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Scrutinizing the effect of various nitrogen containing additives on the micellization behavior of a triblock copolymer
Journal of Colloid and Interface Science 553 (2019) 655–665
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Journal of Colloid and Interface Science journal homepage: www.elsevier.com/locate/jcis
Regular Article
Scrutinizing the effect of various nitrogen containing additives on the micellization behavior of a triblock copolymer Payal Narang, Niketa Yadav, Pannuru Venkatesu ⇑ Department of Chemistry, University of Delhi, Delhi 110007, India
g r a p h i c a l a b s t r a c t
a r t i c l e
i n f o
Article history: Received 3 April 2019 Revised 20 June 2019 Accepted 21 June 2019 Available online 22 June 2019 Keywords: Triblock copolymer Additives Critical micellization temperature Osmolytes Denaturants
a b s t r a c t Hypothesis: PEG-PPG-PEG contains hydrophobic (PPG) as well as hydrophilic (PEG) blocks have gained popularity due to their different physiochemical properties that make them useful in several scientific areas and industrial applications such as detergency, stabilizers for dispersion, foaming and many more. Scientific communities reported that additives have ability to tune the micellization/demicellization tendency of PEG-PPG-PEG which we further extended by the use of several N-containing additives. Especially, chemists and biochemists are interested to extend the potential role of PEG-PPG-PEG copolymer in biomedical sensing applications, that is why triblock copolymer is chosen with various additives in the present study. Experiments: The work reports the results obtained through different kinds of interactions induced among the poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPGPEG) and additives containing different structural moieties. In order to tune micellization tendency of PEG-PPG-PEG, several additives such as trimethylamine-N-oxide (TMAO), betaine, sarcosine, guanidinium hydrochloride (GdnHCl) and urea are introduced in the current part of work and studied using UV–visible and fluorescence spectroscopy, dynamic light scattering (DLS), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy. Findings: The methylamines facilitate the micellization to higher extent in comparison to that in aqueous PEG-PPG-PEG system, thereby decreasing the critical micellization temperature (CMT) values of PEGPPG-PEG. Among studied methylamines, sarcosine has the highest efficacy in inducing the micellization followed by TMAO and betaine to the least extent. Direct interactions among polymeric segments and sarcosine is thought to be the main driving force for micellization of PEG-PPG-PEG. This is not possible for the case of betaine and TMAO due to the presence of the sterically hindered N atom. In contrast to these methylamines, GdnHCl and urea provided favorable binding sites for bridging interactions among polymer segments and thus lead to higher temperature values for CMT of PEG-PPG-PEG. Ó 2019 Elsevier Inc. All rights reserved.
1. Introduction Abbreviations: (PEG-PPG-PEG), Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol); LCST, lower critical solution temperature; TRPs, thermo-responsive polymers; dH, hydrodynamic diameter. ⇑ Corresponding author. E-mail address: [email protected] (P. Venkatesu). https://doi.org/10.1016/j.jcis.2019.06.074 0021-9797/Ó 2019 Elsevier Inc. All rights reserved.
Block copolymers contain hydrophilic as well as hydrophobic blocks in their structure. They are known to self assemble when dissolving in a selective solvent which can either solvate the
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hydrophilic block or hydrophobic block more in comparison to the other [1]. This self-assembled structure of a polymer is also known as micelles as observed in case of low molecular weight surfactants. The molecular weight and biocompatibility of micelles formed from block copolymers and surfactants are the source of the major difference in elucidating their use in different areas of science [1]. Altering the temperature properties of aqueous solution by using different additives is found to be the useful method to tune the micelles formation process [1–4]. Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) triblock copolymer, also known as Pluronic F-108 is an amphiphilic thermo-responsive block copolymer containing PEG as hydrophilic block and PPG as hydrophobic block in its structural integrity [5,6]. This is available in different molecular weights depending on the number of PEG and PPG segments are present [2]. Like other block copolymers, PEG-PPG-PEG can self assemble in the presence of water as solvent above at a particular concentration termed the critical micelle concentration (CMC). This happens at a specified temperature known as critical micelle temperature (CMT) [5,7–8]. Aqueous solution of copolymer contains hydrophobic as well as hydrophilic blocks have gained popularity due to their different physiochemical properties that make them useful in several scientific areas and industrial applications such as detergency, stabilizers for dispersion, foaming agents and many more [5,7–9]. Pluronic F-108 is a kind of water soluble copolymer whose micellization and aggregation behavior is reported to be influenced by light, pH [6], temperature and ionic strength of the solution mixture [5,10–13]. Due to its versatile ability to respond to external stimuli, its properties can be altered in many ways which contribute to its widespread applications in aggregation [14,15], drug delivery [16], rechargeable batteries [17] and food packaging industries [18], etc. Additionally, it is reported recently that thermal and mechanical properties of low fracture resistance epoxy resin can be modified on addition of triblock copolymers depending on varying ratios of PEG:PPG [19,20]. It has also been reported that introducing starch segments in triblock copolymer mixtures makes them useful in the preparation of bone hemostatic wax [21]. The phase transition temperature of PEG-PPG-PEG is altered significantly in the presence of various additives as a function of their concentration. Basically, naturally occurring osmolytes are molecules which protect our cells from osmotic pressure and are ubiquitous in living organism [22]. Osmolytes are the small molecular mass additives with the ability to alter the functional behavior of macromolecules and are known to protect cells from various stresses [23]. Poly (ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-PPO-PEO) corresponds to PEG-PPG-PEG in structure except the position of methyl group is different in PPO block of polymer chain [24]. The PEO-PPO-PEO molecule is widely studied under the influence of different additives such as surfactants [2,8,25–27], hofmeister series cations and anions [9] and various salts [1,3,28–29]. The binding affinity of various monovalent cations and divalent cations on triblock copolymer was investigated by Zhang and group [30]. Subsequently, the presence of urea was found to increase CMC and CMT of the PEO-PPO-PEO copolymer [31]. Structural indentity of additives such as trehalose, sucrose, sorbitol, TMAO and betaine play a prominent role in deciding the phase transition behavior of thermo-responsive polymers (TRPs) and have been extensively studied by our research group [32–34]. Among the class of osmolytes, the three different methylamines such as trimethylamine-N-oxide (TMAO), betaine, sarcosine, plus urea (polar osmolytes) and guanidinium hydrochloride (GdnHCl) (a denaturant for proteins) were chosen for the study. Scientific communities, especially chemists and biochemists are interested in extending the potential role of PEG-PPG-PEG copoly-
mer in biomedical sensing applications, which is why triblock copolymer is chosen with various additives in the present study. Various biophysical spectroscopic studies were employed in evaluating the influence of TMAO, betaine, sarcosine, urea and GdnHCl on the micellization behavior of Pluronic F-108. The published literature indicates that little effort has been previously directed to the study of this problem. UV–visible and fluorescence spectroscopy, dynamic light scattering (DLS), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy studies were used for the current investigation. This effort has led us to find new ways to tune the micellization behavior of triblock copolymer and further extend its potential applications in biomedical research. 2. Experimental section 2.1. Materials and sample preparation All the chemicals were purchased from Sigma-Aldrich (USA). These include chemicals such as poly(ethylene glycol)-block-poly (propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) triblock copolymer or Pluronics F-108, pyrene (Py), trimethylamine N-oxide (TMAO) (99%), betaine (98%), sarcosine (98%), guanidinium hydrochloride (GdnHCl) (99%) and urea (99%). All the chemicals were directly used without purification. The molecular weight (Mn) of PEG-PPG-PEG is 14.6 kDa having PEG content almost 82.5%, (PEG)133-(PPG)49-(PEG)133. Double distilled deionized water having 18.3 MO cm resistivity was obtained from Ultra 370 series, Rions India, India and was used to prepare all solutions. An analytical balance (Mettler Toledo) was used to weigh the appropriate mass of polymer and other additives having a precision of ±0.0001 g and dissolved in pure water. The 7 mg/ml concentration of polymer was maintained for all measurements. Except for urea, the additive concentrations in the copolymer solutions were (0.10, 0.25, 0.50, 0.75 and 1.0 M) in all cases. Because of its high solubility however, different concentrations of urea were (0.5, 1.0, 2.0, 3.0 and 4.0 M) in the copolymer solutions. DLS experiments were performed using solutions that have been passed through a 0.45 mm filter obtained from Millipore, Millex-GS. A vaccum syringe was used to draw the solution through the filter. The sample solutions were allowed to equilibrate at room temperature for some time. Furthermore, all the other needed information has already been given in our earlier papers [32–34]. The chemical structures of polymer and all the additives are provided in Scheme 1. 2.2. Methods Spectra were obtained using a UV-1800, Shimadzu Co., Japan double beam UV–visible spectrophotometer equipped with a quartz cuvette sample holder. The sample holder is carrying 1 nm bandwidth and a 0.3 nm wavelength accuracy. An wavelength correction system is automatically built into the system to record UV–visible spectra for its particular wavelength range for each measurement at room temperature. The appropriate amount of solution mixture was poured into cell of 1 cm path length made of quartz. Cary eclipse fluorescence spectrophotometer (Varian optical spectroscopy instruments, Mulgrave, Victoria, Australia) was used to measure fluorescence spectra of probe (Py) in PEGPPG-PEG aqueous solution in the presence and absence of different additives in various concentrations. This instrument is equipped with Peltier device that electro-thermally controls the temperature to high precision. After equilibration of 20 min at each temperature, the spectra of samples were recorded. The excitation wavelength was maintained constant at 335 nm while fluorescence
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emission at 375 nm wavelength was collected as a function of temperature. The size distribution of macromolecular assembly was performed by means of a Zetasizer Nano ZS90 dynamic light scattering (DLS) instrument (Malvern Instruments Ltd., UK). A 4 mW He–Ne built-in laser serves as the light source at 633 nm fixed wavelength (k). A Thermo-Fisher scientific corporation iS 50 FTIR Fourier transform spectrometer was used to record IR spectrum. The details of the procedure are as previously described [32–34]. 2.2.1. Differential scanning calorimetry measurements Critical micellization temperature (CMT) of PEG-PPG-PEG solutions containing various additives was performed with NANO DSC instrument (TA Instruments, USA). It is equipped with a sample and reference cell containing 0.650 mL cell volume. The changes in heat absorption or evolution were recorded as a function of temperature. The pressure was maintained at 3 atm while maintaining a scan rate of 2 °C/min. All the samples were equilibrated for 5 min. The degassing system provided is used to degas the sample before putting into the cells. Before starting the experiment, water-water scans were performed for baseline correction within the specified temperature range. All the data obtained was finalized by NANO analyzer software to obtain the clear CMTs of PEG-PPG-PEG. 3. Results and discussion 3.1. UV–visible spectroscopy analysis of PEG-PPG-PEG in presence of various additives UV–visible spectroscopic studies are employed to check the tendency for micellization of PEG-PPG-PEG in presence of additives such as TMAO, betaine, sarcosine, GndHCl and urea in aqueous solution. Pyrene (Py) is taken as an external probe to investigate the changes around the polymeric environment in aqueous system [5]. To avoid its interactions with polymer or additives, the amount taken was very less (1 mM). Furthermore, Py is a kind of probe which shows negligible absorbance in pure aqueous system. Py probe is hydrophobic in nature and shows very little or negligible feasible interactions with water. Fig. 1 represents the UV–visible spectra of Py in PEG-PPG-PEG for the wavelength range (190– 700 nm) at 25 °C temperature. In the absence of any additive, Py in PEG-PPG-PEG is observed to show five non-distinctive peaks at 265, 275, 305, 320 and 335 nm [5]. The peak values are quite consistent with the existing values in literature. These five peaks clearly signify that the polymer is providing the hydrophobic environment to Py. Fig. 1(a) represents the variation in absorbance values of five peaks of Py in PEG-PPG-PEG containing varying concentrations of TMAO from 0.1 to 1.0 M. The absorbance keeps on increasing with increase in the concentration of TMAO in sequential manner. The absorbance value reaches approximately 0.067 a.u. for 1.0 M of TMAO. In the same way, Fig. 1(b and c) shows the change in absorbance spectra of Py in PEG-PPG-PEG containing another two methylamines, betaine and sarcosine, respectively. The increment in absorbance for all the five peaks is less prominent for betaine as compared to that of sarcosine. The presence of sarcosine and betaine are showing the absorbance value of 0.08 and 0.05 a.u., respectively for their maximum concentration. Assisting the influence of GndHCl on the UV–visible absorbance spectra of PEG-PPG-PEG in different concentrations (0.1–1.0 M) is depicted in Fig. 1(d). The spectra show the increment in absorbance value along with increase the concentration. The increment is not much prominent as in case of three methylamines studied. The reason may lie in its different kinds of interaction in comparison to that of methylamines studied. A polar osmolytes molecule, urea is also added to Py in PEG-PPG-PEG solution mixture to check its effect along with various charged species. We have observed
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less intensified five peaks of Py in PEG-PPG-PEG (Fig. 1(e)). The urea is also observed to increase the absorbance values however, peaks are less prominent. Urea is behaving quite differently than all other additives studied as some peaks are vanishing in its presence which may be basically due to its ability to form bridging interactions with polymer that no longer enhances the hydrophobicity around polymer to much extent. The difference in structural integrity among all the studied additives containing charged moieties is making the difference in their UV–visible spectra [33,34]. The increment in absorbance values for all the additives indicate that Py started interacted more and more with hydrophobic moieties of polymer. Moreover, it is found to be in accordance with the concentration of the additive. 3.2. Steady state spectroscopy analysis of PEG-PPG-PEG in presence of various additives The interactions of the various additives with the amphiphilic copolymer PEG-PPG-PEG can be studied using Py as a probe for steady state fluorescence spectroscopy. The spectra are collected at room temperature keeping the excitation wavelength at 335 nm. Fig. 2 reflects the variation in steady state fluorescence spectra of Py in PEG-PPG-PEG in presence and absence of various additives as a function of concentration. The emission intensity is observed at 375 and 390 nm for Py in PEG-PPG-PEG aqueous system [5]. Fig. 2(a) depicts the variation in emission spectra of Py in PEG-PPG-PEG with increase in the concentration of TMAO from 0.1 to 1.0 M. The fluorescence intensity is observed to show a direct relationship to the concentration of TMAO and maximum increment of approx. 475 a.u. is observed for maximum concentration of TMAO. Py is a kind of probe which senses the significant change happening in terms of polarity or hydrophilicity/ hydrophobicity ratio in the microenvironment of Py in PEGPPG-PEG on addition of several additives containing different functional moieties. TMAO is inducing polarization of water molecules around the surface of polymer. However, no significant change in fluorescence intensity is observed at lower concentrations of TMAO approximately up to 0.5 M, although the changes are becoming more pronounced as the concentration increases. Similarly, Fig. 2(b and c) are depicting the alteration in fluorescence intensity values of Py in PEG-PPG-PEG possessing different concentrations of betaine and sarcosine, respectively. The significant change with respect to both increment and value in fluorescence intensity as a function of concentration was observed in the case of both the additives. Like TMAO, betaine and sarcosine are inducing the hydrophobicity around the polymer molecule and which results in enhanced fluorescence intensity due to the formation of small fraction of mesoglobules and aggregates of polymer in the solution. Additionally, at low concentrations of betaine and sarcosine (0.5 M), no appreciable variation is observed. The mechanism for inducing the micellization of polymer PEG-PPGPEG can be different for different methylamines used depending on their chemical structures. Furthermore, Fig. 2(d) presents the variation in steady state fluorescence spectra of PEG-PPG-PEG upon addition of GdnHCl. Very different from methylamines discussed above, the fluorescence intensity values decreased to 60 from 136 a.u as concentration increases. Moreover, the changes are not a very strong function of concentration. Fig. 2(e) reflects the changes in fluorescence intensity of Py in PEG-PPG-PEG with urea concentration advancing from 0.5 M to 4.0 M. It is found that a more significant decrease in fluorescence intensity is observed at the lowest concentrations. The fluorescence intensity of Py in PEG-PPG-PEG does not reach the values associated with the absence of additives for any concentration of urea. Overall from steady state fluorescence, one can observe the three methylamines are behaving differently from urea
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Wavelength (nm) Fig. 1. UV visible spectra of pyrene in PEG-PPG-PEG aqueous solution containing (a) TMAO, (b) betaine, (c) sarcosine, (d) GndHCl and (e) urea as additives in varying concentrations. Aqueous PEG-PPG-PEG (black), 0.10 M (red), 0.25 M (blue), 0.50 M (dark cyan), 0.75 M (pink) and 1.00 M (dark yellow). (e) Aqueous PEG-PPG-PEG (black), 0.50 M (red), 1.0 M (blue), 2.0 M (dark cyan), 3.0 M (pink) and 4.0 M (dark yellow) under atmospheric conditions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
and GdnHCl. Different types of interactions due to different atoms present in their structural units is playing the key role resulting in aforesaid changes observed in fluorescence spectra. Further, we have analysed the ratio I1/I3 as I375/I390 of Py in PEGPPG-PEG in presence of all the varying concentrations of additives and presented in supporting information as Fig. S1. As we already know that the significant change is happening in terms of polarity or hydrophilicity/hydrophobicity ratio in the microenvironment of Py in PEG-PPG-PEG on addition of several additives containing dif-
ferent functional moieties. The decrease in fluorescence intensity ratio I1/I3 with increase in concentration of TMAO, betaine and sarcosine from 0.1 to 1.0 M in reflects the decrease in microenvironmental polarity of solution and the solution mixture is becoming more hydrophobic which is quite consistent with the literature [35,36]. Their ability to induce micellization is the main reason that facilitates the increase in hydrophobicity around the Py. These osmolytes have the ability to disrupt the water structure around the polymer segment through polarization of water mole-
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Wavelength (nm) Fig. 2. Steady state fluorescence spectra of pyrene in PEG-PPG-PEG aqueous solution containing (a) TMAO, (b) betaine, (c) sarcosine, (d) GdnHCl and (e) urea as additives in varying concentrations. (a–d) Aqueous PEG-PPG-PEG (black), 0.10 M (red), 0.25 M (blue), 0.50 M (dark cyan), 0.75 M (pink) and 1.00 M (dark yellow). (e) Aqueous PEG-PPGPEG (black), 0.50 M (red), 1.0 M (blue), 2.0 M (dark cyan), 3.0 M (pink) and 4.0 M (dark yellow) under atmospheric conditions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
cules which further influences the ratio of hydrophilicity/ hydrophobicity of Py in PEG-PPG-PEG and thus results in changes in the fluorescence spectra. Additionally, the ratio I1/I3 of Py in PEG-PPG-PEG in presence of GdnHCl is not showing any significant alteration in polarity and only variation in hydrophilicity/hydrophobicity ratio is obtained which may be due to the partial accumulation of particular ions around the polymer segments. Furthermore, it is found to be a denaturant for proteins through some direct binding interactions with macromolecule [37,38]. However, in the case of urea, we do not observe much variation in polarity of the solution mixture at
lower concentrations, while an increment in ratio I1/I3 of Py is predicted at higher concentrations of urea, which supports the idea of increase in polarity. This is very different from all other cases which may be due to the ability of urea to form hydrophilic binding with polymer segments through its well established bridging tendency [39]. Thus, the alteration in ratio I1/I3 of Py in PEG-PPG-PEG is clearly deciphering the specific role of a particular additive to induce the changes in micro-environment from hydrophilic to hydrophobic or vice versa, which basically influences the balance of hydrophobic effects versus hydrogen bonding interactions with the EO and PPO blocks.
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3.3 Volume. distribution analysis of PEG-PPG-PEG in presence of various additives Dynamic light scattering (DLS) is very useful technique to get an idea about the hydrated size of the macromolecular particles present in solution mixture. Fig. 3 illustrates the size distribution of PEG-PPG-PEG in the absence and presence of several additives along with their concentration variation. The size distribution variation is shown as the alteration in volume percentage with respect to the change in hydrodynamic diameter (dH) of polymer. The additives do not scatter light individually in the solution mixture
due to their relatively small size in comparison to that of polymer. Fig. 3(a) depicts how the light scattering power varies with the size of particles in the solution as a function of added TMAO concentration increasing in the range 0.1–1.0 M. The particle size in the PEGPPG-PEG aqueous solution is of the order of 10 nm in agreement with literature value [25]. Interestingly, the volume percentage peak at 10 nm is observed to shift more and more towards the higher sized values with increasing the concentration of TMAO in triblock copolymer. The easy formation of polymeric micelles may be the reason for this peak shift. In other words, TMAO is showing its ability to induce the micellzation of polymer as its
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Hydrodynamic diameter dH (nm) Fig. 3. Volume distribution graph of DLS spectra of PEG-PPG-PEG aqueous solution as a function of hydrodynamic diameter (dH) containing (a) TMAO, (b) betaine, (c) sarcosine, (d) GdnHCl and (e) urea as additives in varying concentrations. (a–d) Aqueous PEG-PPG-PEG (black), 0.10 M (red), 0.25 M (blue), 0.50 M (dark cyan), 0.75 M (pink) and 1.00 M (dark yellow). (e) Aqueous PEG-PPG-PEG (black), 0.50 M (red), 1.0 M (blue), 2.0 M (dark cyan), 3.0 M (pink) and 4.0 M (dark yellow) under atmospheric conditions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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affinity to attract water molecules associated to PEG-PPG-PEG increases in a concentration dependent manner. The volume distribution graph of PEG-PPG-PEG is also investigated in the presence of betaine and sarcosine in the concentration range from 0.1 to 1.0 M. In the similar way to TMAO, peak value at 10 nm is observed to shift at higher dH value due to the aggregation of polymeric micelles and their size keeps on increasing in the concentration manner of betaine (Fig. 3(b)). Sarcosine is also showing more shift in dH values towards higher values. The structure of sarcosine is quite different from betaine and TMAO with respect to non-sterically hindered N atom. The ability of the N atom to bind directly to the polymeric segment is making the micelles more stable at room temperature. This all serves as the basis for the aforesaid changes in volume distribution graph [34]. Overall, all the methylamine based osmolytes have the ability to facilitate the micellization behavior of PEG-PPG-PEG and further aggregation of polymeric micelles via the different types of interactions which they induce. On the other hand, Fig. 3(d) presents the variation in volume percentage for differently sized micro-assemblies present in solution after adding varying concentrations of GdnHCl. The peak values at 10 nm do not show much shift abrupt decrease as compared to all the three methylamines studied. The hydrogen bonding interactions between polymer segments and GdnHCl are the major reason for stabilization of coiled form of polymer and no more shifting of 10 nm peak intensity value with varying concentrations of GdnHCl [23]. The NH2 group present in GdnHCl has the ability to get involved in hydrophilic kind of interactions with the polymer which do not allow easy formation of micelles and hence not much variation in volume percentage is observed. Fig. 3(e) reflects the size variation of macromolecular particles in the presence of urea in the concentration range from 0.5 to 4.0 M. As urea acts as a binding ligand among polymer segments containing hydrophilic binding moieties [25], it has the ability to solubilize the polymer in its coiled form to higher extent or higher level of concentration of urea. This more stabilizing ability of urea towards the coiled form of the PEG-PPG-PEG polymer does not provide shift in the volume percentage peak at higher dH values. Moreover, larger aggregates may form however, they are very less in number at room temperature that volume occupied by them are negligibly small in comparison to that of the particles at 10 nm.
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Wavenumber(cm-1) Fig. 4. FTIR spectra of PEG-PPG-PEG in D2O containing (a) TMAO, (b) betaine, (c) sarcosine, (d) GdnHCl and (e) urea as additives in varying concentrations. (a–d) Aqueous PEG-PPG-PEG (black), 0.10 M (red), 0.25 M (blue), 0.50 M (dark cyan), 0.75 M (pink) and 1.00 M (dark yellow). (e) Aqueous PEG-PPG-PEG (black), 0.50 M (red), 1.0 M (blue), 2.0 M (dark cyan) and 3.0 M (pink) under atmospheric conditions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
3.4. Fourier transform infrared (FTIR) spectroscopic analysis of PEGPPG-PEG in presence of various additives The clear evidence in support of molecular interplay among PEG-PPG-PEG and different additives can be predicted from FTIR spectroscopy. It is a great tool for determining how the bonding interactions are getting affected in presence of TMAO, betaine, sarcosine, GdnHCl and urea. Fig. 4 shows the FTIR spectra of PEG-PPGPEG in D2O in the absence and the presence of five additives as a function of their concentrations. The absorbance at 1220 cm 1 in the FTIR spectra is attributable to the CAOAC stretching vibrations that usually fall in the range 1100–1250 cm 1 [34]. Two absorbance peaks of triblock copolymers between 1400 and 1500 cm 1 are observed on addition of TMAO at concentrations extending over the range from 0.1 to 1.0 M. The pattern is quite consistent with reported literature values [34]. Furthermore, these peaks keep on enhancing in absorbance value with the concentration of TMAO which clearly reflects that the more concentrated solutions of TMAO are facilitating more hydrophobic collapse through a higher extent of polarization induced among D2O molecules. Subsequently, the peak at 1220 cm 1 is decreasing which is mainly because of less interaction of polymer segments with D2O in presence of TMAO. In the similar way, the betaine and sarcosine concentration variation behavior as studied by FTIR spectroscopy is
presented in Fig. 4(b) and (c). The new peaks arise on addition of betaine to the PEG-PPG-PEG in D2O solution. One peak between 1600 and 1700 cm 1 is attributed to the COO– group present in betaine while several small peaks are observed between 1300 and 1500 cm 1 resulting from the interactions of betaine with D2O molecules around PEG-PPG-PEG. The absorbance values for these peaks show an increasing trend with concentration of betaine. Additionally, CAOAC bonding interactions are decreasing with betaine concentration due to thelow probability of interactions among D2O and polymeric segments. Sarcosine is also showing new peaks, one at around 1600 cm 1 and other between 1450 and 1280 cm 1, which can be attributed to the interactions of the polymer segments with the nonsterically hindered N atom in sarcosine. The absorbance enhancement for new peak is a maximum for the case of sarcosine in comparison to all the three methylamines studies. This may be due to the direct bonding probability of sarcosine towards the polymer segments [34]. The influence of GdnHCl addition in PEG-PPG-PEG in D2O solution as studied by FTIR spectra is represented in Fig. 4(d). The presence of GdnHCl increased the absorbance value for CAOAC stretching vibrations in addition to introducing new peaks in the
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range of 1400–1600 cm 1. GdnHCl induces hydrophilic interactions in a manner which is very different from the methylamines, leading to higher absorbance values at 1220 cm 1 attributed to the CAO stretching interactions. The peak intensity values at 1220 cm 1 are not showing the regular trend which may be due to a variety of CAO interactions associated with the addition of additives containing O atom in increasing concentration manner. Finally, the addition of urea in the concentration range 0.5–4.0 M in PEG-PPG-PEG in D2O introduces new peak values in the wavelength range 1400 to 1600 cm 1 (Fig. 4(e)). The absorbance values for these peaks are increasing with the concentration of urea. The peak value at 1590 cm 1 is attributed to the deuterated urea present in the solution mixture [25] which also shows enhancement in the value of absorbance which increases with increasing concentration of urea. Overall, one can say that several kinds of molecular interactions are playing a role in producing the FTIR spectra. This is due to the presence of different elements present in the structural unit of additives resulting in a variety of interactions induced. More intensified new peaks are observe in the case of urea and sarcosine with increasing concentrations which may arise as a result of the bridging affinity of urea and the direct binding interactions of N atom in sarcosine to polymer segments, respectively. 3.5. Differential scanning calorimetry (DSC) analysis of PEG-PPG-PEG in presence of various additives Differential scanning calorimetry (DSC) is a important and sensitive methods for investigating the transition in the micellization temperature of PEG-PPG-PEG due to the presence of different additives with increasing concentrations. Fig. 5 depicts the alteration in heat capacity values of PEG-PPG-PEG in the presence of five different additives, TMAO, betaine, sarcosine, GdnHCl and urea as a function of temperature at 0.5 M concentration. It can be interpreted clearly that GdnHCl and urea are facilitating the CMT value of
0.5 M urea
Endothermic process
0.5 M GndHCl
0.5 M sarcosine
0.5 M betaine
0.5 M TMAO
PEG-PPG-PEG in H 2O
28 30 32 34 36 38 40 42 44 46 48 50
Temperature (oC) Fig. 5. DSC curves of PEG-PPG-PEG aqueous solution containing a particular concentration 0.5 M of various additives. PEG-PPG-PEG in H2O (black), TMAO (red), betaine (blue), sarcosine (dark cyan), GdnHCl (pink) and urea (dark yellow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
PEG-PPG-PEG towards higher temperature value and methylamines to the lower temperature values. The peak temperature after which heat capacity value does not change much or shows little decrease is said to be its phase transition temperature [40–47]. Fig. S2(a) depicts the heat capacity variation of PEG-PPG-PEG in TMAO with respect to temperature in supporting information. The critical micellization temperature (CMT) of PEG-PPG-PEG is observed at around 39.0 °C which is found to be in correlation with the literature [5]. The CMT values of PEG-PPG-PEG are found to approach the lower temperature value with increasing concentration of TMAO. This value reaches up to 30.7 °C for 1.0 M concentration of TMAO (Fig. S2(a)). The polarization ability of TMAO is making the agglomeration of micelles of PEG-PPG-PEG formation easy at lower temperature values in comparison to PEG-PPG-PEG in aqueous solution [34]. Likewise, the presence of betaine and sarcosine (two different methylamines), are also observed to alter the CMT values of PEG-PPG-PEG to a significant extent and the variation in values of CMT can be predicted from Fig. S2(b and c), respectively. Both the methylamines are found to decrease the CMT values of PEG-PPG-PEG; however, the extent of the shift in the values of CMT towards lower temperatures is more prominent for sarcosine as compared to that of betaine and TMAO. In the case of 1.0 M sarcosine, the minimum CMT value occurs at 28.5 °C while the presence of 1.0 M betaine in PEG-PPG-PEG aqueous solution brings the CMT value to a minimum near 31.0 °C. All the CMT values are presented in Table 1. Furthermore, Fig. S2(d) represents the heat capacity variation allowing the changes in CMT values of PEG-PPG-PEG solutions containing GdnHCl to be understood as a function of temperature. In contrast to the methylamines, which we have studied, the presence of GdnHCl is influencing the interactions in such a way that the CMT values increase to higher values in comparison to that of PEG-PPG-PEG in water i.e. CMT values are increasing with the concentration of GdnHCl. The presence of NH2 groups in structure of GdnHCl may form bridging interactions with the hydroxyl group in polymer segments and thus making it more soluble at higher temperatures. The CMT of PEG-PPG-PEG in presence of 1.0 M concentration of GdnHCl is approaching the value of 41.7 °C. The higher concentrations of GdnHCl (2.0 and 3.0 M) do not show good transition in heat capacity values in DSC measurements. By contrast, the effect of urea on the micellization tendency of PEG-PPG-PEG is depicted in Fig. S2(e). The CMT values of PEGPPG-PEG are observed to increase with increasing urea concentration in the same manner as GdnHCl. Interestingly, urea has the ability to solubilize the polymer to higher temperature values through its binding efficiency to polymeric segments. The increment in CMT values is more prominent in the case of urea as compared to GdnHCl. The urea and GdnHCl are forming favourable bonding interactions with polymer and making its more soluble with increasing temperature. Although the CMT values for PEGPPG-PEG, which may increased to different extents. However, the expected abrupt increase in heat capacity values of PEG-PPG-PEG in presence of 4.0 and 5.0 M urea is not much and no clear transition is observed. Very different from urea and GdnHCl, methylamine based osmolytes are facilitating the hydrophobicity around the polymer segments through direct and indirect bonding interactions. Among three methylamines, direct hydrogen bonding interactions are possible only for the case of sarcosine involving non-sterically hindered N atom. However, betaine and TMAO has the ability to attract the water molecules surrounding polymer segments and thus affecting the CMT value of PEG-PPG-PEG through indirect interactions. GdnHCl and urea are behaving differently from the three methylamines i.e. TMAO, betaine and sarcosine. The former have the ability to make some hydrophilic kind of interactions due to the presence of NH2 groups, and specifically urea is known as a
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P. Narang et al. / Journal of Colloid and Interface Science 553 (2019) 655–665 Table 1 The CMTs values of PEG-PPG-PEG aqueous system obtained from DSC studies in presence of varying concentrations of TMAO, betaine, sarcosine, GdnHCl and urea. Concentration of Additive [M]
0.0 0.1 0.25 0.5 0.75 1.0 2.0 3.0
Critical micellization temperature/(°C) TMAO
Betaine
Sarcosine
GdnHCl
Urea
39.0 ± 0.1 38.2 ± 0.1 36.6 ± 0.1 34.2 ± 0.2 32.3 ± 0.2 30.7 ± 0.1 – –
39.0 ± 0.1 38.4 ± 0.2 37.0 ± 0.1 35.2 ± 0.2 32.7 ± 0.1 31.0 ± 0.1 – –
39.0 ± 0.1 37.9 ± 0.1 35.3 ± 0.2 33.4 ± 0.2 31.2 ± 0.1 28.5 ± 0.1 – –
39.0 ± 0.1 39.1 ± 0.1 39.4 ± 0.1 40.1 ± 0.2 40.7 ± 0.1 41.7 ± 0.2 – –
39.0 ± 0.1 39.1 ± 0.2 39.1 ± 0.1 39.3 ± 0.1 39.5 ± 0.1 40.2 ± 0.2 41.8 ± 0.1 44.0 ± 0.1
bridging ligand between the polymer segments, [39] whereas GdnHCl is a denaturant for proteins through direct bonding favourable interactions [38]. This kind of hydrophilic interaction plays the major role in inducing the micellization of PEG-PPG-PEG towards higher temperature values. By contrast, the polarization of water molecules induced by methylamines (TMAO and betaine) results in the disruption of H-bonds with polymer segments and thus leads to more hydrophobic environment. This explains the micellization of PEG-PPG-PEG at lower temperature values in comparison to the PEG-PPG-PEG in aqueous solution. Fig. S3 illustrates the critical micellization temperature (CMT) values of PEG-PPG-PEG in presence of all the five studied additives. The methylamine based osmolytes are observed to have the negative slope for CMT values with increase in their concentrations. The sarcosine is observed to facilitate maximum decrement in CMT values in comparison to TMAO and betaine. This may happen due to the difference existing among their structural units. The presence of sterically hindered tertiary N atom prevents the direct interactions between polymeric segments and betaine/TMAO [34]. Among methylamines, the CMT values follow the order as:
sarcosine > TMAO > betaine Additionally, it is suspected that the trendin CMT values of methylamines as observed in DSC experiments are in accordance with the trend observed from all the other biophysical techniques. This is to say, the extent of enhancement in hydrophobicity among the three methylamines via UV–visible and fluorescence spectroscopic measurements is found similar to trend in their CMT values. By contrast, GdnHCl and urea have the ability to induce hydrophilic interactions for PEG-PPG-PEG which may be due to their favorable bridging association among polymer segments resulting in enhanced CMT values of PEG-PPG-PEG. At the particular concentration (1.0 M), GdnHCl facilitates the micellization to lesser extent than urea when compared to the PEG-PPG-PEG in aqueous solution. The sequence for their increment is given as:
GdnHCl > urea Overall, the order of additives for their facilitating ability towards micellization of PEG-PPG-PEG is as follows:
sarcosine > TMAO > betaine > urea > GdnHCl
Scheme 1. Chemical structures of PEG-PPG-PEG, TMAO, betaine, sarcosine, GdnHCl and urea.
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Scheme 2. Molecular interactions induced by different kind of additives on the CMT behavior of PEG-PPG-PEG.
Clearly, copolymerization with a hydrophobic comonomer can lower the CMT of PEG-PPG-PEG. On the contrary, copolymerization with hydrophilic comonomer alters the CMT of triblock copolymer to higher values. The influence of two different kinds of additives is depicted in Scheme 2. It is noteworthy to compare the CMT values of Pluronics in the presence of various additives which were studied earlier [1,2]. The presence of ionic salt such as potassium chloride (KCl) in the aqueous solution of Pluronics of varying molecular weight (depending on the number of PEO and PPO units present) decreases the CMT values as compared to free KCl solution of Pluronics [1]. Furthermore, it has been reported by Bahadur and co-workers [2] that presence of ionic surfactants such as sodium dodecyl sulphate (NaDS) and dodecyltrimethylammonium bromide (DTABr) reduces the micellization propensity and thus induces demicellization. However, the presence of NaBr made micellization faster and thus more concentration of surfactant is needed to approach the same CMT value. Thus, one can say that they both acts in opposition. Obviously, the tuning of the CMT values of triblock co-polymer in the presence of different additives can be altered depending on the nature and structure of the additives. 4. Conclusion The CMT value of PEG-PPG-PEG by itself is unsatisfactory for many applications in various areas of science. The presence of various additives can alter the micellization tendency to a different extent depending on the interactions with the polymer induced by them on the basis of their structures [2,3,8,25–27]. The presence of any of the three methylamines such as TMAO, betaine and sarcosine in the solution is found to decrease the micellization temperature values of PEG-PPG-PEG as the concentration increases. Among them, sarcosine has the maximum ability to prompt the micellization. Betaine is the least effected due to its ability to form bonding interactions directly to the polymer segments which is completely absent in the case of betaine and TMAO. Very differently, GdnHCl and urea are found to increase the CMT values of PEG-PPG-PEG. The reason may lie in their ability to interpolate among various polymeric segments and thus solubilize it up to higher temperature values. The overall order for facilitating the micellization behavior is provided as:
Sarcosine > TMAO > Betaine > urea > GdnHCl The current study will find numerous applications in biomedical field and pharmaceutical industries. The efficiency of additives to tune the CMT values of triblock copolymer can be exploited to adjust the temperature required for a specific area of interest. Moreover, the study leads us to understand how the functional group can directly or indirectly associate to the polymer segments and thus allows us to find the specific drugs (hydrophobic or hydrophilic) that can be trapped in the triblock copolymer when participating in a vesicle. Our study explicitly elucidates how the different additives alter the CMT or CMC of PEG-PPG-PEG in water
to various extents depending on the atoms constituting their structures and their arrangements. Nonetheless, the detailed mechanism for thermosensitive polymers must continue to be considered a subject for further intensive investigation.
Acknowledgments We acknowledge the financial support from the SERB, Department of Science and Technology (DST), New Delhi, India (Grant No. EMR/2016/001149). P.N. is grateful to UGC, New Delhi for providing SRF (Senior Research Fellowship).
Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jcis.2019.06.074.
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Journal of Colloid and Interface Science journal homepage: www.elsevier.com/locate/jcis
Regular Article
Scrutinizing the effect of various nitrogen containing additives on the micellization behavior of a triblock copolymer Payal Narang, Niketa Yadav, Pannuru Venkatesu ⇑ Department of Chemistry, University of Delhi, Delhi 110007, India
g r a p h i c a l a b s t r a c t
a r t i c l e
i n f o
Article history: Received 3 April 2019 Revised 20 June 2019 Accepted 21 June 2019 Available online 22 June 2019 Keywords: Triblock copolymer Additives Critical micellization temperature Osmolytes Denaturants
a b s t r a c t Hypothesis: PEG-PPG-PEG contains hydrophobic (PPG) as well as hydrophilic (PEG) blocks have gained popularity due to their different physiochemical properties that make them useful in several scientific areas and industrial applications such as detergency, stabilizers for dispersion, foaming and many more. Scientific communities reported that additives have ability to tune the micellization/demicellization tendency of PEG-PPG-PEG which we further extended by the use of several N-containing additives. Especially, chemists and biochemists are interested to extend the potential role of PEG-PPG-PEG copolymer in biomedical sensing applications, that is why triblock copolymer is chosen with various additives in the present study. Experiments: The work reports the results obtained through different kinds of interactions induced among the poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPGPEG) and additives containing different structural moieties. In order to tune micellization tendency of PEG-PPG-PEG, several additives such as trimethylamine-N-oxide (TMAO), betaine, sarcosine, guanidinium hydrochloride (GdnHCl) and urea are introduced in the current part of work and studied using UV–visible and fluorescence spectroscopy, dynamic light scattering (DLS), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy. Findings: The methylamines facilitate the micellization to higher extent in comparison to that in aqueous PEG-PPG-PEG system, thereby decreasing the critical micellization temperature (CMT) values of PEGPPG-PEG. Among studied methylamines, sarcosine has the highest efficacy in inducing the micellization followed by TMAO and betaine to the least extent. Direct interactions among polymeric segments and sarcosine is thought to be the main driving force for micellization of PEG-PPG-PEG. This is not possible for the case of betaine and TMAO due to the presence of the sterically hindered N atom. In contrast to these methylamines, GdnHCl and urea provided favorable binding sites for bridging interactions among polymer segments and thus lead to higher temperature values for CMT of PEG-PPG-PEG. Ó 2019 Elsevier Inc. All rights reserved.
1. Introduction Abbreviations: (PEG-PPG-PEG), Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol); LCST, lower critical solution temperature; TRPs, thermo-responsive polymers; dH, hydrodynamic diameter. ⇑ Corresponding author. E-mail address: [email protected] (P. Venkatesu). https://doi.org/10.1016/j.jcis.2019.06.074 0021-9797/Ó 2019 Elsevier Inc. All rights reserved.
Block copolymers contain hydrophilic as well as hydrophobic blocks in their structure. They are known to self assemble when dissolving in a selective solvent which can either solvate the
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hydrophilic block or hydrophobic block more in comparison to the other [1]. This self-assembled structure of a polymer is also known as micelles as observed in case of low molecular weight surfactants. The molecular weight and biocompatibility of micelles formed from block copolymers and surfactants are the source of the major difference in elucidating their use in different areas of science [1]. Altering the temperature properties of aqueous solution by using different additives is found to be the useful method to tune the micelles formation process [1–4]. Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) triblock copolymer, also known as Pluronic F-108 is an amphiphilic thermo-responsive block copolymer containing PEG as hydrophilic block and PPG as hydrophobic block in its structural integrity [5,6]. This is available in different molecular weights depending on the number of PEG and PPG segments are present [2]. Like other block copolymers, PEG-PPG-PEG can self assemble in the presence of water as solvent above at a particular concentration termed the critical micelle concentration (CMC). This happens at a specified temperature known as critical micelle temperature (CMT) [5,7–8]. Aqueous solution of copolymer contains hydrophobic as well as hydrophilic blocks have gained popularity due to their different physiochemical properties that make them useful in several scientific areas and industrial applications such as detergency, stabilizers for dispersion, foaming agents and many more [5,7–9]. Pluronic F-108 is a kind of water soluble copolymer whose micellization and aggregation behavior is reported to be influenced by light, pH [6], temperature and ionic strength of the solution mixture [5,10–13]. Due to its versatile ability to respond to external stimuli, its properties can be altered in many ways which contribute to its widespread applications in aggregation [14,15], drug delivery [16], rechargeable batteries [17] and food packaging industries [18], etc. Additionally, it is reported recently that thermal and mechanical properties of low fracture resistance epoxy resin can be modified on addition of triblock copolymers depending on varying ratios of PEG:PPG [19,20]. It has also been reported that introducing starch segments in triblock copolymer mixtures makes them useful in the preparation of bone hemostatic wax [21]. The phase transition temperature of PEG-PPG-PEG is altered significantly in the presence of various additives as a function of their concentration. Basically, naturally occurring osmolytes are molecules which protect our cells from osmotic pressure and are ubiquitous in living organism [22]. Osmolytes are the small molecular mass additives with the ability to alter the functional behavior of macromolecules and are known to protect cells from various stresses [23]. Poly (ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-PPO-PEO) corresponds to PEG-PPG-PEG in structure except the position of methyl group is different in PPO block of polymer chain [24]. The PEO-PPO-PEO molecule is widely studied under the influence of different additives such as surfactants [2,8,25–27], hofmeister series cations and anions [9] and various salts [1,3,28–29]. The binding affinity of various monovalent cations and divalent cations on triblock copolymer was investigated by Zhang and group [30]. Subsequently, the presence of urea was found to increase CMC and CMT of the PEO-PPO-PEO copolymer [31]. Structural indentity of additives such as trehalose, sucrose, sorbitol, TMAO and betaine play a prominent role in deciding the phase transition behavior of thermo-responsive polymers (TRPs) and have been extensively studied by our research group [32–34]. Among the class of osmolytes, the three different methylamines such as trimethylamine-N-oxide (TMAO), betaine, sarcosine, plus urea (polar osmolytes) and guanidinium hydrochloride (GdnHCl) (a denaturant for proteins) were chosen for the study. Scientific communities, especially chemists and biochemists are interested in extending the potential role of PEG-PPG-PEG copoly-
mer in biomedical sensing applications, which is why triblock copolymer is chosen with various additives in the present study. Various biophysical spectroscopic studies were employed in evaluating the influence of TMAO, betaine, sarcosine, urea and GdnHCl on the micellization behavior of Pluronic F-108. The published literature indicates that little effort has been previously directed to the study of this problem. UV–visible and fluorescence spectroscopy, dynamic light scattering (DLS), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy studies were used for the current investigation. This effort has led us to find new ways to tune the micellization behavior of triblock copolymer and further extend its potential applications in biomedical research. 2. Experimental section 2.1. Materials and sample preparation All the chemicals were purchased from Sigma-Aldrich (USA). These include chemicals such as poly(ethylene glycol)-block-poly (propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) triblock copolymer or Pluronics F-108, pyrene (Py), trimethylamine N-oxide (TMAO) (99%), betaine (98%), sarcosine (98%), guanidinium hydrochloride (GdnHCl) (99%) and urea (99%). All the chemicals were directly used without purification. The molecular weight (Mn) of PEG-PPG-PEG is 14.6 kDa having PEG content almost 82.5%, (PEG)133-(PPG)49-(PEG)133. Double distilled deionized water having 18.3 MO cm resistivity was obtained from Ultra 370 series, Rions India, India and was used to prepare all solutions. An analytical balance (Mettler Toledo) was used to weigh the appropriate mass of polymer and other additives having a precision of ±0.0001 g and dissolved in pure water. The 7 mg/ml concentration of polymer was maintained for all measurements. Except for urea, the additive concentrations in the copolymer solutions were (0.10, 0.25, 0.50, 0.75 and 1.0 M) in all cases. Because of its high solubility however, different concentrations of urea were (0.5, 1.0, 2.0, 3.0 and 4.0 M) in the copolymer solutions. DLS experiments were performed using solutions that have been passed through a 0.45 mm filter obtained from Millipore, Millex-GS. A vaccum syringe was used to draw the solution through the filter. The sample solutions were allowed to equilibrate at room temperature for some time. Furthermore, all the other needed information has already been given in our earlier papers [32–34]. The chemical structures of polymer and all the additives are provided in Scheme 1. 2.2. Methods Spectra were obtained using a UV-1800, Shimadzu Co., Japan double beam UV–visible spectrophotometer equipped with a quartz cuvette sample holder. The sample holder is carrying 1 nm bandwidth and a 0.3 nm wavelength accuracy. An wavelength correction system is automatically built into the system to record UV–visible spectra for its particular wavelength range for each measurement at room temperature. The appropriate amount of solution mixture was poured into cell of 1 cm path length made of quartz. Cary eclipse fluorescence spectrophotometer (Varian optical spectroscopy instruments, Mulgrave, Victoria, Australia) was used to measure fluorescence spectra of probe (Py) in PEGPPG-PEG aqueous solution in the presence and absence of different additives in various concentrations. This instrument is equipped with Peltier device that electro-thermally controls the temperature to high precision. After equilibration of 20 min at each temperature, the spectra of samples were recorded. The excitation wavelength was maintained constant at 335 nm while fluorescence
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emission at 375 nm wavelength was collected as a function of temperature. The size distribution of macromolecular assembly was performed by means of a Zetasizer Nano ZS90 dynamic light scattering (DLS) instrument (Malvern Instruments Ltd., UK). A 4 mW He–Ne built-in laser serves as the light source at 633 nm fixed wavelength (k). A Thermo-Fisher scientific corporation iS 50 FTIR Fourier transform spectrometer was used to record IR spectrum. The details of the procedure are as previously described [32–34]. 2.2.1. Differential scanning calorimetry measurements Critical micellization temperature (CMT) of PEG-PPG-PEG solutions containing various additives was performed with NANO DSC instrument (TA Instruments, USA). It is equipped with a sample and reference cell containing 0.650 mL cell volume. The changes in heat absorption or evolution were recorded as a function of temperature. The pressure was maintained at 3 atm while maintaining a scan rate of 2 °C/min. All the samples were equilibrated for 5 min. The degassing system provided is used to degas the sample before putting into the cells. Before starting the experiment, water-water scans were performed for baseline correction within the specified temperature range. All the data obtained was finalized by NANO analyzer software to obtain the clear CMTs of PEG-PPG-PEG. 3. Results and discussion 3.1. UV–visible spectroscopy analysis of PEG-PPG-PEG in presence of various additives UV–visible spectroscopic studies are employed to check the tendency for micellization of PEG-PPG-PEG in presence of additives such as TMAO, betaine, sarcosine, GndHCl and urea in aqueous solution. Pyrene (Py) is taken as an external probe to investigate the changes around the polymeric environment in aqueous system [5]. To avoid its interactions with polymer or additives, the amount taken was very less (1 mM). Furthermore, Py is a kind of probe which shows negligible absorbance in pure aqueous system. Py probe is hydrophobic in nature and shows very little or negligible feasible interactions with water. Fig. 1 represents the UV–visible spectra of Py in PEG-PPG-PEG for the wavelength range (190– 700 nm) at 25 °C temperature. In the absence of any additive, Py in PEG-PPG-PEG is observed to show five non-distinctive peaks at 265, 275, 305, 320 and 335 nm [5]. The peak values are quite consistent with the existing values in literature. These five peaks clearly signify that the polymer is providing the hydrophobic environment to Py. Fig. 1(a) represents the variation in absorbance values of five peaks of Py in PEG-PPG-PEG containing varying concentrations of TMAO from 0.1 to 1.0 M. The absorbance keeps on increasing with increase in the concentration of TMAO in sequential manner. The absorbance value reaches approximately 0.067 a.u. for 1.0 M of TMAO. In the same way, Fig. 1(b and c) shows the change in absorbance spectra of Py in PEG-PPG-PEG containing another two methylamines, betaine and sarcosine, respectively. The increment in absorbance for all the five peaks is less prominent for betaine as compared to that of sarcosine. The presence of sarcosine and betaine are showing the absorbance value of 0.08 and 0.05 a.u., respectively for their maximum concentration. Assisting the influence of GndHCl on the UV–visible absorbance spectra of PEG-PPG-PEG in different concentrations (0.1–1.0 M) is depicted in Fig. 1(d). The spectra show the increment in absorbance value along with increase the concentration. The increment is not much prominent as in case of three methylamines studied. The reason may lie in its different kinds of interaction in comparison to that of methylamines studied. A polar osmolytes molecule, urea is also added to Py in PEG-PPG-PEG solution mixture to check its effect along with various charged species. We have observed
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less intensified five peaks of Py in PEG-PPG-PEG (Fig. 1(e)). The urea is also observed to increase the absorbance values however, peaks are less prominent. Urea is behaving quite differently than all other additives studied as some peaks are vanishing in its presence which may be basically due to its ability to form bridging interactions with polymer that no longer enhances the hydrophobicity around polymer to much extent. The difference in structural integrity among all the studied additives containing charged moieties is making the difference in their UV–visible spectra [33,34]. The increment in absorbance values for all the additives indicate that Py started interacted more and more with hydrophobic moieties of polymer. Moreover, it is found to be in accordance with the concentration of the additive. 3.2. Steady state spectroscopy analysis of PEG-PPG-PEG in presence of various additives The interactions of the various additives with the amphiphilic copolymer PEG-PPG-PEG can be studied using Py as a probe for steady state fluorescence spectroscopy. The spectra are collected at room temperature keeping the excitation wavelength at 335 nm. Fig. 2 reflects the variation in steady state fluorescence spectra of Py in PEG-PPG-PEG in presence and absence of various additives as a function of concentration. The emission intensity is observed at 375 and 390 nm for Py in PEG-PPG-PEG aqueous system [5]. Fig. 2(a) depicts the variation in emission spectra of Py in PEG-PPG-PEG with increase in the concentration of TMAO from 0.1 to 1.0 M. The fluorescence intensity is observed to show a direct relationship to the concentration of TMAO and maximum increment of approx. 475 a.u. is observed for maximum concentration of TMAO. Py is a kind of probe which senses the significant change happening in terms of polarity or hydrophilicity/ hydrophobicity ratio in the microenvironment of Py in PEGPPG-PEG on addition of several additives containing different functional moieties. TMAO is inducing polarization of water molecules around the surface of polymer. However, no significant change in fluorescence intensity is observed at lower concentrations of TMAO approximately up to 0.5 M, although the changes are becoming more pronounced as the concentration increases. Similarly, Fig. 2(b and c) are depicting the alteration in fluorescence intensity values of Py in PEG-PPG-PEG possessing different concentrations of betaine and sarcosine, respectively. The significant change with respect to both increment and value in fluorescence intensity as a function of concentration was observed in the case of both the additives. Like TMAO, betaine and sarcosine are inducing the hydrophobicity around the polymer molecule and which results in enhanced fluorescence intensity due to the formation of small fraction of mesoglobules and aggregates of polymer in the solution. Additionally, at low concentrations of betaine and sarcosine (0.5 M), no appreciable variation is observed. The mechanism for inducing the micellization of polymer PEG-PPGPEG can be different for different methylamines used depending on their chemical structures. Furthermore, Fig. 2(d) presents the variation in steady state fluorescence spectra of PEG-PPG-PEG upon addition of GdnHCl. Very different from methylamines discussed above, the fluorescence intensity values decreased to 60 from 136 a.u as concentration increases. Moreover, the changes are not a very strong function of concentration. Fig. 2(e) reflects the changes in fluorescence intensity of Py in PEG-PPG-PEG with urea concentration advancing from 0.5 M to 4.0 M. It is found that a more significant decrease in fluorescence intensity is observed at the lowest concentrations. The fluorescence intensity of Py in PEG-PPG-PEG does not reach the values associated with the absence of additives for any concentration of urea. Overall from steady state fluorescence, one can observe the three methylamines are behaving differently from urea
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Wavelength (nm) Fig. 1. UV visible spectra of pyrene in PEG-PPG-PEG aqueous solution containing (a) TMAO, (b) betaine, (c) sarcosine, (d) GndHCl and (e) urea as additives in varying concentrations. Aqueous PEG-PPG-PEG (black), 0.10 M (red), 0.25 M (blue), 0.50 M (dark cyan), 0.75 M (pink) and 1.00 M (dark yellow). (e) Aqueous PEG-PPG-PEG (black), 0.50 M (red), 1.0 M (blue), 2.0 M (dark cyan), 3.0 M (pink) and 4.0 M (dark yellow) under atmospheric conditions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
and GdnHCl. Different types of interactions due to different atoms present in their structural units is playing the key role resulting in aforesaid changes observed in fluorescence spectra. Further, we have analysed the ratio I1/I3 as I375/I390 of Py in PEGPPG-PEG in presence of all the varying concentrations of additives and presented in supporting information as Fig. S1. As we already know that the significant change is happening in terms of polarity or hydrophilicity/hydrophobicity ratio in the microenvironment of Py in PEG-PPG-PEG on addition of several additives containing dif-
ferent functional moieties. The decrease in fluorescence intensity ratio I1/I3 with increase in concentration of TMAO, betaine and sarcosine from 0.1 to 1.0 M in reflects the decrease in microenvironmental polarity of solution and the solution mixture is becoming more hydrophobic which is quite consistent with the literature [35,36]. Their ability to induce micellization is the main reason that facilitates the increase in hydrophobicity around the Py. These osmolytes have the ability to disrupt the water structure around the polymer segment through polarization of water mole-
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cules which further influences the ratio of hydrophilicity/ hydrophobicity of Py in PEG-PPG-PEG and thus results in changes in the fluorescence spectra. Additionally, the ratio I1/I3 of Py in PEG-PPG-PEG in presence of GdnHCl is not showing any significant alteration in polarity and only variation in hydrophilicity/hydrophobicity ratio is obtained which may be due to the partial accumulation of particular ions around the polymer segments. Furthermore, it is found to be a denaturant for proteins through some direct binding interactions with macromolecule [37,38]. However, in the case of urea, we do not observe much variation in polarity of the solution mixture at
lower concentrations, while an increment in ratio I1/I3 of Py is predicted at higher concentrations of urea, which supports the idea of increase in polarity. This is very different from all other cases which may be due to the ability of urea to form hydrophilic binding with polymer segments through its well established bridging tendency [39]. Thus, the alteration in ratio I1/I3 of Py in PEG-PPG-PEG is clearly deciphering the specific role of a particular additive to induce the changes in micro-environment from hydrophilic to hydrophobic or vice versa, which basically influences the balance of hydrophobic effects versus hydrogen bonding interactions with the EO and PPO blocks.
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3.3 Volume. distribution analysis of PEG-PPG-PEG in presence of various additives Dynamic light scattering (DLS) is very useful technique to get an idea about the hydrated size of the macromolecular particles present in solution mixture. Fig. 3 illustrates the size distribution of PEG-PPG-PEG in the absence and presence of several additives along with their concentration variation. The size distribution variation is shown as the alteration in volume percentage with respect to the change in hydrodynamic diameter (dH) of polymer. The additives do not scatter light individually in the solution mixture
due to their relatively small size in comparison to that of polymer. Fig. 3(a) depicts how the light scattering power varies with the size of particles in the solution as a function of added TMAO concentration increasing in the range 0.1–1.0 M. The particle size in the PEGPPG-PEG aqueous solution is of the order of 10 nm in agreement with literature value [25]. Interestingly, the volume percentage peak at 10 nm is observed to shift more and more towards the higher sized values with increasing the concentration of TMAO in triblock copolymer. The easy formation of polymeric micelles may be the reason for this peak shift. In other words, TMAO is showing its ability to induce the micellzation of polymer as its
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affinity to attract water molecules associated to PEG-PPG-PEG increases in a concentration dependent manner. The volume distribution graph of PEG-PPG-PEG is also investigated in the presence of betaine and sarcosine in the concentration range from 0.1 to 1.0 M. In the similar way to TMAO, peak value at 10 nm is observed to shift at higher dH value due to the aggregation of polymeric micelles and their size keeps on increasing in the concentration manner of betaine (Fig. 3(b)). Sarcosine is also showing more shift in dH values towards higher values. The structure of sarcosine is quite different from betaine and TMAO with respect to non-sterically hindered N atom. The ability of the N atom to bind directly to the polymeric segment is making the micelles more stable at room temperature. This all serves as the basis for the aforesaid changes in volume distribution graph [34]. Overall, all the methylamine based osmolytes have the ability to facilitate the micellization behavior of PEG-PPG-PEG and further aggregation of polymeric micelles via the different types of interactions which they induce. On the other hand, Fig. 3(d) presents the variation in volume percentage for differently sized micro-assemblies present in solution after adding varying concentrations of GdnHCl. The peak values at 10 nm do not show much shift abrupt decrease as compared to all the three methylamines studied. The hydrogen bonding interactions between polymer segments and GdnHCl are the major reason for stabilization of coiled form of polymer and no more shifting of 10 nm peak intensity value with varying concentrations of GdnHCl [23]. The NH2 group present in GdnHCl has the ability to get involved in hydrophilic kind of interactions with the polymer which do not allow easy formation of micelles and hence not much variation in volume percentage is observed. Fig. 3(e) reflects the size variation of macromolecular particles in the presence of urea in the concentration range from 0.5 to 4.0 M. As urea acts as a binding ligand among polymer segments containing hydrophilic binding moieties [25], it has the ability to solubilize the polymer in its coiled form to higher extent or higher level of concentration of urea. This more stabilizing ability of urea towards the coiled form of the PEG-PPG-PEG polymer does not provide shift in the volume percentage peak at higher dH values. Moreover, larger aggregates may form however, they are very less in number at room temperature that volume occupied by them are negligibly small in comparison to that of the particles at 10 nm.
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Wavenumber(cm-1) Fig. 4. FTIR spectra of PEG-PPG-PEG in D2O containing (a) TMAO, (b) betaine, (c) sarcosine, (d) GdnHCl and (e) urea as additives in varying concentrations. (a–d) Aqueous PEG-PPG-PEG (black), 0.10 M (red), 0.25 M (blue), 0.50 M (dark cyan), 0.75 M (pink) and 1.00 M (dark yellow). (e) Aqueous PEG-PPG-PEG (black), 0.50 M (red), 1.0 M (blue), 2.0 M (dark cyan) and 3.0 M (pink) under atmospheric conditions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
3.4. Fourier transform infrared (FTIR) spectroscopic analysis of PEGPPG-PEG in presence of various additives The clear evidence in support of molecular interplay among PEG-PPG-PEG and different additives can be predicted from FTIR spectroscopy. It is a great tool for determining how the bonding interactions are getting affected in presence of TMAO, betaine, sarcosine, GdnHCl and urea. Fig. 4 shows the FTIR spectra of PEG-PPGPEG in D2O in the absence and the presence of five additives as a function of their concentrations. The absorbance at 1220 cm 1 in the FTIR spectra is attributable to the CAOAC stretching vibrations that usually fall in the range 1100–1250 cm 1 [34]. Two absorbance peaks of triblock copolymers between 1400 and 1500 cm 1 are observed on addition of TMAO at concentrations extending over the range from 0.1 to 1.0 M. The pattern is quite consistent with reported literature values [34]. Furthermore, these peaks keep on enhancing in absorbance value with the concentration of TMAO which clearly reflects that the more concentrated solutions of TMAO are facilitating more hydrophobic collapse through a higher extent of polarization induced among D2O molecules. Subsequently, the peak at 1220 cm 1 is decreasing which is mainly because of less interaction of polymer segments with D2O in presence of TMAO. In the similar way, the betaine and sarcosine concentration variation behavior as studied by FTIR spectroscopy is
presented in Fig. 4(b) and (c). The new peaks arise on addition of betaine to the PEG-PPG-PEG in D2O solution. One peak between 1600 and 1700 cm 1 is attributed to the COO– group present in betaine while several small peaks are observed between 1300 and 1500 cm 1 resulting from the interactions of betaine with D2O molecules around PEG-PPG-PEG. The absorbance values for these peaks show an increasing trend with concentration of betaine. Additionally, CAOAC bonding interactions are decreasing with betaine concentration due to thelow probability of interactions among D2O and polymeric segments. Sarcosine is also showing new peaks, one at around 1600 cm 1 and other between 1450 and 1280 cm 1, which can be attributed to the interactions of the polymer segments with the nonsterically hindered N atom in sarcosine. The absorbance enhancement for new peak is a maximum for the case of sarcosine in comparison to all the three methylamines studies. This may be due to the direct bonding probability of sarcosine towards the polymer segments [34]. The influence of GdnHCl addition in PEG-PPG-PEG in D2O solution as studied by FTIR spectra is represented in Fig. 4(d). The presence of GdnHCl increased the absorbance value for CAOAC stretching vibrations in addition to introducing new peaks in the
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range of 1400–1600 cm 1. GdnHCl induces hydrophilic interactions in a manner which is very different from the methylamines, leading to higher absorbance values at 1220 cm 1 attributed to the CAO stretching interactions. The peak intensity values at 1220 cm 1 are not showing the regular trend which may be due to a variety of CAO interactions associated with the addition of additives containing O atom in increasing concentration manner. Finally, the addition of urea in the concentration range 0.5–4.0 M in PEG-PPG-PEG in D2O introduces new peak values in the wavelength range 1400 to 1600 cm 1 (Fig. 4(e)). The absorbance values for these peaks are increasing with the concentration of urea. The peak value at 1590 cm 1 is attributed to the deuterated urea present in the solution mixture [25] which also shows enhancement in the value of absorbance which increases with increasing concentration of urea. Overall, one can say that several kinds of molecular interactions are playing a role in producing the FTIR spectra. This is due to the presence of different elements present in the structural unit of additives resulting in a variety of interactions induced. More intensified new peaks are observe in the case of urea and sarcosine with increasing concentrations which may arise as a result of the bridging affinity of urea and the direct binding interactions of N atom in sarcosine to polymer segments, respectively. 3.5. Differential scanning calorimetry (DSC) analysis of PEG-PPG-PEG in presence of various additives Differential scanning calorimetry (DSC) is a important and sensitive methods for investigating the transition in the micellization temperature of PEG-PPG-PEG due to the presence of different additives with increasing concentrations. Fig. 5 depicts the alteration in heat capacity values of PEG-PPG-PEG in the presence of five different additives, TMAO, betaine, sarcosine, GdnHCl and urea as a function of temperature at 0.5 M concentration. It can be interpreted clearly that GdnHCl and urea are facilitating the CMT value of
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28 30 32 34 36 38 40 42 44 46 48 50
Temperature (oC) Fig. 5. DSC curves of PEG-PPG-PEG aqueous solution containing a particular concentration 0.5 M of various additives. PEG-PPG-PEG in H2O (black), TMAO (red), betaine (blue), sarcosine (dark cyan), GdnHCl (pink) and urea (dark yellow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
PEG-PPG-PEG towards higher temperature value and methylamines to the lower temperature values. The peak temperature after which heat capacity value does not change much or shows little decrease is said to be its phase transition temperature [40–47]. Fig. S2(a) depicts the heat capacity variation of PEG-PPG-PEG in TMAO with respect to temperature in supporting information. The critical micellization temperature (CMT) of PEG-PPG-PEG is observed at around 39.0 °C which is found to be in correlation with the literature [5]. The CMT values of PEG-PPG-PEG are found to approach the lower temperature value with increasing concentration of TMAO. This value reaches up to 30.7 °C for 1.0 M concentration of TMAO (Fig. S2(a)). The polarization ability of TMAO is making the agglomeration of micelles of PEG-PPG-PEG formation easy at lower temperature values in comparison to PEG-PPG-PEG in aqueous solution [34]. Likewise, the presence of betaine and sarcosine (two different methylamines), are also observed to alter the CMT values of PEG-PPG-PEG to a significant extent and the variation in values of CMT can be predicted from Fig. S2(b and c), respectively. Both the methylamines are found to decrease the CMT values of PEG-PPG-PEG; however, the extent of the shift in the values of CMT towards lower temperatures is more prominent for sarcosine as compared to that of betaine and TMAO. In the case of 1.0 M sarcosine, the minimum CMT value occurs at 28.5 °C while the presence of 1.0 M betaine in PEG-PPG-PEG aqueous solution brings the CMT value to a minimum near 31.0 °C. All the CMT values are presented in Table 1. Furthermore, Fig. S2(d) represents the heat capacity variation allowing the changes in CMT values of PEG-PPG-PEG solutions containing GdnHCl to be understood as a function of temperature. In contrast to the methylamines, which we have studied, the presence of GdnHCl is influencing the interactions in such a way that the CMT values increase to higher values in comparison to that of PEG-PPG-PEG in water i.e. CMT values are increasing with the concentration of GdnHCl. The presence of NH2 groups in structure of GdnHCl may form bridging interactions with the hydroxyl group in polymer segments and thus making it more soluble at higher temperatures. The CMT of PEG-PPG-PEG in presence of 1.0 M concentration of GdnHCl is approaching the value of 41.7 °C. The higher concentrations of GdnHCl (2.0 and 3.0 M) do not show good transition in heat capacity values in DSC measurements. By contrast, the effect of urea on the micellization tendency of PEG-PPG-PEG is depicted in Fig. S2(e). The CMT values of PEGPPG-PEG are observed to increase with increasing urea concentration in the same manner as GdnHCl. Interestingly, urea has the ability to solubilize the polymer to higher temperature values through its binding efficiency to polymeric segments. The increment in CMT values is more prominent in the case of urea as compared to GdnHCl. The urea and GdnHCl are forming favourable bonding interactions with polymer and making its more soluble with increasing temperature. Although the CMT values for PEGPPG-PEG, which may increased to different extents. However, the expected abrupt increase in heat capacity values of PEG-PPG-PEG in presence of 4.0 and 5.0 M urea is not much and no clear transition is observed. Very different from urea and GdnHCl, methylamine based osmolytes are facilitating the hydrophobicity around the polymer segments through direct and indirect bonding interactions. Among three methylamines, direct hydrogen bonding interactions are possible only for the case of sarcosine involving non-sterically hindered N atom. However, betaine and TMAO has the ability to attract the water molecules surrounding polymer segments and thus affecting the CMT value of PEG-PPG-PEG through indirect interactions. GdnHCl and urea are behaving differently from the three methylamines i.e. TMAO, betaine and sarcosine. The former have the ability to make some hydrophilic kind of interactions due to the presence of NH2 groups, and specifically urea is known as a
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P. Narang et al. / Journal of Colloid and Interface Science 553 (2019) 655–665 Table 1 The CMTs values of PEG-PPG-PEG aqueous system obtained from DSC studies in presence of varying concentrations of TMAO, betaine, sarcosine, GdnHCl and urea. Concentration of Additive [M]
0.0 0.1 0.25 0.5 0.75 1.0 2.0 3.0
Critical micellization temperature/(°C) TMAO
Betaine
Sarcosine
GdnHCl
Urea
39.0 ± 0.1 38.2 ± 0.1 36.6 ± 0.1 34.2 ± 0.2 32.3 ± 0.2 30.7 ± 0.1 – –
39.0 ± 0.1 38.4 ± 0.2 37.0 ± 0.1 35.2 ± 0.2 32.7 ± 0.1 31.0 ± 0.1 – –
39.0 ± 0.1 37.9 ± 0.1 35.3 ± 0.2 33.4 ± 0.2 31.2 ± 0.1 28.5 ± 0.1 – –
39.0 ± 0.1 39.1 ± 0.1 39.4 ± 0.1 40.1 ± 0.2 40.7 ± 0.1 41.7 ± 0.2 – –
39.0 ± 0.1 39.1 ± 0.2 39.1 ± 0.1 39.3 ± 0.1 39.5 ± 0.1 40.2 ± 0.2 41.8 ± 0.1 44.0 ± 0.1
bridging ligand between the polymer segments, [39] whereas GdnHCl is a denaturant for proteins through direct bonding favourable interactions [38]. This kind of hydrophilic interaction plays the major role in inducing the micellization of PEG-PPG-PEG towards higher temperature values. By contrast, the polarization of water molecules induced by methylamines (TMAO and betaine) results in the disruption of H-bonds with polymer segments and thus leads to more hydrophobic environment. This explains the micellization of PEG-PPG-PEG at lower temperature values in comparison to the PEG-PPG-PEG in aqueous solution. Fig. S3 illustrates the critical micellization temperature (CMT) values of PEG-PPG-PEG in presence of all the five studied additives. The methylamine based osmolytes are observed to have the negative slope for CMT values with increase in their concentrations. The sarcosine is observed to facilitate maximum decrement in CMT values in comparison to TMAO and betaine. This may happen due to the difference existing among their structural units. The presence of sterically hindered tertiary N atom prevents the direct interactions between polymeric segments and betaine/TMAO [34]. Among methylamines, the CMT values follow the order as:
sarcosine > TMAO > betaine Additionally, it is suspected that the trendin CMT values of methylamines as observed in DSC experiments are in accordance with the trend observed from all the other biophysical techniques. This is to say, the extent of enhancement in hydrophobicity among the three methylamines via UV–visible and fluorescence spectroscopic measurements is found similar to trend in their CMT values. By contrast, GdnHCl and urea have the ability to induce hydrophilic interactions for PEG-PPG-PEG which may be due to their favorable bridging association among polymer segments resulting in enhanced CMT values of PEG-PPG-PEG. At the particular concentration (1.0 M), GdnHCl facilitates the micellization to lesser extent than urea when compared to the PEG-PPG-PEG in aqueous solution. The sequence for their increment is given as:
GdnHCl > urea Overall, the order of additives for their facilitating ability towards micellization of PEG-PPG-PEG is as follows:
sarcosine > TMAO > betaine > urea > GdnHCl
Scheme 1. Chemical structures of PEG-PPG-PEG, TMAO, betaine, sarcosine, GdnHCl and urea.
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Scheme 2. Molecular interactions induced by different kind of additives on the CMT behavior of PEG-PPG-PEG.
Clearly, copolymerization with a hydrophobic comonomer can lower the CMT of PEG-PPG-PEG. On the contrary, copolymerization with hydrophilic comonomer alters the CMT of triblock copolymer to higher values. The influence of two different kinds of additives is depicted in Scheme 2. It is noteworthy to compare the CMT values of Pluronics in the presence of various additives which were studied earlier [1,2]. The presence of ionic salt such as potassium chloride (KCl) in the aqueous solution of Pluronics of varying molecular weight (depending on the number of PEO and PPO units present) decreases the CMT values as compared to free KCl solution of Pluronics [1]. Furthermore, it has been reported by Bahadur and co-workers [2] that presence of ionic surfactants such as sodium dodecyl sulphate (NaDS) and dodecyltrimethylammonium bromide (DTABr) reduces the micellization propensity and thus induces demicellization. However, the presence of NaBr made micellization faster and thus more concentration of surfactant is needed to approach the same CMT value. Thus, one can say that they both acts in opposition. Obviously, the tuning of the CMT values of triblock co-polymer in the presence of different additives can be altered depending on the nature and structure of the additives. 4. Conclusion The CMT value of PEG-PPG-PEG by itself is unsatisfactory for many applications in various areas of science. The presence of various additives can alter the micellization tendency to a different extent depending on the interactions with the polymer induced by them on the basis of their structures [2,3,8,25–27]. The presence of any of the three methylamines such as TMAO, betaine and sarcosine in the solution is found to decrease the micellization temperature values of PEG-PPG-PEG as the concentration increases. Among them, sarcosine has the maximum ability to prompt the micellization. Betaine is the least effected due to its ability to form bonding interactions directly to the polymer segments which is completely absent in the case of betaine and TMAO. Very differently, GdnHCl and urea are found to increase the CMT values of PEG-PPG-PEG. The reason may lie in their ability to interpolate among various polymeric segments and thus solubilize it up to higher temperature values. The overall order for facilitating the micellization behavior is provided as:
Sarcosine > TMAO > Betaine > urea > GdnHCl The current study will find numerous applications in biomedical field and pharmaceutical industries. The efficiency of additives to tune the CMT values of triblock copolymer can be exploited to adjust the temperature required for a specific area of interest. Moreover, the study leads us to understand how the functional group can directly or indirectly associate to the polymer segments and thus allows us to find the specific drugs (hydrophobic or hydrophilic) that can be trapped in the triblock copolymer when participating in a vesicle. Our study explicitly elucidates how the different additives alter the CMT or CMC of PEG-PPG-PEG in water
to various extents depending on the atoms constituting their structures and their arrangements. Nonetheless, the detailed mechanism for thermosensitive polymers must continue to be considered a subject for further intensive investigation.
Acknowledgments We acknowledge the financial support from the SERB, Department of Science and Technology (DST), New Delhi, India (Grant No. EMR/2016/001149). P.N. is grateful to UGC, New Delhi for providing SRF (Senior Research Fellowship).
Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jcis.2019.06.074.
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