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A review on

Pluronic block copolymer micelles: structure and dynamics By Mohammad Atif Faiz Afzal

1. Introduction

Poly-ethylene oxide and poly-propylene oxide tri-block copolymers, commercially known as

Pluronics or Poloxamers have been studied extensively due to its wide applications in drug delivery,

synthesis of mesoporous materials, emulsification, lubrication, foaming, detergency, cleaning and

dispersion stabilization. Few of the Pluronic structures are also approved by US Food and Drug

Administration (FDA) as injectable materials for human body and therefore Pluronics have been

extensively studied as drug delivery systems in the last decade. Pluronics play a vital role in cancer therapy

by carrying and delivering anti-cancer drugs to specified targets including lung, breast, ovarian, gastric and

oesophagus tumors.

Pluronics are amphiphilic copolymers containing hydrophilic and hydrophobic blocks arranged in

a triblock structure. The hydrophilic and hydrophobic blocks consist of poly-ethylene oxide (PEO) and poly-

propylene oxide (PPO) respectively and the number of these hydrophilic and hydrophobic units in the

polymeric chain characterizes the properties of Pluronics. Due to the amphiphillic properties, Pluronics

are known to self-assemble into micelles in aqueous solution above a critical polymer concentration called

critical micelle concentration (cmc).

The study on the micellization of Pluronic block copolymers started in the early 1990’s. The

primary problem was to understand the structure and the dynamics of micelle formation. A productive

insight on the micellization process was obtained when Alexandridis et al explained the process on the

basis of thermodynamics [1]. They discovered that the process of micellization is entropy driven and this

is considered as a major breakthrough in the field of Pluronics. During the same time Linse et al explained

the process of micellization on the basis of mean field lattice theory [2]. The above mentioned authors

also studied cmc, critical micellization temperature (cmt), the aggregation number and the hydrodynamic

radius of various Pluronic block copolymers in aqueous solutions. These findings lay the ground work for

further research on Pluronic block copolymer micelles. Later, extensive research has been performed to

study the phase behavior of these micelles.

In early 2000’s, vast efforts were invested in trying to manipulate the structure, cmc and cmt of

Pluronic block copolymer micelles by changing the solvent composition or by adding some additives. For

example, the effect of urea [3], effect of using mixed aqueous solutions [4-6], non-aqueous polar

solvents[4], organic solvents[7] and the effect of addition of different salts[8], ionic and non-ionic

surfactants[9, 10] on the structure of the micelles was explored. Subsequently, molecular simulations

were conducted by other scientists to further understand the structural properties and interactions in

micellar solutions[11-13] [14].

In this report, a comprehensive review of the structure and dynamics of Pluronic micelles is

presented. The fundamentals of Pluronics synthesis, thermodynamics of micelle formation, molecular

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structure and solvent quality effects on the micelle structure and dynamics have been reviewed. Various

applications of Pluronic micelles are also reported, with drug delivery being the main focus.

2. Pluronic Micelles 2.1 Chemistry of Pluronics

Pluronics (also known poloxamers) are commercially available and can be obtained in a range of

molecular weights and PPO/PEO ratios. Pluronics are synthesized by anionic polymerization of alkyl oxide

in the presence of an alkaline catalyst, generally sodium or potassium hydroxide. Anionic polymerization

was first discovered in 1956 by Szwarc and since then it has been used to synthesize a variety of block

copolymers [15]. In case of Pluronics, the polymerization is proceeded by first adding propylene oxide and

then subsequently adding ethylene oxide to low molecular weight propylene glycol (molecular weight less

than 750). After the reaction, the catalyst is neutralized and removed. Figure 1 shows the sequence of

reactions producing PEO-PPO-PEO triblock copolymer [16]. Pluronics with varying molecular weight can

be produced using this method.

Figure 1:- sequence of reactions showing the formation PEO-PPO-PEO triblock copolymer

Pluronic block copolymers exist as unimers in the aqueous medium below CMC and above CMC

these unimers aggregate to form micelles in a very narrow concentration range and are in equilibrium

with the unassociated unimers. Pluronic copolymers form micelles at much lower concentration when

compared to low molecular weight surfactants. Micelles formed from Pluronics consist of a swollen core

of lyophobic PPO blocks and flexible corona of lyophilic PEO blocks. Micellization of Pluronics is

characterized by CMC, critical micelle temperature (CMT), molecular weight of the micelle and the

aggregation/association number. Micelles are also characterized based on their size and shape which

includes the radius of gyration (Rg), radius of core (Rc), thickness of corona (L), hydrodynamic radius (Rh)

and the ratio Rg/Rh [17]. The structure of micelles can be determined by using various characterization

techniques depending on the characteristics we are looking for. Table 1 shows the listings of different

techniques used for different micelle characteristics [18].

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Table 1:- Experimental techniques for micelle characterization [18]

Techniques Micelle Characteristics

TEM (Transmission Electron Microscope) Shape, size

SANS (Small Angle Neutron Scattering) and SAXS (Small Angle X-Ray Scattering)

Molecular weight (weight average), Rg, Rcore, macrolattice structures,

SLS (Static Light Scattering) Molecular weight (weight average), Rg

DLS (Dynamic Light Scattering) Rh

SEC (Size Exclusion Chromatography) Rh, dynamics of micellar equilibrium

Ultracentrifgation Micelle density, molecular weight (Z average), micelle/unimer weight ratio

Fluorescence techniques Chain dynamics, CMC, hybridization of micelles

NMR (Nuclear Magnetic Resonance) Chain dynamics

Viscometry Rh, intrinsic viscosity

Stop flow techniques Kinetics of micelle formation and dissociation

As Pluronics can exist in a large range of molecular weight and hydrophilic lipophilic balance (HLB),

a nomenclature is given to clearly differentiate different Pluronics. The notation of Pluronics starts with a

letter and followed by two or three digit number. The letter indicates the phase of Pluronic which includes

either P (for paste), L (for liquid) or F (for flakes) , whereas the last digit signifies the percentage of ethylene

oxide and the first one or two digits of the number when multiplied by 300 gives the approximate

molecular weight of PPO block (Vaughn, T.H.,1951). For example, Pluronic P105 represents a Pluronic in

the paste form with 40% ethylene oxide and molecular weight of PPO block being on the order of 3000.

Table 2 shows the commercially available Pluronics provided by BASF along with their properties [19]. It

can be seen that a very wide distribution of molecular weight from 1630 to 14600 is available.

Table 2:- Properties of Pluronic PEO-PPO-PEO copolymers [19]. A: copolymer. B: average molecular weight. C: PEO wt.%. D: melting pour point (OC). E: viscosity (Brookfield) (cps; liquids at 25OC, pastes at 60OC, solids at 77OC). F: surface tension at 0.1%, 25OC (dyn cm-1). G: foam height (mm)(RossMiles, 0.1% at 50OC). H: cloud point in aqueous 1% solution (:C). l: HLB (hydrophilic-lipophilic balance).

A B C D E F G H I

L35 1900 50 7 375 49 25 73 18-23

F38 4700 80 48 260 52 35 >100 >24

L42 1630 20 -26 280 46 0 37 7-12

L43 1850 30 -1 310 47 0 42 7-12

L44 2200 40 16 440 45 25 65 12-18

L62 2500 20 -4 450 43 25 32 1-7

L63 2650 30 10 490 43 30 34 7-12

L64 2900 40 16 850 43 40 58 12-18

P65 3400 50 27 180 46 70 82 12-18

F68 8400 80 52 1000 50 35 >100 >24

L72 2750 20 -7 510 39 15 25 1-7

P75 4150 50 27 250 43 100 82 12-18

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F77 6600 70 48 480 47 100 >100 >24

P84 4200 40 34 280 42 90 74 12-18

P85 4600 50 34 310 42 70 85 12-18

F87 7700 70 49 700 44 80 >100 >24

F88 11400 80 54 2300 48 80 >100 >24

F98 13000 80 58 2700 43 40 >100 >24

P103 4950 30 30 285 34 40 86 7-12

P104 5900 40 32 390 33 50 81 12-18

PI05 6500 50 35 750 39 40 91 12-18

F108 14600 80 57 2800 41 40 >100 >24

L122 5000 20 20 1750 33 20 19 1-7

P123 5750 30 31 350 34 45 90 7-12

F127 12600 70 56 3100 41 40 >100 18-23

2.2 Thermodynamics of Micelle formation

Thermodynamics of micelle formation has been well studied by Alexandridis et al [1, 4, 19, 20].

Micellization of Pluronics in aqueous solutions is essentially entropy driven and obeys closed association

model. The closed association model assumes that there is equilibrium between aggregated structure

(micelle) and the dispersed monomers. The thermodynamic analysis of micelle formation can be

explained by two different models: the phase separation model and the mass-action model. According to

the phase separation model, micelles are formed at CMC which are considered as a new phase and

assumes that the concentration of monomers to be equal to CMC. Mass-action model considers that the

monomers and micelles are in association-dissociation equilibrium. Moroi [21] has evaluated the

relationships between thermodynamic entities and the CMC based on mass action model. He obtained

the following equations for Gibbs free energy of micellization, ΔGm and enthalpy of micellization, ΔHm as

Δ𝐺m = (1 +𝑚

𝑁) 𝑅𝑇 ln(𝑋𝑐𝑚𝑐) +

𝑅𝑇

𝑁ln(2𝑁(𝑁 + 𝑚)) (1)

Δ𝐻m = −𝑅𝑇2 [(1 +𝑚

𝑁) (

𝜕 ln(𝑋𝑐𝑚𝑐)

𝜕𝑇)

𝑃

+ ln(𝑋𝑐𝑚𝑐) (𝜕 (

𝑚𝑁)

𝜕𝑇)

𝑃

+ {𝜕 [(

1𝑁) ln{2𝑁(𝑁 + 𝑚)}]

𝜕𝑇}

𝑃

] (2)

where T is the absolute temperature of the experiment, R is the gas constant, m is the no. of counter ions

bound to the micelle, N is the aggregation number and XCMC is the CMC expressed in mole fraction units.

The second term in equation 6 and the third term in the equation 7 have very less weightage and can be

neglected [21, 22] and written as follows

Δ𝐺m = (1 +𝑚

𝑁) 𝑅𝑇 ln(𝑋𝑐𝑚𝑐) (3)

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Δ𝐻m = −𝑅𝑇2 [(1 +𝑚

𝑁) (

𝜕 ln(𝑋𝑐𝑚𝑐)

𝜕𝑇)

𝑃

+ ln(𝑋𝑐𝑚𝑐) (𝜕 (

𝑚𝑁

)

𝜕𝑇)

𝑃

] (4)

In case of non-ionic surfactants like Pluronics, the equations for ΔGm and ΔHmare given as

Δ𝐺m = 𝑅𝑇 ln(𝑋𝑐𝑚𝑐) (5)

Δ𝐻m = −𝑅𝑇2 (𝜕 ln(𝑋𝑐𝑚𝑐)

𝜕𝑇)

𝑃

(6)

The relationship between the CMC and T can be obtained by fitting to the equation used by Kresheck[23]

which is given as

ln(𝑋𝑐𝑚𝑐) = 𝑎 +𝑏

𝑇+ 𝑐 ln 𝑇 (7)

𝑚

𝑁= 𝑎′ +

𝑏′

𝑇+ 𝑐′ ln 𝑇 (8)

Where a,b, c, a’,b’ and c’ are constants that will be determined by fitting the experimental data. Using the

equation 12 and 13, ΔHm can be evaluated as

Δ𝐻m = −𝑅𝑇2 [(1 +𝑚

𝑁) (−

𝑏

𝑇2+

𝑐

𝑇) + (−

𝑏′

𝑇2+

𝑐′

𝑇) ln 𝑋𝑐𝑚𝑐] (9)

The change in entropy of micellization ∆𝑆𝑚 will be obtained based on the following equation

∆𝑆m =Δ𝐻m − Δ𝐺m

𝑇 (10)

In the case of block copolymers, it has been shown that the enthalpy of micellization is depended on

critical micellization temperature given by

∆H=R[∂ln(X)/∂(1/TCMT)] (11)

where TCMT is the critical micelle temperature , and X is the concentration expressed in mole fraction [24].

When the unimers of Pluronic system form aggregates, the hydrogen bonding structure in water

is restored and the entropy of water increases outweighing the entropy loss due to localization of

monomers. The contribution of entropy plays a major role in micellization process in aqueous solution

with enthalpy playing the minor role [1]. The formation of micelles depends on the aqueous solubility of

the PPO and PEO segments, which is in turn dependent on the temperature. As the hydrophobic effect

increases with temperature, there is a high tendency to form micelles at higher temperatures. As the

temperature increases above CMT the solubility of PEO group decreases and becomes more hydrophobic

because of the conformational changes in EO segments and at a certain temperature PEO groups

aggregate giving rise to phase separation, which is referred to as cloud point [25, 26].

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The experimental results using the isothermal titration calorimeter shows that the heat of

micellization decreases monotonically with an increase in temperature [26]. In contrast, some studies

have shown that the heat of micellization monotonically increases with increase in temperature. Very

recently, it was shown that the heat of micellization increases with temperature to reach a maximum and

then decrease along with an increase in temperature. Figure 2 shows the variation of enthalpy of

micellization of F68 and P65 with temperature [26]. Some studies also show the thermodynamics of

Pluronic micelle in presence of salts [3, 27], surfactants [28, 29], mixed micelle solution [9] and in different

solvents [4, 30, 31].

Figure 2:- Variation of the heat of micellization of the Pluronics F108 (filled circle), F98 (circle), F88 (filled

inverted triangle), and F68 (triangle) as a function of Tm [26]

3. Pluronic Micelle structure 3.1 Shape and Size

The structure of micelles plays an important role in many applications, for example in the

synthesis of mesoporous materials the structure of micelles determines the pore structure in the material.

The size of micelles in Pluronic aqueous solution is of the order 10-20 nm and therefore the scattering

techniques that are appropriate to use is SANS and SAXS [32]. As the electron densities of PEO and PPO

blocks is similar to that of water, it is difficult to characterize using SAXS and thus SANS is best technique

to characterize micellar structure of Pluronics in aqueous solutions. The primary parameters that are used

to study the structure of Pluronic micelles are the aggregation number of micelle, hard sphere volume

fraction, the core radius and the stickiness factor between micelles [33]. As an example, at 50OC Pluronic

P85 micelles have a core radius of about 40 AO and contains 40% water while the corona region extends

from 40-50 AO with less than 10% polymer fraction [34].

Theoretical predictions about the structure of the micelles were presented by Linse and Hatton

based on the mean field lattice theory [2, 19] . According to this theory, the core was assumed to be filled

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with lyophobic block and the outer layer (corona) filled exclusively with lyophilic block. The theory also

assumed that the segment densities is constant in different regions and no solvent penetration to the

core was allowed. Using this theory and minimizing the free energy various micelle properties like micellar

size, aggregation number, CMC etc., were determined. These models give the scaling relations for

aggregation number and micellar size.

Two other models were developed later to study the structure of micelles: the hard sphere model

and the cap-and-gown model [35, 36]. The hard sphere model was given by Mortenson et al. for the P85

micellar system and is based on the core-shell structure and a hard sphere inter-micellar interaction [35].

The cap-and-gown model is given by Liu et al. and is based on a compact and diffused corona structure

[36]. A considerable amount of polydispersity is considered in the hard-sphere model to fit the scattering

intensity distribution, whereas no polydispersity is required in a cap-and-gown model.

3.2 Cylindrical or Ellipsoidal structure

Some studies have shown that the micelles are not spherical in shape but are prolated ellipsoidal

shape. Theoretical studies on L64 studies also suggest that L64 micelles prefer a prolate ellipsoidal

structure [12]. It has also been shown using SANS study that L64 micelles can be best described by

ellipsoidal structures and the aspect ratios are dependent on the temperature[37]. As the temperature

increases, the aspect ratio increase progressively leading to an anisotropic growth of micelles and results

in a worm-like or cylindrical structures [38-40]. At higher temperatures, the association number increases

leading to an increase in the micelle core radius and when the core radius exceeds the stretched length

of PEO block, the micelles tend to change the shape to prolate ellipsoid. The anisotropic growth of micelles

at higher temperatures (near cloud point) is responsible for increased viscosity of the copolymer solution.

Due to this ellipsoidal structure of micelles, the interaction between micelles is predominantly repulsive.

The change from spherical to ellipsoidal structure leads to a minimization of the interaction energy at

shorter distances by alignment of the structures along the majority axis.

A study on P85 shows that the structure of micelles change from spherical to prolate ellipsoid at

60-70OC temperature range[41]. At higher temperature and concentration, the combination of the two

effects: structure change from spherical to prolate ellipsoid and increased hydrophobicity of PEO blocks,

leads to the formation of rod like structures with hexagonal symmetry. Further increase in temperature

leads to the formation of ordered lamellar structure. The change in structure of micelles from spherical

to cylindrical structures can also be induced by addition of other inorganic materials [42, 43].

3.3 Modeling and simulations

An insight to the structure of micelles and micelle-micelle interactions have also been given from

molecular simulations. Considering the large size of Pluronic micelles and slow kinetics of formation it is

difficult to perform molecular dynamic or Monte Carlo simulations to study the structure of micelles.

Therefore, modeling of Pluronic solutions is done based on self-consistent field lattice models or mean

field density functional theory approaches [2]. These models assume an ideal Gaussian chain

representation of Pluronic chains. Though these models give an insight on the morphology and phase, it

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is difficult to incorporate some important phenomenon like hydrogen bonding structure, solvent

clustering, local conformations etc. Bedrov et al have developed a coarse grained, implicit solvent (CGIS)

model for Pluronic chains, which gives a more detailed structural and conformational correlations of PEO

and PPO chains in aqueous solutions [13]. They have reported the results of this model on L64 Pluronics

showing the inter-micellar interactions, intra-micellar structure and the structure of the micellar solutions

with varying concentrations. Figure 3 shows the representative model of Pluronic L64 and F127 in CGIS

model [13]. Several studies have also been performed using Monte Carlo simulations to analyze the

interactions between Pluronic micelles [34, 41]. In these models, the micelles are treated as either solid

spheres or hard spheres with tethered Gaussian chains. These analysis shows that the micelles are fairly

independent of concentration and temperature except with a slight polydispersity in aggregation number.

Yuan et al. have studied P103 structure using a dynamic variant of mean-field density functional theory

[44]. They have reported that the structure of self-assembled aggregates highly depends on the polymer

concentration, which are in agreement with experimental results. Polymer concentration of 10-15% result

in spherical aggregates with large PPO core, while concentrations above 16% shown formation of disc like

micelles.

Figure 3:- Representative configurations of L64 and F127 micelles in the CGIS model [13]. 3.4 Molecular structure effects on micelle structure

The structure of the micelle depends on many factors like the molecular weight of polymer chains,

PEO/PPO ratio, temperature, etc. Results have shown a strong dependence of temperature on CMC of

Pluronic micelles. However, at constant temperature, the CMC can be varied by varying polymer length,

changing EO %, by changing from ABA to BAB type tri-block copolymers or by changing to AB di-block

copolymers. Increasing the polymer length or decreasing EO % decreases the CMC at constant

temperature and accordingly reduces CMT at constant concentration [2, 45]. Increasing the PPO chain

length leads to an increase in micelle core radius and more dehydrated inner layers of micelle [46]. Onset

of micellization for diblock copolymers is initiated at lower concentration values when compared to the

diblock copolymers. Comparison of PPO-PEO-PPO bblock copolymers with PEO-PPO-PEO block

copolymers showed that there is no micellization in PPO-PEO-PPO block copolymers observed up to the

cloud point [1]. The size of the micelle structure also depends on the segment length of copolymers. For

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example, the large segment copolymers form star-like blob structure which is not seen in small segment

copolymers.

3.5 Solvent quality effects 3.5.1 Temperature effects on micelle structure

Results have shown a strong dependence of temperature on CMC of Pluronic micelles. It has been

shown that the aggregation number and surface stickiness increases with temperature and the core

become more dehydrated at higher temperatures [47, 48]. Also, as the temperature increases the

hydrodynamic radius of micelle remains constant even though the aggregation number increases. This

effect is attributed to the dehydration of PEO blocks at higher temperatures [49]. Figure 4 shows a phase

phase diagram of Pluronic P85 and P123 clearly showing dependence of micelle structure on the polymer

concentration and temperature [50]. As one approaches the cloud point the aggregation number

increases, the core becomes more dehydrated and the stickiness factor increases. Extensive studies have

been performed on the effect of pressure, pH, addition of ionic and non-ionic agents, addition of organic

agents on the size and shape of the Pluronic micelles [add references]. More information on these effects

is presented in the following sections. Recently, a model has been developed by Manet et.al which

determines how the preparation parameters influence on the structure of micelles [42].

Figure 4:- Phase diagrams for P85 (left) and P123 (right) [50].

3.5.2 Pressure effect

The effect of pressure has been studied on various amphiphilic surfactant micelles. Few of the

studies reveal that the radius of gyration decreases with increase in pressure whereas the core radius

increase with increase in pressure. The effect of pressure on Pluronic F88 has been studied by Mortensen

et al. which show that the increasing pressure results in melting of micellar crystals and decomposition of

micelles [51]. A detailed study on the pressure-temperature phase behavior of Pluronic F108 at high

concentration is given by Kostko et al [52]. Figure 5 shows the schematic of phase diagram for F108

Pluronic at high concentration of polymer [52]. It can be seen that the range of temperature spanning the

gel phase decreases with increase in pressure. Also the pressure at CMC line increases with increase in

temperature and a similar increase is seen at low temperature gelation boundary whereas the high

temperature gel-melting phase boundary steeply decreases with temperature. This variation in phase of

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micellar solution is attributed to the increased solubility of PPO blocks at higher pressure. Also, is can be

seen that the cloud point is not affected with an increase in pressure. Studies on Pluronic P85 also show

the similar behavior i.e. the phase transition temperature increase with increase in pressure [53]. An

exception in study was that a new phase corresponding to de-mixed lamellae is observed in Pluronic P85

at high temperature and the onset temperature of this new phase decrease with increasing pressure.

Figure 5:- Schematic of pressure-temperature phase behavior of Pluronic F108[52]

3.5.3 Effect of non-aqueous and mixed solvents

Extensive research has been done in the past on the effect of mixed aqueous solvents and non-

aqueous solvents on the structure of micelles in Pluronic solutions. Alexandridis et al. studied the effect

of non-aqueous polar solvent (formadide) on the Pluronic micelle systems for the first time [4]. In this

system, the micelle radii and aggregation number of Pluronic P105 increase with increase in temperature

and also the solvent quantity in the micelle core decreased with temperature increase till 15 OC. Pluronic

systems form reverse micelles in most of the organic solvents [7, 54]. Guo et al. have reported the study

on water-induced reverse micelle formation of Pluronic system in p-xylene [7]. Pluronic micelle structure

in other non-aqueous solvents like ethylammonium nitrate, o-xylene and mixed water and other solvents

like hexanol, hexylamine, formadide, urea, ethanol and glycerol have also been studied [5, 7, 43, 45, 54-

56] .

3.5.4 Effect of salt

It is well known from the past studies that addition of salts have a considerable change in the

structure of micelles. Bahudur et al have extensively studied the Pluronic micelle structures in presence

of added salts [8, 56-58]. Most of the studies have shown that the water-structure- making salts like NaCl

decrease the transition temperature from spherical to rod-like structure in Pluronic micelles [59]. Addition

of salts in the Pluronic solutions results in the onset of micellization process at a lower polymer

concentration (at constant temperature) or at lower CMT (at constant concentration) [8, 27, 57]. The

presence of salts leads to dehydration of PEO near the micelle core increasing the radius of the core as

the dehydrated PEO now becomes the part of micelle core. Addition of KCl to Pluronic P84 and P104 has

shown to increase in aggregation number, however the micelle radius remains constant [8]. The effect of

salt addition to the structure of micelles in Pluronic solution in most of the studies is found to be analogous

to the temperature effect [57]. Micellar volume fraction increases with Pluronic concentration in the

presence of low salt concentration, but is independent at higher salt concentrations. The presence of salts

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also reduce the gel-formation and cloud points to lower values with an exception of KCNS which increased

the cloud point in several Pluronic solutions [37, 60]. This effect is observed to be more pronounced by

addition of PO4 salt followed by HaH2PO4, NaCl and NaBr in the decreasing order [60]. It was reported that

Pluronic P85 forms two types of micelles: monomolecular micelles and polymolecular micelles. Addition

of salts (NaCl and NaBr) to P85 solution resulted in the increase of polymolecular micelles while decreasing

the size of these polymolecular micelles. Therefore, salts play a vital role in tuning the structure of micelles

in Pluronic solutions.

4. Micelle dynamics

4.1 Relaxation processes

Dynamics of micelles of conventional surfactants has been investigated long back by Aniansson

et al. using chemical relaxation methods [61]. It was shown that the free surfactants constantly exchange

with the surfactants in the micelles i.e., there exists a dynamic equilibrium between micelles and free

surfactants and the average lifetime of the surfactant in micelle is given by TR. Apart from this surfactant,

micelle equilibrium the micelles constantly form and break with a lifetime of TM. When micelles are

subject to a rapid change in temperature the micellar systems respond with two relaxation times

corresponding to the exchange of surfactants and micelle formation/breakup respectively. The latter

process is a slow process whereas the exchange process is very fast. Based on this theory of surfactant

micelles, Alexander et.al showed that block copolymer micelles dynamics is also associated with two

relaxation times [62]. However, the free copolymers exchange with micelles can occur either by micelle

collision where the copolymer jump from one micelle to another or by copolymer exiting one micelle and

combing with another micelle [63]. Also, the exchange process in block copolymer micelles is extremely

slow when compared to the surfactant micelles [63]. The disentanglement of the copolymer chains from

a tangled and complex micelle structure result in slowing the relaxation process.

Various characterization techniques like ultrasonic relaxation, gel chromatography, temperature

jump, rheological studies and pulsed field gradient NMR are used to study the dynamics of micelles [64-

67]. Zana et al. have studied the dynamics of Pluronic micelles( PF80 and L64) in aqueous solution [68].

The studies revealed two relaxation processes as similar to that of the surfactant micelles. The fast

relaxation (in microsecond range) was associated with exchange process while the slow relaxation ( in

millisecond range) was associated with micelle formation/break up process. The studies also shows that

the association of micelles is diffusion controlled and the micelle formation/break up process is proceeded

via fission/fusion reactions. The exchange process of free copolymers with micelles and the micelle

formation/breakup plays a vital role many applications like formulation of lubricants, solubilization and

dispersion polymerization. The lifetime TM of the micelles indeed determines the rate at which the micellar

system solubilize and also determines the effectiveness in detergency.

Apart from the two relaxation times, a third relaxation time was also observed at temperatures

close to cloud point [64]. This third relaxation time is related to the clustering of micelles which is the

initial step in phase separation. Kositza et al. first observed this relaxation time in L64 Pluronics near cloud

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point [69, 70]. At higher temperatures, the micelles are fairly large and the concentration of free

copolymers is low which is attested by the disappearance of first relaxation process at higher

temperatures [1]. Therefore, the third relaxation process near cloud point is due to the clustering of

micelles and these clusters phase separate at cloud point. The third relaxation time stays constant till the

first relaxation process completely disappears. Figure 6 shows the variation of three relaxation times with

temperature for various polymer concentration for L64 Pluronic system [69]. It can be seen that the first

relaxation almost vanishes at higher temperatures while the third relaxation time is fairly constant for a

long range of temperature and then increase significantly at higher temperatures. The delay in the

relaxation time for the clustering process is attributed to the decrease in the number density of the

particles, as all the free copolymers are exhausted and also due to the increased particle size [64].

Figure 6:-Relaxation lifetimes τ1 (A), τ2 (B), and τ3 (C) obtained from ILTJ experiments with light scattering detection at 0.625% (O), 1.25% (●), 2.5% (Δ), and 5% (■) L64 (w/v) in aqueous solution as a function of

temperature [64].

4.2 Dynamics discerned from rheology measurements

Rheological properties of Pluronics near the percolation threshold change abruptly exhibiting a

change from simple liquid phase to a gel like elastic phase. The phase below percolation is characterized

by a low viscosity values while the phase above the threshold has very high viscosity values [71].

Calculations based on sticky sphere model of Baxter have showed that the Pluronic micellar systems have

well defined percolation threshold [72]. This model accurately describes the coexistence, spinodal and

percolations lines for the micellar systems. Inset of figure 7 shows the Baxter’s phase diagram as a function

of the reduced temperature and reduced volume fraction [71]. Mallamace et al. have performed SANS

study at various concentrations and temperature for L64 Pluronic system and also investigated the

viscoelasticity near the percolations threshold and relate the results to the theoretical calculations [71].

They observed an abrupt increase in stickiness factor, in agreement with the Baxter’s model, showing that

the Pluronic systems have well defined percolation threshold. Figure 7 shows the phase diagram for L64

Pluronic, in which a well-defined percolation line can be seen in accordance with Baxter’s model (inset of

figure 7). With these experimental and theoretical results on L64 Pluronic system, L64 is proposed as a

model system to study percolation and related dynamics of other Pluronic systems.

13

Figure 7:- The phase diagram, including the cmc–cmt curve, the cloud point curve, the critical

concentration (Cc≃0.05(wt%)) and the critical temperature of the system (Tc≃57.3°C), of the system L64−D2O determined, by means of light scattering measurements. In the inset is reproduced the Baxter's

phase diagram [71].

The percolation transition in complex fluids is generally difficult to characterize due the underlying

viscoelastic nature of these complex systems. The onset of sol-gel transition occurs at the point where

the elastic modulus and the viscous modulus scale identically with frequency [73]. Prior to gelation the

viscous modulus dominates the entire frequency domain, whereas post gelation the elastic modulus

dominates at low frequencies [74]. At higher frequencies, the static structure of gel breaks down due to

the high frequency glassy dynamics. Zanten et al. showed that the diffusive wave spectroscopy (DWS)-

based tracer particle micro rheology is a useful way to study the dynamics of Pluronic L64 systems, which

is considered as model adhesive hard sphere (AHS) system [74]. The results showed that at higher

temperatures the dynamics is dominated by the attractive intermicellar potential. The tracer

microparticle rheology is more influenced by the local micelle dynamics in the near sphere region rather

than the bulk mechanical properties in contrast to traditional rheometry measurements. Very recently,

Zanten et al. performed DWS studies on Pluronic F108, which are considered as spherical soft spheres.

The results showed dehydration of micelle corona with increase in temperature [75]. They showed that

at higher temperatures the dynamics is dominated by soft repulsive intermicellar interactions.

4.3 Modelling and simulation

Pluronic micellar systems are highly dynamical entities with the copolymers constantly

exchanging with micelles and therefore the micellar crystal are considerably intricate structures with

stable long range orders. Theoretical models like density functional model and mean field theory have

been developed long back which directly study the ordered micelles [76, 77]. These theories provide a

14

detailed study about the structure of micelles, however they do not provide insight into the micellar

dynamics. Vlimmeren et al. developed 3D mesoscale model to study the dynamic behavior of complex

polymer solutions [77]. They applied these models to study the dynamic behavior of L64 and 25R4 Pluronic

systems in aqueous solutions. This model is based on the mean field density functional theory for Gaussian

chains. The dynamic mean-field functional model is a combination of “Gaussian mean-field statistics with

a coarse grained Ginzburg-Landau model for time evolution of conserved order parameters”. The model

study on L64 Pluronic systems showed formation of four different phases depending on the polymer

concentration, which are in good agreement with the experimental results. The four phases L64 can exist

are micellar, hexagonal, bicontinous and lamellar phase. The simulations showed the time scale of phase

separation in the order of milli seconds. However, the final structure after phase separation contain high

degree of structure defects, which is attributed to the short equilibration times. The simulations confirm

the experimental studies that the formation of lamellar phase is independent of the block sequence. The

studies also show that the kinetics of phase change is initiated with fast local aggregation and followed by

slow rearrangement by overcoming defects in the structure. Xu et al. developed another model (MesoDyn)

that is also based on dynamic density functional method to simulate phase separation kinetics of Pluronic

systems [78, 79]. Their simulation results showed that as the temperature increases there is a decrease in

interfacial energy, the Pluronic systems become more ordered and the overall phase separation process

slows down.

All the models developed based on density functional or mean field theory study the ordered

micelles but do not provide good insight into dynamical degrees of freedom of the polymeric micellar

systems [80]. A more realistic description of the dynamics of such systems can be given using molecular

dynamics (MD). Molecular dynamics allows to define the role of a single polymer towards the dynamics

of polymeric solutions. Another advantage of molecular dynamics over other theories is there is no need

to define or assume thermodynamic state of the system in MD simulation. However, the longer time

scales in the order of minutes to hours makes it difficult to perform MD simulations on Pluronic micellar

systems. Travesset et al. studied the dynamics and equilibrium properties of Pluronic systems using MD

simulations [80]. The results show that the formation of crystal and the equilibration occur polymer

exchange between micelles. Pluronic system showed a bcc lattice near the disordered transition. For

Pluronics with short hydrophilic blocks and at lower kinetic temperatures, fcc lattice was observed. MD

simulations can be extended to understand the dynamics of many polymer nano-composites with

development of more accurate models.

4.4 Solvent quality effects on dynamics

Considerable amount of efforts have been given to understand the dynamics of Pluronic systems

in aqueous solutions. However, very less literature is available on the study of dynamics of Pluronic

micelles in non-aqueous solutions. The effect of solvent quality on the dynamics of other block copolymers

has been studied by Honda et al [81]. They studied the dynamics of poly(a-methyl styrene)-block-

poly(vinylphenethya1l cohol) (PaMSb-PVPA) in benzyl alcohol. They observed that micellization is a step

wise process including a fast and slow process, similar to what is observed in aqueous Pluronic systems.

The fast process is related to the association of free polymers to form quasi-equilibrium micelles and the

15

slow process relating to the equilibration of micelles and gradual decrease in micelle number. Schlick et

al. studied the dynamics of Pluronic systems in water/o-xylene mixtures using electron spin resonance

spectroscopy and nitroxide spin probes [6]. They determined the local polarities in L64 reverse micelles

with an emphasis in polar core with varying water concentrations. Kositza et al. studied the effect of

addition of sodium dodecyl sulphate (SDS) on the dynamics of the Pluronic L64 aqueous solutions [70].

They showed the change in all the three relaxation times (τ1, τ2, and τ3) with the SDS addition. It is known

that the SDS addition lowers the CMT and smaller micelles with loosen structure are formed. Therefore,

SDS addition caused an increase in 1/τ1 because of the reduced energy barrier for exchange of free

polymer. In contrast, SDS addition caused a decrease in 1/τ2 and 1/τ3. The decrease in 1/τ2 showed an

evidence for a shift from fission/fusion to a stepwise mechanism, which can be reversed by addition of

NaCl.

It is well known that the addition of salt to the Pluronic solution have effect on the shape of the

micelles. Ganguly et al showed that the addition of salt leads to formation of rod like structures [82]. They

observed that this transformation of micelles from sphere to rod is time dependent and have a strong

dependence on the type of anion used as well as the copolymer composition. When the anion type was

changed to more water structure making anions i.e along the Hofmeister series in the order Cl-<F-<(PO4)3-,

the rate of growth increased significantly. This dependence is due the ability of the anions to dehydrate

the outer covering of the micelles, which is a major factor for the transformation from sphere to rod like

structure. The molecular weight of the polymer also plays a vital role in the growth rate of the rod like

structures. It was observed that the increase in copolymer molecular weight leads to a decrease in the

growth rate, which is attributed to the faster restructuring ability of the low molecular weight copolymers.

The growth rate to rod like structures also depends on the type of solvent used. In the presence of solvents

like ethanol which have affinity towards both PPO and PEO blocks, the copolymers can restructure very

quickly leading to an increased growth rate towards rod like structures.

5. Bio Applications of Pluronics

5.1 Un-modified Pluronics

Nanotechnology based on polymers has become one of the fast growing and attractive fields due

to its wide applications in nanomedicine. Different nanoscale systems like liposomes, micelles, nanogels,

polyplexes and other nano-materials are being used in nanomedicine. Pluronics are one such example to

be used in nanomedine which is a promising material for drug delivery, gene delivery and for imaging.

Immense research is being done on Pluronics to ensure safe and efficient delivery of drugs and genes.

Pluronic micelles have a hydrophobic core and hence act as carriers for in-soluble compounds and

this transfer of compounds to the micelle core is called solubilization. Due to this solubilization property

of Pluronic micelles, they have been extensively studied as potential hydrophobic drug carriers. Immense

research has been undertaken in the past to understand the interaction between the Pluronic micelles

and various drugs [83-85]. Controlling the release of drugs from these micelle cores is one of the major

challenges recently, and therefore vast research is being done to obtain controlled drug release [58, 86-

88]. Drug release is followed by the disruption of the micelle structure; therefore the focus is on

16

understanding the dynamics of disruption and breakage of micelle structure for controlled drug release

[42, 86, 89, 90].

The size of micellar core formed from Pluronic polymers is in the range of 4-20 nm. Therefore,

Pluronic micelle core can act as carrier for hydrophobic nano-particles, low molecular mass drugs, proteins

and genes in aqueous solutions. Encapsulation of hydrophobic drugs is of vital importance in cancer

therapy and Pluronics are promising materials for encapsulating and solubilizing hydrophobic anti-cancer

drugs [91]. Various hydrophobic anticancer drugs like doxorubicin have been successfully encapsulated in

the core of Pluronic micelles. Drug encapsulated micelle not only increase the solubility of drugs but also

increase passive targeting of the tumor [92, 93].

5.2 Interaction of drugs with Pluronic micelles

Puronics micelles have good stability in blood and have high drug loading capacity which makes

them ideal for drug delivery applications. The hydrophilic outer corona stabilizes the interface between

hydrophobic drug and external medium [94]. This interaction increases metabolic stability and the blood

circulation time and also prevents the burst release of drugs [95]. Drugs can be encapsulated into the core

of Pluronic micelles either by physical entrapment or by chemical conjugation of drugs to the core of

micelles [96]. In chemical conjugation the drug is covalently coupled to PPO blocks in the core of Pluronic

micelles[97]. Some studies showed that, chemically conjugated drugs stay in the blood for a longer time

and the uptake of the drugs by non-targeted organs is lowered making the delivery system more effective

[98]. Many drugs can also be easily entrapped physically into the micelle core by simply mixing the drugs

in the Pluronic solution. For example, drugs including Doxorubicin, Paclitaxel and Ruboxyl can be physically

entrapped into the micellar core and can be released at specific target by ultrasound [97].

Drug encapsulated micellar solution can be prepared usin thin-film hydration method. The drugs

are initially dissolved in ethanol using ultrasound and then Pluronic is dissolved in the solution. The

solution is then evaporated to remove ethanol and the obtained drug/polymer film is then hydrated with

PBS or de-ionized water and subsequently stirred to obtain a micelle solution. The unincorporated drug

aggregate can be removed by centrifuging the solution [99, 100]. Another method to load the drugs is the

novel nano-precipitation method [101]. In this method, the drug and polymer is dissolved in acetonitrile

and the solution is subsequently added drop wise to an aqueous solution. The colloidal solution is

centrifuged to remove unencapsulated drug and residual Pluronic. The solution mixture is evaporated and

then hydrated with water. The solution mixture is subsequently frozen and then lyophilized for storage.

In modern medicine, it is of vital importance to design drug delivery systems that can specifically

target selected tissues. For example, several anti-cancer drugs like doxorubicin are fairly toxic to normal

tissue and it is important to target only the tumor. Targeted delivery is also important in gene delivery

where the genes are delivered to a specified part of a targeted organ. Targeted drug delivery not only

reduces the side effects but also reduces the drug wastage making it more cost efficient. Pluronic micelles

sequester hydrophobic drugs and thus reduce the exposure of drugs in the systemic circulation and

preventing any harm to healthy cells [97]. Batrakova et al. showed that low concentrated Pluronics reverse

the drug resistant behavior of cancerous cells and also result in less accumulation of doxorubicin in cells

17

[102]. At higher concentrations of Pluronics, monomers are still present which are in equilibrium with

micelles and are still able to overcome the multidrug resistant behavior of cancerous cells. Pluronic

systems have been found very effective in transport of anti-cancer drugs like doxorubicin to the targeted

tissues and triggering the drug release on application of low frequency ultrasound [97].

5.3 Pluronics blended with salts and the effect of pH

Addition of salts in the Pluronic solutions results in the onset of micellization process at a lower

polymer concentration (at constant temperature) or at lower CMT (at constant concentration) [8, 27, 57].

The presence of salts leads to dehydration of PEO near the micelle core increasing the radius of the core

making more space for encapsulation of drugs. Therefore, the solubility of drug increases with the

addition of salt. It was observed that, as the ionic strength of the solution increases the amount of drug

encapsulated increases. For example, Pandit et al. studied the effect of inorganic salts and observed

increased solubility of hydrophobic drug propyl paraben in presence of salts [103]. The addition of salts

generates more hydrophobic microenvironment and also increases the number of micelles and therefore

increasing the total volume available for solubilization of hydrophobic drugs. Studies on the another drug

prednisolone also showed an increase in solubilization with increase in salt concentration in Pluronic P85

solution [60]. Figure 8 shows the increase in solubility of drug with increasing the salt concentration. The

solubility of many drugs also increases considerably with a change in pH. Kadam et al. have studied the

effect of pH on the solubility of hydrochlorothiazide drug [96]. They have shown that the solubility

increases with decreasing pH from 6.7 to 3.7. Below the pH value of 6, the HCT drug remains as an

uncharged molecule and therefore prefers to stay in the micelle core, increasing the solubility. Figure 8

shows the variation of solubility with Pluronic concentration at various pH values. It can be seen that at

higher Pluronic concentrations the solubility is higher for low pH values. In another studies by Yang et al.

it was shown that the hydrodynamic radius of chitosan oligosaccharide (CSO) conjugated Pluronic micelle

increases from 24 to 38 nm with decrease in pH value from 7.6 to 4.75 [104]. The swelling of the CSO-

Pluronic micelle is due to electro-static repulsion between the positive charged CSO chains at lower pH

values.

Figure 8:- A-Solubility of HCT with increasing salt concentration. B- Solubility of HCT vs. P103

concentration at different pH at 28 °C [96].

A B

18

5.4 Pluronics blended with other polymers

Many efforts are being made to modify the Pluronic structure to improve the drug-loading

capacity and to obtain efficient drug delivery. One of the methods is to blend in the Pluronics with other

miscible polymers to form a single phase of mixed micelles [105, 106]. Mixed micelles with Pluronics have

been widely studied to provide multi-functionality to the micellar systems for obtaining controlled and

targeted drug delivery. There are two types of mixed micelles that has been studied: Pluronic/Pluronic

mixed micelle and Pluronic/non-Pluronic mixed micelles. Recently Fang et al. have studied the Pluronic

P123/F127 mixed micelles for the encapsulation of paclitaxel (PTX), an anti-cancer drug [107, 108]. Figure

9 shows the formation of mixed micelle along with the encapsulation of PTX drug in the core of mixed

micelle [107]. The mixed micelles showed increased drug loading and longer circulation time, therefore

significantly enhanced the anti-cancer activity. Saxena et al. reported a new delivery system consisting of

Pluronic 407/TPGS mixed micelles for delivery of gambogic acid (GA) to treat breast cancer [109]. These

mixed micelle systems showed high cellular uptake of GA and 2.9 times higher toxicity towards multidrug

resistant cancerous cells. Very recently, Sosnik et al. reported mixed micelles of Pluronics and poloxamines

and studied the encapsulation of anti-HIV drug efavirenz [110]. The mixed micelles showed 8430 fold

increase in the drug loading capacity and also displayed higher physical stability in comparison with pure

poloxamines. These mixed micellar systems are highly versatile in bioavailability as shown in figure 10,

and therefore are potential drug delivery systems for anti-HIV pharmacotherapy [110].

Figure 9:- Representation of the strategy of developing Pluronic P123/F127 mixed polymeric

micelles [107].

19

Figure 10: Schematic representation mixed polymeric micelles and encapsulation of EFV.

F127:T904 displayed greater encapsulation efficiency while F127:T304 micelles hamper the incorporation

of EFV when compared to only F127 micelles [110].

Many studies have also been reported on the Pluronic/PLA mixed micelles for drug delivery, which

also have enhanced bioavailability and increased intracellular uptake of drugs [111, 112]. In these mixed

micelles of Pluronic/PLA, Pluronics provide encapsulation stabilizing effect while the pH sensitive PLA

facilitates controlled drug release in acidic cancerous environment. Pluronics/PLGA blends have been

successfully used for gene delivery [113, 114]. Initially pure PLGA were used for gene delivery, however

these systems were poor in release of DNA vaccines. Adding Pluronics to this delivery system facilitates

controlled release and also help preserving the biological activity of genes. Pluronics are also used to

hydrophilize the PLGA scaffolds to develop a polymeric matrix for pDNA delivery[113]. Such PLGA scaffolds

with Pluronics were observed to have higher transfection efficiency of the pDNA when compared to pure

PLGA scaffolds. Table 3 shows the list of modifications of Pluronics by blending with other polymers and

specific applications.

20

Table 3:- Modification of PEO-PPO-PEO triblock copolymers by blending with other polymers

Modification Unique feature Application Ref Pluronic and polyacrylic acid Oral in situ temperature-and pH-

sensitive hydrogels For the delivery of an anticancer drug, epirubicin.

[115, 116]

Polyethylene glycol- polycaprolactone/Pluronic P105 or PEG-PCL/Pluronic P105

Composite doxorubicin-loaded micelles are radio-sensitive. High cellular uptake, improved drug retention, and enhanced antitumor effect relative to free doxorubicin

For the delivery of an anticancer drug, doxorubicin

[117]

Pluronic407/TPGS mixed micelles

Increased cellular uptake and sustained release of drug

Delivery of gambogic acid to breast and multidrug-resistant cancer

[109]

Folate conjugated Pluronic F127/Chitosan Core-Shell Nanoparticles

More stable nano-particles and showed greater cytotoxicity towards MCF-7 cells than free DOX

High anti-cancer activity [99]

poly(ethylene oxide)-poly[118]-poly(ethylene oxide) (PEO-PHB-PEO) and Pluronic F-127

Increased drug loading efficiency and drug stability

In tumor accumulation [118]

Folate and β-cyclodextrin decorated Pluronic F127-b-poly(ε-caprolactone) copoly- mer

Biodegradable, and target specific cellular uptake

As nanocarriers for targeted drug delivery.

[119]

F127-metal-drug coordination-bonding

pH-responsive In antitumor therapies [120]

P123 and F127 mixed micelles High encapsulation efficiency (>90%), good stability in lyophilized form and pH-dependent in vitro release

Delivery of anticancer drug to melanoma

[107, 108, 121]

P123 and L121 Binary mixture High stability due to Pluronic P123 and high solubilization capacity due to Pluronic L121.

As anticancer drug delivery systems

[122]

Physical mixture of alginate and PF127

Greater porosity and no degradation Selegiline skin permeation [123]

Mixed MPEG–PLA/Pluronic Mixed micelles significantly reduced the tumor size than the control (Taxotere)

Enhanced bioavailability and to overcome multidrug resistance of docetaxel in cancer therapy.

[112]

Polyethyleneglycol- poly(DL-lactic-co-glycolic acid) (PEG-PLGA) and Pluronic 105 (P105)

The combination of PEG-PLGA and Pluronic further improved both the tumor-suppressive activity and the intracellular accumulation of DOX,

To reverse the multidrug resistance in tumor cells.

[124]

Silk sericin/ Pluronic nanoparticles

Self-assembled micellar nanostructures capable of carrying both hydrophilic (FITC-inulin) and hydrophobic (anticancer drug paclitaxel) drugs.

Delivery of both hydrophobic and hydrophilic drugs to target sites.

[125]

Mixed micelles of hydrophobic Pluronic L81 and relatively hydrophilic Pluronic P123

Mixed micelles are very small in size, showed fairly high entrapment efficiency, loading capacity and sustained release profile for aceclofenac, a model hydrophobe.

Controlled and targeted drug delivery

[126]

21

5.5 Chemically modified Pluronics

Multifunctionality in the Pluronic systems can be induced by chemically modifying the Pluronic

structure by addition of other polymers or other materials. For example, Pluronics have been chemically

modified by poly-caprolactone (PCL), PLGA, polyethyleneimine and folic acid [127-129]. PXT drugs are

known to have good compatibility with PCL, and therefore Pluronics modified with PCL can entrap more

PXT drug molecules. PCL modified Pluronics also reverse the multi-drug resistance of cancer cells, increase

intracellular concentration and increase circulation time, thus making them highly effective delivery

systems for sensitizing resistant tumors [128]. Figure 11 shows the scheme of the synthesis of PCL

modified Pluronic P105 [128]. Polyethyleneimine (PEI) has been demonstrated to have high gene

transfection efficiency, but PEI aggregate have very short circulation time which limits its applications in-

vivo. Many methods have been developed to modify the PEI to increase its biocompatibility while

retaining its gene transfection efficiency. Recently, Pluronics have also been used to enhance PEI

properties [127]. PEI-Pluronic conjugates have excellent gene transfection efficiency as well as good

biocompatibility. Figure 12 shows the scheme of the synthesis of PEI-Pluronic conjugates [127]. Gao et al.

have also reported Pluronic modified low molecular weight PEI for degradable gene delivery systems [130,

131]. They showed that the Pluronics with high HLB homogenously distribute in the cytoplasm while

Pluronics with lower HLB result in localization inside the nucleus.

Figure 11:- scheme of the synthesis of poly(caprolactone)-modified Pluronic P105 polymers (C) [128].

22

Figure 12:- Synthetic scheme of PEI–Pluronic copolymers (PCMs) [127].

Most of the drug delivery systems for cancer therapy have very less selectivity for tumor cells,

which would have high toxicity towards healthy cells. Developing drug delivery systems with selectivity

for cell types not only increase drug efficiency but also reduces side effects on normal cells. Various

targeting molecules like folic acid, RGD peptide, mannose and galactose can be conjugated to the drug

delivery systems to increase targeted delivery. In case of Pluronic systems, folic acid is the most popular

molecule used for increasing selectivity toward tumor cells. Fang et al. tested folic acid functionalized

Pluronics in-vivo and reported increased bioavailability of these conjugates [108]. Figure 13A shows the

schematic for the synthesis of Folic acid conjugated Pluronics. Folic acid conjugated Pluronics can be mixed

with other Pluronics to form targeted mixed micelles as shown in figure 13B [108]. Multifunctional

superparamagnetic particles can be produced by solubilizing iron oxide particles by folic acid conjugated

Pluronics which have combined targeting, diagnosis and therapy applications [132]. Very recently, Zhou

et al. reported Pluronics conjugated with folic acid and β-cyclodectrin, in which the folic acid acts as

targeting molecule whereas β-cyclodectrin provide increased bioavailability [119]. Table 4 shows the list

of chemical modifications done to the Pluronics and their applications.

23

Figure 13:- (A) Schematic illustration of the synthetic steps for Pluronic F127 functionalization and conjugation of folic acid. (B) Representation of the strategy of developing targeted polymeric mixed

micelles [108].

Table 4:- Chemical modification of PEO-PPO-PEO triblock copolymers

Modification Unique feature Application Ref Poly (ethylenimine) conjugated Pluronic copolymers

A marked increase of cellular accumulation compared with Pluronic P123 micelles.

Enhanced anticancer activity and also used as biocompatible gene delivery carriers.

[127, 130, 131, 133, 134]

Poly(caprolactone)-modified Pluronic P105 m

Sensitize the resistant SKOV-3/PTX tumor cells.

Delivery of paclitaxel and treatment of the resistant ovarian tumors.

[128]

Gold-nanoparticle-crosslinked Pluronic micelles

More micelle stability and cellular uptake High anti-cancer activity against glutathione pretreated U87 cells

[135]

Folate and β-cyclodextrin decorated F127-b-poly(ε-caprolactone) copolymer

Biodegradable, and target specific cellular uptake

As nanocarriers for targeted drug delivery.

[119]

Carboxylated PluronicF127 (F127COOH)

Alleviating potential toxicity, enhancing the stability and improving targeting efficiency of CdTe/ZnS quantum dots (QDs) in tumor

In human pancreatic cancer detection and targeted drug delivery

[136]

Alginate–Pluronic F127 composite copolymer

Exhibited linear permeation properties for the transdermal delivery of selegiline.

As a topical therapeutic formulation for selegiline.

[123]

A

B

G

24

Pluronic F127-Chitosan Nanocapsules

The nanocapsules are ~37 nm at 37 °C and expand to ~240 nm when cooled to 4 °C in aqueous solutions, exhibiting>200 times change in volume.

For encapsulating small therapeutic agents to treat diseases particularly when it is combined with cryotherapy

[137]

Anti-HIF-1a antibody-conjugated Carboxyl-terminated Pluronic P123

Specifically bounds with stomach cancer MGC-803 cells

Tumor targeting therapy [138]

Folic acid conjugated F127 decorated with polyacrylic acid-bound iron oxides

MRI agent as well as diagnosis and therapeutic agent that specifically targets cancer cells that overexpress folate receptors in their cell membranes.

For combined targeting, diagnosis, and therapy applications

[132]

Lactobionic acid (LA)-conjugated Pluronic P105 (P105)

Remarkable increase in the dissolubility for silybin in LA-P105 micelle solution

Target-specific delivery vehicles for diverse water-insoluble therapeutic and diagnostic agents.

[139]

Hyaluronic acid (HA) grafted Pluronic F127

Thermosensitive hydrogel with sustained release characteristics

Anti-cancer treatment and for tissue regeneration

[140]

Core-Functionalized PEO-PPO-PEO Copolymer

Greatly enhanced cytotoxicity for MCF-7 human breast cancer cells and high extent of cellular uptake

Used for overcoming the multidrug resistance (MDR) effect

[92]

Heparin-conjugated Pluronic F-127

Has good injectability and the release properties can be tuned.

For protein delivery [141, 142]

Loosely cross-linked poly(acrylic acid) grafted with Pluronic F127 and L92

Pluronic L92 exhibited highly porous structure, while the microgels containing Pluronic F127 were generally larger and possessed smooth surfaces, a homogeneous structure, and lower ion-exchange capacity.

Delivery of anti-cancer and hydrophobic drugs

[143]

Chitosan oligosaccharide (CSO)-g-Pluronic P103 copolymers

pH- and temperature-responsive polymeric drug carriers

Controlled release of Doxorubicin drug for anti-cancer therapy

[104]

Multiple alpha-cyclodextrin (alpha-CD) threaded on Pluronic coplymer

Low cytotoxicity and high transfection efficiency

Sustained gene delivery [144]

Pluronic P123 modified polyamidoamine (PAMAM)

Low cytotoxicity and higher transfection efficiency

Carrier for gene delivery [145]

Poly(diethylamino ethyl methacrylate) blocks conjugated Pluronic F127

These copolymers electrostatically condense plasmid DNA into nanostructures (nanoplexes) and further self-assemble above critical concentration to form thermoreversible hydrogels at physiological temperatures.

Act as both nanoscale gene delivery vectors and macroscale sustained delivery agents

[146]

Hydrogel of Di-acrylated Pluronic F127

No chemical degradation and maintained the gene expression

Controlled release of plasmid DNA

[147]

Gelatin grafted Pluronic F127

Thermosensitive and excellent cell viability

Tissue regeneration (cartilage), gene and drug delivery

[148]

PLGA-Pluronic F68 copolymer

Can load bovine serum albumin effectively and keep it stable after it is released from the nano-particles

For protein delivery [129]

25

6. Non-Bio Applications of Pluronics

6.1 Unmodified Pluronics

An important application of Pluronic micelles is the storage of nano-materials in the core of

micelle. Micelles can act as host to many nano-particles/drugs and make stabilized dispersions of these

particles in aqueous solutions. These nano-containers can help transport of particles/drugs in aqueous

that are insoluble or unstable in water. For example, Pluronic micelles can act as nano-containers for

magnetic nano-particles, gold nano particles, CNTS, drugs like doxorubicin, paclitexal, etc [149-151]. One

of the problems related to carbon nano-tubes (CNTS) is their insolubility in water due to large vander walls

forces. Though there are various techniques to disperse CNTS in aqueous solutions, recently it was shown

that Pluronic micelles can also be used to disperse CNTS in water [150]. Pluronic micelles can also

encapsulate gold nano-particles to reduce its cytotoxity and improve stability in aqueous solution [149].

Pluronics can encapsulate superparamagnetic nano-particles for magnetic resonance imaging and

nanothermotherapy [152]. Recent studies have shown that Pluronic micelles can also encapsulate

quantum dots preserving the optical and colloidal stability of quantum dots in biological systems [153].

Nano-particles are highly unstable in aqueous solutions and tend to flocculate. To prevent

flocculation, these nano-particles need to be kinetically stabilized by steric means to obtain stable

dispersion of these nano-particles. Pluronic systems are extensively used to stabilize various nano-

particles. One of the major examples is the stabilization of magnetic nano-particles to use in magnetic

resonance imaging (MRI). Pluronics decorate the outer surface of magnetic nano-particles in an aqueous

solution and stabilize the particles. The polymeric chains fold and self-assemble on the particles providing

dispersion stability as shown in the figure 14. Apart from stabilizing, the external corono consisting of PEO

blocks provide antifouling property to the particles and helps prevent aggregation and protein adsorption

[95]. The stabilization of particles is temperature dependent as the PPO and PEO blocks in Pluronics

become highly hydrophobic with increase in temperature. Pluronics also influence the size of the particles,

the protein binding to the particles and dispersion stability. Along with stabilization, the Pluronic/nano-

particle system can also be loaded with drugs and hence providing drug delivery and imaging properties

simultaneously [154].

Figure 14:- Schematic showing stabilization of magnetic nano-particles by Pluronics [154].

26

Pluronic micelles have also been widely used to synthesize mesoporous materials. Pluronics are

mixed with particles in aqueous medium and the Pluronics form micellar structures which get entrapped

inside the material. The particles are then subjected to calcination which decomposes the micellar

structures resulting in mesoporous structure. Pluronics have been widely used to synthesize various

materials including TiO2, steel, Mn3O4, bioactive glass, carbon materials and silica based materials like SBA-

15, organosilicates and ferrosilicates [155-162]. Thin film mesoporous structures of TiO2, ZnO, ZrO2 have

also been successfully synthesized using Pluronics [163, 164]. The pore structure highly depends on the

type of Pluronics used during the synthesis. Ardizzone et.al have reported the effect of Pluronics molecular

weight and HLB on the porosity of TiO2 materials [162]. They showed that Pluronics with low molecular

weight and intermediate HLB values generate larger surface areas and pore volumes. Pluronics have also

been extensively used in the synthesis of nano-particles and in tuning the size/shape of the nano-particles.

For example, Pluronics have used in synthesis of gold nano-particles, Uranium oxide nano-particles,

hydroxyapatite nano-particles and magnetic microbeads [165-169].

6.2 Pluronics blended with other polymers

It is well known that the properties of Pluronics can be significantly enhanced by addition of

surfactants and other polymers. In synthesis of mesoporous silica, Pluronics can be mixed with mixed with

n-butanol (BuOH) and tetraethoxysilane (TEOS) for tailoring the pore structure [170, 171]. Figure 15 shows

the phase diagram of mesoporous silica with the variation of BuOH and TEOS [170]. Zhao et al. have

reported a method for the synthesis of highly ordered mesoporous structures by using

formaldehyde/phenol resols and Pluronics [155]. Hydrocarbon molecules like hexadecane or decane are

used in the Pluronic systems for the swelling of the structure to produce larger pore size. Also, by varying

the hydrocarbon molecules the pore size can be tailored from 4nm to 6 nm. The authors proposed a

scheme (Figure 16) of possible interaction between Pluronics with resols which includes one-layer

hydrogen bond interaction between resols and PEO segments. This organic-organic cooperative assembly

as shown in figure 16 favors the formation of mesoporous carbon structure which is a very promising

material for various applications. In another study, Ozdural et al. mixed SDS along with Pluronics to

synthesize magnetic microbeads [165, 166]. They were successful in producing magnetic polyvinylbutyral

microbeads and magnetic nitrocellulose microbeads using this Pluronic/SDS mixture.

27

Figure 15: Phase diagram of mesophase structures established according to the XRD measurements.

Each sample is prepared with a molar ratio of 0.017 P123/x TEOS/y BuOH/1.83 HCl/195 H2O [170].

Figure 16:- (A) A Possible Formation Mechanism of Mesoporous Polymers with a Variety of Structures in

an Aqueous Solution under Basic Conditions, (B) Resol Anions Formed at a Relatively Strong Basic

Condition, and (C) a Pore Size Swelling Process of Hydrocarbon Molecules in the P123 System [155].

6.3 Chemically modified Pluronics

Pluronics have been chemically modified to induce multi-functionality in various applications like

dispersion of particles, synthesis of mesoporous structures and pH/temperature sensitive materials.

Petrov et al. modified Pluronics with pyrene to produce micelles which can be used to stabilize multi-

walled carbon nanotubes in aqueous media [150]. Figure 17 shows schematic of synthesis of pyrene

28

functionalized Pluronics and interaction with multi-walled carbon nanotube. In another study, Pluronics

have been modified by amines to disperse quantum dots in aqueous media [172]. The amine terminated

hydrophilic blocks were used for Gd3+ chelation and the quantum dots remain well protected in the core

with excellent optical and colloidal stability. Park and co-workers have modified Pluronics in various ways

as shown in figure 18 to produce pH and temperature sensitive materials [173]. In another study, Park et

al. have reported spiropyran conjugated Pluronics to develop calorimeter detector [174].

Figure 17:- Synthesis of pyrene-functionalized stabilized polymeric micelles and their non-covalent

interactions with multi-walled carbon nanotubes [150].

Figure 18:-. Phase diagram of mesophase structures. Each sample is prepared with a molar ratio of 0.017 P123/x TEOS/y BuOH/1.83 HCl/195 H2O [173].

29

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