at Tgel, which is comparable to PEPEs alone, but could be reached at lower PEPE concentrations. In the future, a thorough mechanistic investigation of the gelation process would be of interest.

Hierarchically branched silver nanostructures (HBAgNSs) as surface plasmon regulating platforms for multiplexed colorimetric DNA detection

We synthesized hierarchically branched silver nanostructures (HBAgNSs) with distinctive morphologies and optical properties using non-ionic triblock copolymers under a variety of conditions. The synthetic conditions in terms of the critical micelle concentration (CMC) and temperature (CMT) are judiciously controlled to determine how the polymers in the form of micelles or unimers play a significant role in the growth of the nanostructures. The surface of the silver nanostructures can be densely functionalized with DNA, which is further utilized for the multiplexed colorimetric detection of three DNA targets in conjunction with plasmonic nanoparticle probes.

Thermoreversible high-temperature gelation of an ionic liquid with poly(benzyl methacrylate-b-methyl methacrylate-b-benzyl methacrylate) triblock copolymer

In this paper, we describe a novel thermosensitive triblock copolymer in an ionic liquid (IL) that shows a low-temperature-sol–high-temperature-gel transition. A well-defined ABA triblock copolymer consisting of poly(benzyl methacrylate) as the terminal A blocks and poly(methyl methacrylate) as the middle B block (P(BnMA-b-MMA-b-BnMA), BMB) was successfully synthesized using atom transfer radical polymerization (ATRP) from a bifunctional initiator. The number-average molecular weights of the PBnMA blocks and the PMMA block were estimated to be 25 kDa and 33 kDa, respectively. The temperature dependence of the hydrodynamic radius obtained from dynamic light scattering showed that in dilute solutions (0.1 wt%) the triblock copolymer exhibited lower critical micellization temperature (LCMT)-type aggregation behaviour around 135 °C in a common hydrophobic IL, 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([C2mim][NTf2]). Dynamic viscoelastic measurements for a 20 wt% BMB solution in [C2mim][NTf2] confirmed that a viscous liquid at low temperature (G′ (storage elastic modulus) G′′) upon heating above the aggregation temperature of the PBnMA terminal blocks. No gelation was observed when the triblock copolymer concentration was below 10 wt%. Furthermore, the thermoreversible ion gel exhibited excellent sol–gel transition reversibility for multiple heating/cooling cycles performed over several days.