Photocleavable and tunable thermoresponsive amphiphilic random copolymer: Self-assembly into micelles, dye encapsulation, and triggered release

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Photocleavable and Tunable Thermoresponsive Amphiphilic Random

Copolymer: Self-Assembly into Micelles, Dye Encapsulation, and

Triggered Release

Somdeb Jana, Avijit Bose, Anupam Saha, Tarun K. Mandal

Polymer Science Unit, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India

Correspondence to: T. K. Mandal (E-mail: psutkm@iacs.res.in)

Received 30 November 2016; accepted 27 January 2017; published online 00 Month 2017

DOI: 10.1002/pola.28537

ABSTRACT: A double-responsive amphiphilic random copoly-

mer (P(OEtOxA)-ran-PNBA) composed of thermoresponsive

poly(oligo(2-ethyl-2-oxazoline)acrylate) (P(OEtOxA)) segments

and photocleavable poly(2-nitrobenzyl acrylate) (PNBA) seg-

ments is synthesized via combination of cationic ring-opening

polymerization (CROP) and reversible addition-fragmentation

chain transfer (RAFT) polymerization techniques. The

P(OEtOxA)-ran-PNBA copolymer exhibits lower critical solution

aqueous solution. Owing to the amphiphilic nature, the

P(OEtOxA)-ran-PNBA copolymer molecules self-assemble into

well-dispersed spherical micelles in water. There is a disruption

of the copolymer micelles with UV light irradiation as well as

shrinkage of micellar size with increasing temperature above

the LCST of copolymer in solution. Finally, the encapsulation

of hydrophobic guest molecule (nile red) into P(OEtOxA)-ran-

PNBA copolymer micelles and thermo- and photo-triggered

release of nile red are demonstrated. V

2017 Wiley Periodicals,

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(

LCST)-type soluble-to-turbid phase transition in water with

Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 00, 000–000

tunable cloud point (Tcp) with respect to chain length of

P(OEtOxA) segment present. The photocleavage of PNBA seg-

ments by UV irradiation transforms amphiphilic P(OEtOxA)-

ran-PNBA to fully hydrophilic P(OEtOxA)-ran-poly(acrylic acid)

resulting in the appreciable increase of Tcp of copolymer in

KEYWORDS: micelles; ring-opening polymerization; self-assem-

bly; stimuli-sensitive copolymers

INTRODUCTION In recent years, design and synthesis of

stimuli-responsive copolymers have gained immense research

interests because of their wide range of applications including

controlled delivery of drug and genes, tissue engineering,

different stimuli-responsive segments/blocks in one copoly-

mer chain provides more opportunities to fine tune their

solution properties as well as their self-aggregated morphol-

2

8,29

ogies in multiple ways.

Thus, the development of multi-

1

–7

stimuli responsive copolymers are challenging and key to

prepare advanced materials for sophisticated applications. It

is obvious that temperature- and light-sensitive polymeric

materials are very much attractive because of easy accessi-

bility of these two physical stimuli and can be operated from

outside the system without any additional reagents. Ther-

moresponsive polymers have been studied intensely for last

few decades because of their unique characteristic feature of

showing either soluble-to-insoluble or insoluble-to-soluble

phase transitions in solution above the lower critical solution

temperature (LCST) or upper critical solution temperature

catalysis, biosensors and bioimaging etc.

These responsive

polymers are “smart” and “intelligent” because of their inher-

ent active functionalities capable of exhibiting sharp responses

against some minor changes in the external stimuli such as

8

–11

12,13

14,15

16

17

temperature,

light,

pH,

ionic strength, CO₂, glu-

1

8

cose etc. Indeed, amphiphilic responsive copolymers can

self-assemble into various nanostructured macromolecular

architectures (e.g., micelles, vesicles, etc.) in solution that can

spontaneously disassemble or undergo some changes in their

8

,19–21

morphology upon change in their local environment.

Thus, these “smart” copolymer systems are particularly advan-

tageous for encapsulation of drugs and genes and their stimuli

8

,30–34

(

UCST), respectively.

On the other hand, photorespon-

2

sive polymers are also equally attracted attention as their

properties can be tuned with respect to time and space with

directed delivery at the desired site.

1

2,13,35,36

Till date, the responsive behaviors of amphiphilic random/

block copolymers in solution are studied with respect to sin-

shining light on it.

Thus, we can tune many different

properties of such copolymers in solution in more sophisti-

cated and controlled way by changing both its temperature

2

3–27

gle stimulus.

However, the presence of two or more

Additional Supporting Information may be found in the online version of this article.

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and shining light on it. Poly[N-isopropylacrylamide-co-N-(4-

phenylazophenyl)acrylamide] (PNIPAAm-co-PAzoAm) was

the first example of light- and thermo-responsive copolymer

its random copolymer, P(OEtOxMA)-co-PMMA exhibit LCST-

4

9

type phase transition in water. However, there is still many

aspects to explore in terms of designing of new dual- or multi-

responsive block/random copolymers best on this tempera-

ture sensitive polymer segment containing oligo(2-ethyl-2-

oxazoline). Thus, the synthesis of dual photo- and thermo-

responsive random copolymer containing the thermosensitive

oligo(2-ethyl-2-oxazoline) segments would really be interest-

ing as its cloud point would be tunable with respect to the seg-

ments length as well as by tuning the light irradiation time.

Furthermore, there has not been any report of study of self-

assembly of this type of amphiphilic random copolymer into

different micellar morphologies along with subsequent encap-

sulation of guest molecules and their photo/temperature-trig-

gered release.

whose LCST-type phase transition temperature (T ) in water

cp

increased from 21 to 27 8C due to the trans-cis photoisome-

rization of azobenzene moieties upon irradiation with UV

3

7

light as reported by Irie et al. After Irie’s pioneering work,

the synthesis of many different dual thermo- and light-

responsive anphiphilic block copolymers have been reported

where the solution properties and their aggregation state

9

,29,38–40

can be altered by tuning these two stimuli.

Recently,

Yuan et al. synthesized a UV light breakable and tunable

thermoresponsive amphiphilic poly(2-nitrobenzyl methacry-

late)-block-poly(2-(2-methoxyethoxy)ethylmethacrylate-co-oli-

2

go(ethyleneglycol) methacrylate) (PNBM-b-P(MEO MA-co-

3

9

OEGMA)) block copolymer (BCP) by ATRP. They also stud-

ied the self-assembly of this BCP into micelles and their dis-

ruption in water by UV light irradiation followed by their

reassembly into micelles upon heating above its LCST. These

BCPs are well studied in terms of their responsiveness

towards light and temperature and are good candidates to

be assembled into varieties of polymeric nanostructures.

However, the synthesis of such dual/multi-responsive BCPs

generally requires multistep sequential controlled polymeri-

zation techniques or postpolymerization modifications such

as grafting, substitution, or “click” reactions and consequent-

Thus, in this direction, we design and synthesize poly(o-

ligo(2-ethyl-2-oxazoline)acrylate)-random-poly(2-nitrobenzyl

acrylate) (P(OEtOxA)-ran-PNBA) copolymer showing simulta-

neous responsiveness in water toward both light and tem-

perature. This copolymer is synthesized by combination of

cationic ring-opening polymerization (CROP) and reversible

addition–fragmentation chain transfer (RAFT) polymerization

techniques involving first the synthesis of oligo(2-ethyl-2-

oxazoline)-based acrylic macromonomer (OEtOxA) with vary-

ing molecular weights by microwave assisted CROP followed

by direct end-capping of living oligo(2-ethyl-2-oxazoline)

chains with acrylic acid. The copolymerization of OEtOxA

macromonomer with 2-nitrobenzyl acrylate via RAFT poly-

merization technique afford the amphiphilic random

P(OEtOxA)-ran-PNBA copolymer. Indeed, the P(OEtOxA)-ran-

4

1,42

ly it is time-consuming and tedious.

On the other hand,

the synthesis of random copolymer is relatively easy and

less time-consuming, as they can be achieved simply by one-

step copolymerization of two different functional monomers.

Accordingly, Wang et al. recently reported the synthesis of a

multiresponsive amphiphilic poly(2-nitrobenzyl methacry-

late)-co-poly(dimethylaminoethyl methacrylate) (PNBM-co-

PDMAEMA) random copolymer consisting of light-sensitive

PNBA exhibits LCST-type cloud point (T ), which can easily

cp

be tuned by applying UV light irradiation in water. It is

observed that the P(OEtOxA)-ran-PNBA self-assemble into

spherical micelles in water. It is also shown that, upon UV

irradiation, the micellar structure of P(OEtOxA)-ran-PNBA

disrupts due to the photocleavage of NBE groups of PNBA

segments. Additionally, above LCST, there is shrinkage of the

micelles into smaller size. Finally, as a proof of concept, it is

observed that P(OEtOxA)-ran-PNBA copolymer micelles can

encapsulate model hydrophobic guest molecule nile red (NR)

whose released by applying heat or UV light is also studied.

4

3

PNBM and acid-/thermo-responsive PDMAEMA segments.

The self-assembly of this random copolymer into micelles

and its morphology tuning by varying light intensity, temper-

ature, and pH are also studied. Recently, in an excellent

review, Thayumanavan et al. summarized the self-assembly

behaviors of different multistimuli responsive amphiphilic

2

0

random copolymers.

Furthermore, the above mentioned dual/multi responsive

amphiphilic random/block copolymer systems mostly contain

PNIPAAm, PDMAEMA, PEG or P(OEGMA) as the hydrophilic

thermoresponsive segments and they are biocompatible and

EXPERIMENTAL

Materials

4

4,45

hence can be used in biomedical applications.

However,

2-Ethyl-2-oxazoline (EtOx) (99%; Aldrich) was purified by

distillation under reduced pressure over calcium hydride and

stored under argon atmosphere prior to use. Methyl triflate

(MeOTf; 98%), 2-nitrobenzyl alcohol (NBA; 97%), and the

chain transfer agent (CTA), cyanomethyl methyl(phenyl)car-

bamodithioate (CMPC, 98%) were purchased from Aldrich

and used without further purification. Azobisisobutyronitrile

(AIBN) (98%; Avra, India) was recrystallized from hexane.

Acrylic acid (98.5%; Merck, India) and acryloyl chloride

(97%; Merck, India) were used as received. Triethylamine

the nonbiodegradability of P(OEGMA) or PEG make it unsuit-

4

6,47

able for biological applications.

In this context, polymer of

oligo(2-ethyl-2-oxazoline) has recently been identified as a

potential alternative for P(OEGMA) as stealth polymers. The

nonionic and biodegradable as well as biocompatible nature of

4

8

poly(2-ethyl-2-oxazoline) make the polymer of oligo(2-ethyl-

-oxazoline) as a suitable candidate for biomedical applica-

tions. Being low DP, oligo(2-ethyl-2-oxazoline) do not exhibit

2

4

8

any thermoresponsive transition in water. However, very

recently, Schubert et al. showed that its homopolymer, poly(o-

ligo(2-ethyl-2-oxazoline)methacrylate) P(OEtOxMA) as well as

(Et N) (98%; Merck, India) was dried over potassium

3

hydroxide and distilled under argon atmosphere prior to use

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TABLE 1 Polymerization conditions and molecular weight characterization data of OEtOxA macromonomers, P(OEtOxA) homopol-

ymer, and different P(OEtOxA)-ran-PNBA random copolymers

M

n,

M

n,

M

n,

PNBA

Monomer (M)/

Initiator (I)

(Theo.)

(Da)

(SEC)

(Da)

(MALDI)

(Da)

Content (wt %)

1

Polymer Sample

[M]

o

/[I]

o

D- (SEC)

( H NMR)

a

OEtOxA800

EtOx/MeOTf

9

5

823

1,100

–

802

392

–

1.21

–

a

OEtOxA400

EtOx/MeOTf

410

–

P(OEtOxA400

b

)

OEtOxA400/CTA

OEtOxA400/NBA/CTA

50:1

8,400

8,030

6,900

6,500

1.46

1.58

–

P(OEtOxA400)-ran-

PNBA (P1)

50:20:1

–

50

b

P(OEtOxA800)-ran-

PNBA (P2)

OEtOxA800/NBA/CTA

50:15:1

11,500

7,056

–

1.32

40

a

b

CROP for OEtOxA macromonomers: Solvent 5 ACN; [EtOx] 5 4 mol

; Temperature 5 140 8C; Time 5 1 min under Microwave irradiation.

RAFT for P(OEtOxA400) homopolymer and P(OEtOxA)-ran-PNBA copoly-

21

L

mers: Solvent 5 THF; [OEtOxA] 5 0.5 mol L ; [CTA]/[AIBN] 5 1:0.25; Tem-

Yield ꢀ 80%.

perature 5 72 8C; Time 5 18 h. Yield ꢀ40%.

in the reaction. THF was purified by distillation from metallic

sodium with benzophenone. Acetonitrile (ACN) was distilled

over calcium hydride and collected in a dry RB flask contain-

ing molecular sieves (3 Å) prior to use. All the aqueous solu-

tions were prepared from Milli-Q (18.2 MX) water.

was stored under argon atmosphere at 24 8C in a refrigera-

tor. Yield: 78%. Another macromonomer, OEtOxA₈₀₀was also

prepared by varying the initial monomer-to-initiator feed

ratio as described in Table 1.

21

FTIR (KBr pellet, cm ): 1640 (C@O str, amide), 1725 (C@O

Synthesis of Acrylate End-Functional Oligo(2-Ethyl-2-

Oxazoline) (OEtOxA) Macromonomer

str, ester of acrylate) (Supporting Information Fig. S1).

1

H NMR (500 MHz, CDCl ), d (ppm): 6.35 (d, 1H, @CH ), 6.05

3

2

The macromonomer, OEtOxA₄₀₀, was synthesized by micro-

wave assisted CROP following our and the protocol of Weber

(

m, 1H, ACH@CH ), 5.82 (d, 1H, @CH ), 4.23 (m, 2H,

2

5

0,51

ACH AOACOA), 3.40 (b, ANACH A), 3.0 (b, 3H, ANACH ),

2 2 3

et al. after certain modifications.

Typically, microwave

2

.25 (b, 2H, ANACOACH A), 1.07 (b, 3H, ANACOACH ACH )

2 2 3

1

vials (10 mL) were first heated at 150 8C for overnight to

remove any traces of moisture and cooled down to room

temperature under an argon atmosphere before use. Dried

vial (10 mL) was then charged with EtOx (1 mL, 9.83

mmol), acetonitrile (1.5 mL), and an initiator, MeOTf (223

lL, 1.966 mmol). The EtOx monomer concentration was 4 M

with a initial monomer-to-initiator ([M] /[I] ) feed ratio of 5.

13

(Supporting Information Figs. S2 and S3 for H and C NMR,

respectively).

Homopolymerization of OEtOxA₄₀₀Macromonomer

Typically, 450 mg (1.125 mmol) of OEtOxA₄₀₀and 600 mL of

dry THF were taken in 10 mL long neck round bottom flask

and purged with nitrogen gas for 5 min. Subsequently,

6.2 mg (0.0225 mmol) of CMPC CTA and 1.01 mg (5.6 3

0

The vial was sealed with a proper cap and then placed in

the microwave synthesizer and the reaction was continued

for 1 min at 140 8C. The mixture was cooled to ambient tem-

perature using an air compressor. Acrylic acid (202 lL,

23

10 mmol) of AIBN were separately taken in 400 mL of dry

THF, and this mixture was injected into the reaction mixture

via a degassed syringe. Nitrogen purging was continued for

further 45 min with constant magnetic stirring to remove

any traces of oxygen. Finally, the mixture was sealed with a

silicone rubber septum and placed in a preheated oil bath

under stirring condition at 70 8C. The ratio of [Macromono-

mer]:[CTA]:[AIBN] was 50:1:0.25. After 24 h, the polymeriza-

tion was quenched by quickly cooling the flask under tap

water. The obtained polymer solution was diluted with slight

excess of THF and precipitated into cold diethyl ether. The

precipitated P(OEtOxA₄₀₀) was collected and dried in a vacu-

um oven at 25 8C. The polymer was dissolved in water and

purified by dialysis against double distilled water for 2 days

using a membrane with a molecular weight cutoff of 2000 g

2.949 mmol) was then added in 1.5-fold excess amount with

respect to initiator via a degassed syringe through the sep-

tum of the capped microwave vial containing living oligo(2-

ethyl-2-oxazoline) (OEtOx) chains. Afterward, 2-fold excess of

3

Et N (548 lL, 3.932 mmol) with respect to initiator was

added into the OEtOx solution via degassed syringe. Finally,

end-capping reaction was performed by heating the solution

at 80 8C in an oil bath under stirring with a bar magnet for

12 h. Acetonitrile was removed in a rotary evaporator and

the remaining viscous liquid was dissolved in chloroform.

The organic part was then extracted three times with satu-

rated aqueous sodium hydrogen carbonate (NaHCO ) solu-

3

tion and twice with saturated brine (NaCl) solution. The

organic phase was collected by a separating funnel and dried

over anhydrous sodium sulphate (Na SO ) and filtered. The

21

mol and was isolated by evaporating the water in a lyophi-

lizer. The resulting light pink colored powdery polymer was

stored in vacuum desiccator at room temperature. Yield:

43%.

2

4

resultant white viscous oligomeric macromonomer was iso-

lated under reduced pressure using a rotary evaporator and

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1

H

NMR (500 MHz, CDCl₃),

d

(ppm): 4.13 (b, 2H,

quenching, copolymer isolation and its purification procedures

were similar to that used for homopolymerization. The final ran-

dom copolymer was light yellow in color and sticky solid in

nature. The compositions of the copolymers were determined

from integration of the appropriate signals in the H NMR spec-

trum of the purified product, which will be discussed later in

Results and Discussion section.

ACH AOACOA), 3.48 (b, ANACH A), 3.02 (b, 3H,

ANACH ), 2.35 (b, 2H, ANACOACH A), 1.12 (b, 3H,

ANACH ACH ).

2

3

2

3

1

Synthesis of 2-Nitrobenzyl Acrylate (NBA) Monomer

NBA monomer was prepared by following our earlier

5

0

reported reaction protocol. Typically, 2-nitrobenzyl alcohol

3.8 g, 25 mmol) was dissolved in 20 mL of dry THF in a

two-necked RB flask fitted with a nitrogen gas balloon and

rubber septum. Et N (3.5 mL, 25 mmol) was then added via

21

(

FTIR (KBr pellet, cm ): 1644 (C@O str, amide), 1740 (C@O

str, ester), 1528 (C@C str, Aromatic ring) (Supporting Infor-

mation Fig. S1).

3

syringe to the above mixture and stirred magnetically at 0 8C

for 10 min. Afterward, acryloyl chloride (2 mL, 24.72 mmol)

was added dropwise via a syringe with constant magnetic

stirring at 0 8C over a period of 30 min. The reaction mix-

ture was then allowed to come at room temperature and fur-

ther stirred magnetically for overnight. THF was evaporated

by a rotary evaporator, and the crude reaction mixture was

dissolved in 50 mL of ethyl acetate. The resultant reaction

mixture was purified by washing three times with water (3

1

H NMR (500 MHz, CDCl ), d (ppm): 7.88–8.12 (b, HAr),

3

7

.35–7.75 (b, HAr), 5.35 (b, 2H, AOACH AAr), 4.09 (b, 2H,

2

ACH AOACOA), 3.47 (b, ANACH A), 3.02 (b, 3H,

ANACH ), 2.35 (b, 2H, ANACOACH A), 1.01 (b, 3H,

ANACOACH

ing Information Figs. S2 and S6 for H and

respectively).

2

3

2

ACH

3

), 1.38–2.04 (ACH

2

backbone) (Support-

1

13

C NMR,

Photocleavage of P(OEtOxA)-Ran-PNBA Copolymer by UV

Light Irradiation

For photocleavage, typically, the P(OEtOxA₄₀₀)-ram-PNBA

3

40 mL) and one time with brine (1 3 40 mL) solution.

The organic phase was collected in a separating funnel and

dried over anhydrous Na SO and filtered, and then the sol-

2

4

21

(P1) copolymer solution in DI H O (0.04 mg mL ) was tak-

2

vent was removed in a rotary evaporator. The yellow-brown

crude product was purified by silica gel column chromatog-

raphy with 6:1 hexane/ethyl acetate affording a yellow vis-

cous liquid. Yield: 95%.

en in a quartz tube. It was then placed in a photoreactor

(

Luzchem-ICH2, Canada) equipped with a set of UV lamps

k 5 350 nm, Intensity 5 190 lx) and was irradiated for dif-

ferent times. An aliquot (ꢀ2 mL) was then withdrawn from

the tube at different time intervals, and its UV–vis spectra

were recorded for monitoring the extent of photodegradation

^o^f^c^o^p^o^l^y^m^e^r^.^T^h^e^p^h^o^t^o^c^l^e^a^v^a^g^e^o^f^P⁽^O^E^t^O^x^A800)-ram-PNBA

(P2) copolymer was also carried out using similar procedure

at a concentration of 0.04 mg mL

1

H NMR (500 MHz, CDCl ), d (ppm): 8.15 (d, 1H, HAr), 7.65

3

(

m, 2H, HAr), 7.5 (t, 1H, HAr), 5.95 (d, 1H, 5CH ), 6.5 (d,

2

1H, 5CH₂), 6.25 (m, 1H, ACH@CH₂), 5.62 (s, 2H,

AOACH AAr) (Supporting Information Figs. S2 and S4 for

2

13

1

21

H and C NMR, respectively).

.

1

MS (ESI) (35 eV): m/z (%): 230 (100) [M 1 Na ] (Support-

ing Information Fig. S5).

Determination of Cloud Point of Copolymer in Water

before and after UV Irradiation

The cloud point (Tcp) of the aqueous solution of P(OEtOxA)-

ran-PNBA with varying compositions and at different concen-

tration were determined by monitoring the % transmittance

Synthesis of Poly(Oligo(2-Ethyl-2-Oxazoline)Acrylate)-

Ran-Poly(2-Nitrobenzyl Acrylate) [P(OEtOxA)-Ran-PNBA]

Copolymer

(

% T) at k 5 498 nm on a UV2vis spectrophotometer

The random copolymerization of OEtOxA and NBA monomer was

carried using the similar procedure as used for the homopolyme-

rization of the OEtOxA macromonomer by RAFT technique. In a

representative case, 600 mg (1.5 mmol) of OEtOxA400 and 800

mL of dry THF were taken in 10-mL long neck RB flask and was

equipped with a temperature controller. In a typical proce-

dure, 0.2 wt % of aqueous solution of P1 was first filtered

through membrane filter (pore size 0.45 lm). The resultant

transparent solution was then taken in a quartz cuvette and

placed in a UV–vis spectrophotometer. T_c_pwas then deter-

mined by recording the % T changes at 498 nm in the tem-

perature window of 20–90 8C with increasing/decreasing the

2

purged with N gas for 5 min and sealed with a septum. CMPC

2

3

CTA (8.3 mg; 0.03 mmol) and AIBN (1.23 mg; 7.5 X 10 mmol)

were separately taken in 400 mL of dry THF, and the mixture was

consequently added into the reaction mixture via degassed

syringe. Subsequently, 125 mg (0.6 mmol) of NBA was injected

into the reaction mixture via degassed syringe. Finally, the entire

2

1

temperature at 2 8C min

after equilibration for 2 min at

the experimental temperature. T_c_pis actually the tempera-

ture at which the solution transmittance is about 50% to its

original value in the first heating ramp.

reaction mixture was bubbled with N for another 45 min, sealed

2

with a silicone rubber septum and stirred magnetically in a pre-

heated oil bath at 70 8C for 24 h. The molar ratio of reactants

was as follows: [OEtOxA₄₀₀]:[NBA]:[CTA]:[AIBN] 5 50:20:1:0.25.

Another copolymer (P2) from macromonomer OEtOxA₈₀₀and

NBA monomer with the molar ratio of [OEtOxA₈₀₀]:[NBA]:

Tcp of P(OEtOxA)-ran-PNBA copolymers after UV light irradi-

ation was also determined by turbidimetry. In this case, a

quartz cuvette containing 0.2 wt % aqueous solution of a

copolymer was placed in a photoreactor and was irradiated

with a UV light of k 5 350 nm, Intensity 5 190 lx for 60 min

at 20 8C. The color of the copolymer solution was turned to

slightly yellow form colorless after UV irradiation indicating

[CTA]:[AIBN] 5 50:15:1:0.25 (Table 1) was also prepared using

similar procedure as described above. The polymerization

4

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its photocleavage. The cuvette containing this light-yellow

colored transparent solution was then placed in a UV–vis

spectrophotometer and T_c_pwas also measured by a similar

procedure as mentioned above.

ESI Mass Spectrometry

The ESI mass spectrum of NBA monomer was recorded from

acetonitrile solution using quadrupole time-of-flight (QTOF)

Micro YA263 (Waters) mass spectrometer.

NMR Spectroscopy

H NMR and C NMR spectra of OEtOxA macromonomers,

P(OEtOxA) homopolymer, NBA monomer, and P(OEtOxA)-

ran-PNBA copolymers were recorded in CDCl solvent using

Self-Aggregation and Photoinduced Disaggregation of

P(OEtOxA)-ran-PNBA Copolymers

1

13

For self-assembly, P1 and P2 copolymers were first dis-

solved in DI water with an initial concentration of 0.30 mg

3

a Bruker DPX 500 MHz spectrometer.

21

mL . The solution was then kept undisturbed for 5 h at

room temperature for allowing the aggregation of the copol-

ymer molecules to form nanostructures. The aggregation

process was monitored by DLS, FESEM as well as by trans-

mission electron microscopy (TEM).

SEC Measurement

-

Molecular weight (M ) and dispersities (D) of OEtOxA mac-

n

romonomer, P(OEtOxA) homopolymer and P(OEtOxA)-ran-

PNBA copolymers were measured by size exclusion chroma-

tography (SEC) using a Waters 1515 isocratic HPLC pump

connected to three Waters Styragel HR1 (M_n5 100–5000),

HR3 (M_n5 500–30,000), and HR4 (M_n5 5000–5,00,000)

columns and a Waters 2414 refractive index detector at

room temperature (25 8C). THF was used as eluent with a

flow rate of 1 mL min , and narrow polystyrene standards

were used for calibrating the GPC. Waters Breeze Software

was used for molecular weight analysis.

For disaggregation study, after 5 h of aggregation of P1 solu-

tion, an aliquot (ꢀ2 mL) was taken in quartz tube and

placed in

a photoreactor for exposing with UV light

(k 5 350 nm) for 90 min. After that, 1 drop of exposed solu-

tion of P1 was casted on a glass slide/TEM grid and exam-

ined via FESEM and TEM respectively for checking

photodegradation of copolymer nanostructures that may

formed in the aggregation process.

21

Matrix-Assisted Laser Desorption/Ionization Time-of-

Flight Mass Spectrometry

The molecular weights and end group analysis of OEtOxA

macromonomers were performed by matrix-assisted laser

desorption/ionization time-of-flight mass (MALDI-TOF-MS)

technique in a Bruker instrument equipped with a 337 nm

Dye Encapsulation by P(OEtOxA)-Ran-PNBA Copolymer

Micelles and Photo- and Temperature-Induced Release

Study

Nile red (NR) was chosen as the model hydrophobic dye for

its encapsulation by the micelles of P(OEtOxA)-ran-PNBA

2

1

21

copolymer in water. Typically, P1 copolymer (0.30 mg mL

)

nitrogen laser. 2,5-Dihydroxybenzoic acid (DHB, 20 mg mL

dissolved in 2 mL of water and was mixed with 150 mL of

in THF) was used as the matrix in the presence of NaI (4 mg

2

4

21

NR solution in acetone (1.11 3 10

mg mL ). Acetone

mL

in acetone) as counterion. The concentration of the

2

1

was then removed by heating the solution for some time.

The resultant aqueous solution was then kept undisturbed

for overnight at 20 8C to allow micellization of P1 as well as

encapsulation of NR into their hydrophobic core. Afterwards,

excess NR was filtered and separated through centrifuge.

Finally, one part of the NR-encapsulated aqueous P1 micellar

solution (ꢀ 1mL) was irradiated with UV light of

k 5 365 nm and the NR release was monitored through

time-dependent fluorescence spectroscopy. Another part

OEtOxA macromonomer was 1.5 mg mL

in chloroform.

For measurement, final samples were prepared by mixing 15

lL of OEtOxA solution, 20 lL of matrix solution, and 10 lL

of counterion solution. The sample mixture (sample/matrix/

counterion) solution was then mixed homogeneously, spotted

on the sample plate, and allowed to dry at room tempera-

ture. The M

linear mode.

of OEtOxA macromonomer was recorded in the

n

UV–vis Spectroscopy

(

ꢀ1 mL) of the NR-encapsulated P1 micellar solution was

UV–vis spectroscopic measurements were carried out on a

Hewlett-Packard 8453 diode array spectrophotometer

equipped with a Peltier temperature controller.

used to study the temperature-triggered NR release using

fluorescence spectroscopy.

Characterization

Microwave Polymerization

CROP was carried out by taking EtOx monomer and MeOTf

initiator in capped dried reaction vials in an Anton Paar

research grade Microwave Reactor (Model: Monowave 300).

Dynamic Light Scattering

The dynamic light scattering (DLS) experiments were carried

out in Malvern Instrument (model ZEN 3690 Zetasizer Nano

ZS 90, Version 7.03) attached with a He-Ne gas laser

(

632.8 nm). Typically, for DLS analysis, 0.30 mg of P1 and

P2 copolymer was dissolved in 1 mL of DI water and kept

undisturbed 5 h at room temperature to instigate micelliza-

tion. Then the solution was filtered through a membrane fil-

ter paper (pore diameter 5 0.45 lm). DLS measurement of

the resultant filtered solution was then carried out at tem-

peratures of 20 and 65 8C.

FTIR Spectroscopy

FTIR spectra of two macromonomers and copolymers were

recorded from KBr pellets, prepared by mixing the respective

dried samples with dried KBr in 1:100 (w/w) ratios in a

Perkin Elmer FTIR Spectrum-400 spectrometer.

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Field Emission Scanning Electron Microscopy

chain containing a oxazolinium species at the one end was

in-situ terminated by direct addition of acrylic acid and

triethyl amine into the reaction medium (Scheme 1). Two

well-defined OEtOx macromonomers of varying molecular

For field emission scanning electron microscopy (FESEM) analy-

sis, aqueous copolymer solutions (concentration5 0.30 mg

2

1

mL , before and after UV light irradiation) were drop casted

on a small pieces of thoroughly washed glass slide and allowed

the film to dry overnight in ambient condition. The glass slides

were then placed on a copper tape supported on a metal stub

and sputter coated with platinum to make it conducting. The

coated samples were then placed in a ZEISS field emission scan-

ning electron microscope and were imaged at an accelerating

voltage of 15 kV.

weights (M s) (OEtOxA800 and OEtOxA400) were prepared by

n

varying the initial monomer-to-initiator feed ratios (Table 1).

FTIR spectrum (Supporting Information Fig. S1) of OEtOxA800

2

1

revealed two intense bands at 1640 and 1725 cm due to

the >C@O stretching vibrations of the amide moiety of EtOx

unit and the acrylate ester functionality of the macromono-

1

mer respectively. H NMR spectra of OEtOxA800 showed sig-

nals at 3.40 and 4.23 ppm (Supporting Information Fig. S2A)

Transmission Electron Microscopy

were the characteristic of methylene protons of ANACH A

2

1

Aqueous P1 and P2 sample solutions (0.3 mg mL ) were

drop casted onto carbon-coated cupper grids and let the

samples dried completely. The images were then recorded

on a JEOL JEM-1400 Plus electron microscope operated at

an accelerating voltage of 120 kV.

and ACH AOACOA moieties of backbone along with three

2

distinct signals at 6.35, 6.05, and 5.82 ppm corresponding to

1

3

the vinyl protons of OEtOxA moiety. The C NMR spectrum

Supporting Information Fig. S3) of OEtOxA₈₀₀further

(

showed two clearly distinguishable signals for ester and

amide carbonyl carbon at 165.8 and 174.7 ppm, respectively.

Photoluminescence Spectroscopy

13

C NMR (Supporting Information Fig. S3) of OEtOxA₈₀₀also

A FluoroMax-3 spectrophotometer from Horiba JobinYvon

was used to record the emission spectra of NR and NR-

encapsulated P1 copolymer micellar solution in aqueous

showed the signals at 128.2 and 131.7 ppm corresponding

to the vinyl carbons. These results confirmed the successful

polymerization of EtOx and attachment of acrylate function-

ality to generate OEtOxA macromonomer.

2

1

medium (0.32 mg mL ). The excitation wavelength was

50 nm (3 3 3 slit).

5

In the second step, NBA monomer was synthesized by the

reaction of 2-nitrobenzyl alcohol with acryloyl chloride in

dry THF (Step II of Scheme 1) following our earlier reported

protocol. The successful synthesis of NBA monomer was

established from the appearance of three distinct signals at

RESULTS AND DISCUSSION

Synthesis of Poly(Oligo(2-Ethyl-2-Oxazoline)Acrylate)-

Ran-Poly(2-Nitrobenzyl Acrylate) [P(OEtOxA)-Ran-PNBA]

Copolymer

5

0

5

.95, 6.25, and 6.5 ppm as well as a signal at 5.62 ppm in

It has been reported that the aqueous solution of poly(2-eth-

yl-2-oxazoline) (PEtOx) exhibited LCST-type phase transition

in the range of 61–64 8C depending on its molecular weights

1

the H NMR spectrum corresponding to the vinyl protons

and benzylic protons of the NBA moiety (Supporting Infor-

mation Fig. S2B). Also, the C NMR spectrum of NBA mono-

mer showed signals at 165.58 ppm for carbonyl carbon of

ester and at 63.09 ppm for benzylic carbon (Supporting

Information Fig. S4). The base peak in the ESI-MS spectrum

1

3

4

8

(

20–500 kDa). However, in this case, it was observed that

oligo(2-ethyl-2-oxazoline)s (OEtOx)s of very low molar

masses (800–1000 Da) did not show any such transition in

water in the measurable temperature ranges of 10–90 8C.

But, one can expect that the polymer of OEtOx monomer

(

Supporting Information Fig. S5) at m/z 230.02 exactly cor-

responded to the mass of NBA monomer with a sodium cat-

ion. All these data indicated the successful synthesis of NBA.

[

P(OEtOx)] would show LCST-type thermoresponsiveness if

it can be polymerized by introducing a vinyl group at one of

its end. On the other hand, it is known that poly(2-nitroben-

zyl acrylate) (PNBA) is a photoresponsive hydrophobic poly-

mer and can easily be converted into hydrophilic

Finally, the copolymerization of OEtOxA macromonomer

(OEtOxA₄₀₀or OEtOxA₈₀₀) with NBA was carried out by

RAFT technique using CMPA as CTA and a pinch of AIBN as

the initiator in THF. This process produced two random

copolymers, P(OEtOxA₄₀₀)-ran-PNBA and P(OEtOxA₈₀₀)-ran-

PNBA, which were designated as P1 and P2 respectively

(Table 1). FTIR spectrum (Supporting Information Fig. S1) of

5

2

poly(acrylic acid) (PAA) upon irradiation with UV light.

Thus, it is expected that the random copolymerization of

OEtOx macromomer and NBA monomer of varying feed com-

positions would certainly result in a series of copolymers

with tunable responsiveness towards both temperature and

light. This prompted us to synthesize various P(OEtOxA)-

ran-PNBA copolymers using different types of polymerization

techniques as shown in Scheme 1. First step of the synthesis

is the preparation of hydrophilic OEtOxA macromonomer

where a direct end capping method was used for the func-

tionalization of oligo(2-ethyl-2-oxazoline) with a acrylate

21

P2 copolymer showed characteristic bands at 1644 cm for

>C@O stretching of amide moiety of the P(OEtOxA) segment

2

1

and at 1740 cm for >C@O stretching of ester functionality

present in P(OEtOxA) or PNBA unit. It also showed a band

21

at 1528 cm due to the C@C stretching vibration of aromat-

ic ring of PNBA moiety. These results clearly indicated the

presence of both the P(OEtOxA) and PNBA segments in the

5

1

group. To do this, microwave-assisted CROP of EtOx was

performed using MeOTf as the initiator in acetonitrile at 140

copolymer. Furthermore, H NMR spectrum (Supporting

Information Fig. S2C) of P2 revealed clear signals at 5.35

5

3,54

8C (Step 1 of Scheme 1).

The resultant living OEtOx

ppm (board) for benzylic ACH A protons, 7.35–7.75 and

2

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SCHEME 1 Synthetic pathway for P(OEtOxA)-ran-PNBA copolymer.

7

.88–8.12 ppm for aromatic protons of phenyl groups of the

be fitted to OEtOxA containing an acrylate functionality in

one end and a methyl group in the other end along with 6,

7, and 8 numbers of EtOx monomer units, respectively, as

described in Figure 1. It should also mention that each spe-

cies is ionized by sodium cation as sodium iodide was used

as a salt for MALDI-TOF-MS experiment. Similar results were

also obtained for OEtOxA400 macromonomer (Supporting

Information Fig. S7). These results confirmed the presence of

a polymerizable acrylate group at the end of OEtOx chain.

PNBA moiety, 3.47 ppm (board) for the ANACH A protons

and 4.09 ppm for the methylene protons of ACH AOACOA

units of P(OEtOxA) backbone with all the other expected sig-

nals confirming the presence of both P(OEtOxA) and PNBA

2

1

3

segments in the final copolymer. The C NMR spectrum

Supporting Information Fig. S6) of P2 also showed clear sig-

(

nals at 125, 129, 131, 134, and 147 ppm for the aromatic

carbons and at 63.57 ppm for the benzylic carbon of NBA

moiety along with the signals at 26.71 ppm for the

ANACH A carbon and at 9.96 ppm for the ANACH ACH

The molecular weights (M s) and dispersities ( D- s) of

n

OEtOxA₈₀₀and OEtOxA₄₀₀macromonomers were determined

2

3

carbon of P(OEtOxA) moiety. All these data clearly revealed

from the analyses of MALDI spectra using “Polytools” soft-

the successful synthesis of P(OEtOxA)-ran-NBA copolymer.

ware and were found to be 804 and 392 Da with D- s of 1.03

and 1.31, respectively (Table 1). Note that we were unable

The OEtOxA macromonomer samples were also analyzed by

MALDI-TOF-MS to ascertain its end group as well as its M_n.

MALDI-TOF spectrum of OEtOxA₈₀₀showed a series of peaks

set apart by 99 Da, which is exactly the same as the molar

mass of the repeating unit of EtOx (Fig. 1). Among these, the

indicative peaks at m/z 5 705.825, 804.851, and 904.395

corresponding to the highest intensity molecular ions could

to measure M and D- of final copolymers by this technique.

n

We further measured M s and D- s of OEtOxA macromono-

n

mers and copolymers (P1 and P2) by SEC technique. SEC

trace (Fig. 2) of OEtOxA₈₀₀revealed a unimodal curve with

moderately narrow D- of 1.21 suggesting the controlled

nature of CROP of EtOx monomer (Table 1). The M_nof

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FIGURE 1 MALDI-TOF MS spectrum of OEtOxA800 macromonomer and end group analysis.

OEtOxA800 was measured to be 1100 Da, which was close to

that (802 Da) measured from MALDI-TOF experiment (Table

resonance peak at d(e) 1.19 ppm corresponds to the methyl

protons (ANACOACH ACH ) of P(OEtOxA) and the peak at

2

3

1

). This value was also very close to that (M_n_,_N_M_R5 790.3

d(f) 5.36 ppm corresponds to the benzyl protons (AOACH₂-

Ar) of PNBA. PNBA content of the copolymers was then

determined from the ratio of integrated intensities of these

well-resolved signals and was found to be 40 wt % for P2

respectively (Table 1). Whereas that for P1 was 50 wt %

1

Da) obtained from H NMR analysis of OEtOxA₈₀₀. But, we

were unable to measure M and D- of OEtOxA

mer from SEC because of very low M_n.

macromono-

400

n

Furthermore, the SEC trace of P2 copolymer was also unimo-

dal in nature and there was a shifting of the chromatogram

towards lower retention time compared to that of OEtOxA₈₀₀

macromonomer (Fig. 2). More precisely, SEC trace of P2

copolymer was shifted to higher molar mass (equivalent to a

molar mass of 6.05 kDa) compared to that of OEtOxA₈₀₀

after copolymerization with NBA, which clearly revealed the

formation of P(OEtOxA800)-ran-PNBA copolymer. As can be

seen from Supporting Information Figure S8, the SEC trace

(

Table 1).

Thermoresponsiveness of Copolymers in Water

As mentioned above, PEtOx with high degree of polymeriza-

tion (DP) exhibited LCST-type soluble-to-insoluble phase

4

8,57

transition in the range of 61–64 8C in water.

Further,

Schubert et al. also demonstrated the existence of LCST-type

phase transition in the aqueous solution of poly(oligo(2-eth-

yl-2-oxazoline)methacrylate) (POEtOxMA) containing very

short hydrophilic PEtOx side chains and hydrophobic poly-

of P1 was also unimodal in nature. M s and D- s of P1 and P2

n

copolymers were calculated from SEC analysis and were

found to be 6.5 kDa and 1.58 for P1 and 7.05 kDa and 1.32

for P2, respectively (Table 1). SEC measurement of the

copolymers using polystyrene standards yielded slightly low-

er molecular weight compare to the theoretically calculated

value presumably due to the interaction between NBA chro-

4

9

methacrylate backbone. This is because upon increasing

temperature, the aqueous solution of PEtOx or PEtOx con-

taining polymers became turbid because of their molecular

association into larger aggregates by hydrophobic noncova-

lent interaction among the pendent ethyl groups. In this

case, it should be noted that P(OEtOxA)-ran-PNBA copoly-

mers were highly soluble in water and giving transparent

solutions even though they contained hydrophobic PNBA

segment. Therefore, the study of their thermoresponsive

behavior in water would be highly interesting. As expected,

the transparent aqueous solution of P1 (0.2 wt %) became

turbid upon heating and transparency reappeared upon cool-

ing, indicating the presence of LCST-type phase transition as

can be seen from the photographs shown in Scheme 2.

5

mophore containing copolymers and column materials. The

moderately high D- values and broadening of SEC traces of

P1 and P2 prepared by RAFT copolymerization can be

ascribed to the interference of NBA monomer, which is a

5

6

radical scavenger during polymerization.

Furthermore, the PNBA content in these two copolymers

1

(

P1, P2) was estimated from their corresponding H NMR

spectrum (Supporting Information Fig. S2C). P(OEtOxA₈₀₀)-

ran-PNBA (P2) copolymer exhibited the characteristic proton

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PNBA (P1) solution at its different concentration, which

clearly revealed that Tcp have a strong dependency with con-

centration [Fig. 4(A)]. Tcp of P1 was found to decreased ini-

tially from 42 to 30 8C with increasing concentration from

0.05 to 0.2 wt % as can be seen from Figure 4(A) because of

the enhancement of intermolecular aggregation between

6

0

polymer chains [Fig. 4(A)]. The measured T s was then

cp

plotted against concentration to calculate the actual LCST of

the copolymer in water was found to be 30.1 8C at minimum

copolymer concentration of 0.292 wt % [Fig. 4(B)].

Dual Photo- and Thermo-Responsiveness of Copolymer

in Water

As mentioned above, the PNBA segment of the copolymer con-

tains a photoresponsive o-nitrobenzyl ester (NBE) moiety,

5

0,52

which can be cleaved by UV light irradiation.

k 5 350 nm) irradiation, the benzylic C-O bond of NBE moiety

breaks down to produce o-nitrosobenzaldehyde and a carboxyl-

Upon UV light

(

6

1

ic acid as shown in Scheme 2. Thus, the photo-responsiveness

of P(OEtOxA)-ran-PNBA (P1) copolymer in aqueous solution

2

1

(

0.04 mg mL ) was studied by irradiating with UV light for dif-

ferent intervals of time and the corresponding UV-vis spectra of

were recorded for monitoring the photocleavage PNBA. It

showed a clear absorption band at 280 nm corresponding to

the o-nitrobenzyl ester (NBE) moiety of PNBA segment of copol-

ymer before irradiation (Supporting Information Fig. S9). The

intensity of this peak (kmax 5 280 nm) indeed decreased with

increasing UV irradiation time due to cleavage of NBE moiety

and reached a minimum after 40 min (Supporting Information

Fig. S9). While an additional band was appeared at around

320 nm due to the formation of 2-nitrosobenzaldehyde in solu-

tion (Supporting Information Fig. S9). This process was accom-

panied by a color change of the solution of P1 copolymer from

colorless to light yellow (photographs in Scheme 2). Conse-

quently, the hydrophobic PNBA segment converted into hydro-

philic poly(acrylic acid) (PAA), which resulted in the

transformation of amphiphilic (P(OEtOxA)-ran-PNBA) to fully

hydrophilic (P(OEtOxA)-ran-PAA) copolymer (Scheme 2).

FIGURE 2 SEC traces of OEtOxA800 macromonomer and

P(OEtOxA800)-ran-PNBA (P2) copolymer.

When the temperature of this solution was increased, the

transmittance gradually decreased from 100 to 0% with a T_c_p

at 30 8C (50% transmittance) and the process was fully revers-

ible without any hysteresis (Fig. 3). It is apparent that the

appearance of LCST in aqueous copolymer solution is solely

because of P(OEtOxA) segment even if hydrophobic PNBA seg-

ment is covalently attached. Thus, to investigate the effect of

hydrophobic PNBA segment in the LCST property of this copol-

ymer, we measured the T_c_pof P(OEtOxA₄₀₀) homopolymer

having M

n

value almost close to that of P1 copolymer in water

Therefore it would be more interesting to investigate the

LCST behavior of the resultant (P(OEtOxA)-ran-PAA copoly-

mer in water. To investigate, aqueous P1 solution (0.2 wt %)

was first irradiated with UV light for 60 min and T_c_pof this

exposed solution was measured by turbidimetry. The trans-

parent light yellow solution obtained after UV light irradia-

tion became turbid upon heating, and transparency

reappeared upon cooling, indicating that the exposed solu-

tion also exhibited LCST-type phase transition (photographs

in Scheme 2). As mentioned above, before UV light irradia-

tion, T_c_pof P1 copolymer in water was 30 8C, which was

increased to 39 8C after UV irradiation (Fig. 3). Also, it was

observed that the Tcp of 0.05 wt % P1 solution increased

from 44 (before UV irradiation) to 58 8C (exposed with UV

irradiation) (Supporting Information Fig. S10). In the case of

P2 copolymer (0.2 wt %) in water, the T_c_pwas 46 8C before

UV irradiation, which was also increased to 61 8C after UV

irradiation (Fig. 5). Therefore, the first conclusion was that the

cloud point of P2 was increased by 16 8C (from 30 to 46 8C)

(

Table 1 and Supporting Information Fig. S8). The T_c_pof 0.2 wt

%

of P(OEtOxA₄₀₀) was found to be 61 8C (Fig. 3) as measured

from heating and cooling cycle without any hysteresis. Where-

as the T_c_pof 0.2 wt % of P1 copolymer in water was 30 8C (Fig.

3). Therefore, it is very clear that the presence of 50 wt % of

hydrophobic PNBA in the P1 resulted in decrease of the T_c_pof

P(OEtOxA400) by more than 30 8C. Such lowering of LCST of a

copolymer simply by incorporation of hydrophobic moiety

was also reported for poly(ethoxytri(ethylene glycol) acrylate-

co-o-nitrobenzyl acrylate) (PTEGEA-co-PNBA) copolymer by

Zhao and coworkers. They showed a decrease of the Tcp of a

copolymer by 15 8C compared to that of PTEGEA segment

upon incorporation of 13 mol % of hydrophobic PNBA seg-

ment. The thermoresponsiveness of P2 copolymer in water

was described later in this section.

5

8

It is known that the LCST/UCST-type Tcp of a polymer solu-

tion strongly depends on its concentration.

we further measured T s of aqueous P(OEtOxA₄₀₀)-ran-

cp

4

9,59

Therefore,

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SCHEME 2 Photocleavage of P(OEtOxA)-ran-PNBA copolymer (A); Photographs of P(OEtOxA400)-ran-PNBA (P1) in water (0.2 wt %)

before UV irradiation and after UV irradiation indicating the LCST-type soluble-to-insoluble transition (B). [Color figure can be

viewed at wileyonlinelibrary.com]

compared to that of P1 due to the increase of length of ther-

moresponsive P(OEtOxA) segments from P1 to P2. Further-

more it should be noted that T_c_pvalues of UV light irradiated

copolymers’ solution was about 10 8C higher than that of the

nonirradiated solution. Such increase of T_c_pvalues can be

explained in the following way. The photocleavage of NBE

moiety of PNBA segment of P(OEtOxA)-ran-PNBA copolymer

resulting in the transformation of hydrophobic PNBA seg-

ments into hydrophilic PAA segments (Scheme 2). Thus, the

irreversible photocleavage of NBE moieties of PNBA increases

the overall hydrophilicity of the P(OEtOxA)-ran-PNBA copoly-

mer due to its transformation into P(OEtOxA)-ran-PAA copoly-

mer and consequently, increases the cloud point by more than

solvent where two polymer blocks have differences in their

6

2

solubility. However, such micelle formations due to differ-

ence in solubility of two polymer segments of an amphiphilic

2

0,43

random copolymers are comparatively less reported.

This prompted us to investigate the self-aggregation of

P(OEtOxA)-ran-PNBA copolymer into micelles as P(OEtOxA)

segment is soluble in water, whereas PNBA segment is not.

21

The aqueous P1 copolymer solution (0.3 mg mL ) was kept

undisturbed for some time to allow its self-aggregation and

the solution was examined by FESEM at 20 8C, which is

below the LCST of P1 copolymer. The FESEM image [Fig.

6(A)] of aqueous P1 copolymer solution showed the forma-

tion of dispersed spherical nanostructures with an average

diameter of 71 nm. These spherical nanosized particles [Fig.

10 8C. Thus, we can easily tune the T_c_pof copolymer solution

6

(A)] are nothing but the micelles formed by the self-

over a large window of temperature ranging from 28 to 60 8C

not only by varying concentration but also simply by irradiat-

ing with UV light, making these copolymer highly appropriate

for varieties of potential applications.

aggregation of amphiphilic P1 copolymer in water. The for-

mation of micelles was also confirmed from TEM study. The

2

1

aqueous P1 and P2 copolymer solution (ꢀ0.30 mg mL

)

were examined through TEM at 20 8C and images were tak-

en, which clearly showed the formation of nanostructured

spherical micelles with an average diameters of 90 and

80 nm for P1 [Fig. 6(B)] and P2 (Supporting Information

Fig. S11), respectively. We further examined both aqueous

Self-Aggregation of P(OEtOxA)-Ran-PNBA Copolymer into

Micelles and Their UV- and Temperature-Induced

Disaggregation

It is very common that amphiphilic block copolymers self-

assemble into micelles when they are dissolved in a selective

2

1

P1 and P2 copolymer solution (0.3 mg mL ) by DLS at 20

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micelles measured by DLS was always higher than that of

the same particles measured by FESEM and TEM. Thus, DLS,

FESEM, and TEM results clearly confirmed the formation of

spherical micelles due to the self-aggregation of P(OEtOxA)-

ran-PNBA molecules in water as schematically shown in

Scheme 3. The self-aggregation phenomenon of amphiphilic

random copolymer into micelles has already been reported

2

0,43

by quite few research groups.

In this case, the micelle

formation can be attributed to the difference in polarities of

P(OEtOxA) and PNBA segments with respect to H O, where

2

hydrophobic PNBA segments remain inside the core of the

micelle and the hydrophilic P(OEtOxA) segments stretches

toward the solvent front forming the corona (Scheme 3).

Thus, to investigate the effect of UV light irradiation on the

self-assembly of the copolymer P(OEtOxA)-ran-PNBA in

water, aqueous P1 micellar solution was irradiated with UV

light for 45 min. The snapshot images evinced that the color-

less micellar solution of P1 converted to a light yellow solu-

tion after UV light irradiation, suggesting some definite

changes [Fig. 6(A,C)]. As mentioned above, before irradiation,

P1 copolymer self-assembled into micelles with an average

FIGURE 3 % transmittances at wavelength of 500 nm of 0.2 wt

%

aqueous solution of P(OEtOxA400) homopolymer and 0.2 wt

diameter of 71 nm (FESEM) in H O [Fig. 6(A)]. However,

2

aqueous solution of P(OEtOxA400)-ran-PNBA (P1) copolymer

FESEM image of the aqueous P1 micellar solution after UV

light irradiation did not show any particles (micelles); rather,

a continuous polymer film was observed [Fig. 6(C)]. This is

mainly because of the fact that upon light irradiation, PNBA

segments of P(OEtOxA)-ran-PNBA copolymer converted

hydrophilic PAA segments (Scheme 2), which resulted in the

formation of fully hydrophilic P(OEtOxA)-ran-PAA from

amphiphilic P(OEtOxA)-ran-PNBA copolymer. This transfor-

mation accompanied with the change of hydrophilic–lipophil-

ic balance (HLB) of copolymer molecule, leading to the

simple disruption of micellar assemblies as schematically

shown in Scheme 3.

before UV irradiation and after UV light irradiation. The trans-

mittances were measured with a UV–vis spectrometer. [Color

figure can be viewed at wileyonlinelibrary.com]

8C to provide further evidence of self-aggregation of copoly-

mer molecules into micelles. The DLS data clearly indicated

the presence of particles with average hydrodynamic diame-

ters (D s) of 165 and 191 nm for P1 and P2, respectively

h

(

Fig. 7). The formation of such particles can be ascribed to

the self-assembly of P(OEtOxA)-ran-PNBA copolymer into

micelles (Scheme 3) as established through FESEM and TEM

mentioned above [Fig. 6(A,B)]. As expected, the D_hof the

FIGURE 4 % transmittance curves for P(OEtOxA400)-ran-PNBA (P1) copolymer with varying concentration in deionized water (heat-

21

2

ing rate 2 8C min ) (A); LCST-type phase diagram of binary mixture of P(OEtOxA400)-ran-PNBA (P1) copolymer and H O (B). [Color

figure can be viewed at wileyonlinelibrary.com]

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Furthermore, P(OEtOxA)-ran-PNBA copolymer exhibited

LCST-type thermoresponsiveness in water as mentioned

above. Therefore, one would expect some kind of change in

the micellar structures of this copolymer above its cloud

point before UV irradiation. To check this, aqueous micellar

2

1

solution of P1 copolymer (0.3 mg mL ) was heated above

LCST (60 8C) and was examined by DLS. The D_hof the P1

micelles was found to be 140 nm with a PDI 5 0.104 at 60

8C, which is lower than that of the same micelles (165 nm

with a PDI 5 0.250) when the measurement was carried out

at 20 8C (Fig. 7). D_hvalue of P2 copolymer micelles was

166 nm with PDI of 0.156 at 60 8C, which is also lower than

that (190 nm with a PDI of 0.219) same micelles measured

at 25 8C (Fig. 7). We reason that at low temperature,

P(OEtOxA) segments present in the corona of copolymer

micelles remain in the extended coil form because of the

hydrogen bonding interaction with water molecules. Upon

increasing the temperature above LCST, hydrophilic

P(OEtOxA) corona becomes hydrophobic and collapsed over

micellar core resulting in the shrinkage of the micellar size

4

0,43,63

(

Scheme 3).

Shrinkage of micellar size at above LCST

FIGURE 5 Variation of % transmittance (at k 5 500 nm) of 0.2

wt % aqueous solution of P(OEtOxA800)-ran-PNBA (P2) before

UV light irradiation and after 1 h of UV irradiation (k 5 365 nm)

with temperature. [Color figure can be viewed at wileyonlineli-

brary.com]

was also observed from TEM study, which showed spherical

particles with average diameter of 45 nm for P1 copolymer

at 65 8C [Fig. 6(D)], comparatively lower than that (ꢀ90 and

7

1 nm) measured by TEM [Fig. 6(B)] and FESEM [Fig. 6(A)],

FIGURE 6 FESEM image and photograph of P(OEtOxA)400-ran-PNBA (P1) micellar solution in H

image of P(OEtOxA)400-ran-PNBA (P1) micellar solution in H O before UV irradiation (B); FESEM image and photograph of the

aqueous P1 micellar solution after UV light irradiation for 45 min (C); TEM image of the P1 micellar solution at 65 8C (D). ([P1] in

2

O before UV irradiation (A); TEM

2

21

2

H O 5 0.3 mg mL ). [Color figure can be viewed at wileyonlinelibrary.com]

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Encapsulation of Dye and Its Photo- and Temperature-

Induced Release

A model hydrophobic dye, nile red (NR) was used to study

the encapsulation of guest molecules inside the hydrophobic

core of P(OEtOxA)-ran-PNBA copolymer micelles and their

photo- and temperature-induced release. NR is mostly insol-

uble in water; therefore, it does not exhibit any fluorescence.

However, the intensity dramatically enhances if the dye

resides in a hydrophobic environment, for example inside of

a hydrophobic micellar core. In this case, the spectrum [Fig.

8(A)] of NR-encapsulated P1 micelle (for encapsulation pro-

tocol, see Experimental section) revealed a clear intense

peak at around 630 nm (k_e_x5 550 nm), while there was no

observable fluorescence peak of an aqueous solution of NR

prepared under identical condition in the absence of P1

micelle [Fig. 8(A)]. This result indicated the encapsulation of

NR inside P1 micelles in aqueous solution. Afterwards, NR-

encapsulated aqueous P1 micelle was subjected to UV light

irradiation for NR release. Figure 8(B) showed that the

intensity of emission at k_m_a_x5 630 nm for NR present inside

the micellar core decreased with increasing UV irradiation

time (0–30 min). As can be seen clearly, the emission inten-

sity of NR was decreased dramatically to almost zero upon

light irradiation for only 10 min [Fig. 8(B)]. Actually, NR-

loaded P1 micelles were disrupted upon UV irradiation due

to the photocleavage of NBE moieties of PNBA segments;

consequently there was a release of loaded NR from hydro-

phobic micellar core to water medium outside of the

micelles (Scheme 3). However, NR is not soluble in water

and therefore it would not display any fluorescence. Hence,

the emission intensity of NR decreased with increasing UV

irradiation time which in turns confirmed the photo-

triggered release of NR (Scheme 3).

FIGURE 7 DLS data of P(OEtOxA400)-ran-PNBA (P1) and

P(OEtOxA800)-ran-PNBA (P2) copolymers in

2

H O (0.30 mg

21

mL ) at two different temperatures. [Color figure can be

viewed at wileyonlinelibrary.com]

respectively at 20 8C. Thus, above the T_c_p(60 8C), hydropho-

bicity of the micellar corona increases resulting in the

shrinkage of micelle (Scheme 3) as established from FESEM

and TEM and DLS analysis.

SCHEME 3 Schematic representation of P(OEtOxA)-ran-PNBA copolymer self-aggregation into micelles and nile red (NR) encapsu-

lation followed by its temperature- and photo-induced release. [Color figure can be viewed at wileyonlinelibrary.com]

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FIGURE 8 Emission spectra of NR-encapsulated P(OEtOxA400)-ran-PNBA (P1) copolymer micelles and neat NR in absence of P1

copolymer in water (A); Emission spectra of remaining NR inside the P(OEtOxA400)-ran-PNBA (P1) copolymer micellar core in

water after UV light irradiation for different times (B) and at different temperatures (C). [Color figure can be viewed at wileyonline-

library.com]

The emission intensity of NR resides in the micellar core

also recorded with increasing temperatures from 20 to 60 8C

easily control the release of encapsulated guest molecules

from aqueous P(OEtOxA)-ran-PNBA copolymer micellar solu-

tion simply by altering the temperature and UV light irradia-

tion time.

[

Fig. 8(C)]. The data clearly showed that the emission inten-

sity of NR decreased gradually with increasing temperature

Fig. 8(C)]. The reason for such decrease of NR intensity is

[

the transformation of P(OEtOxA) corona of micelles from

hydrophilic to hydrophobic nature resulting in the collapse

of corona over micellar core and ultimately some disruption

of micellar assembly upon increasing temperature. This leads

to the release of encapsulated NR from micellar core into

aqueous medium. However, the emission intensity was mini-

mum at 60 8C, that is, just above the LCST of the copolymer

CONCLUSIONS

In summary, we have designed and synthesized doubly-

responsive amphiphilic random P(OEtOxA)-ran-PNBA copoly-

mer with light-sensitive PNBA segments and thermo-

responsive P(OEtOxA) segments via the combination of

microwave-assisted CROP and RAFT polymerization techni-

ques. Indeed, P(OEtOxA)-ran-PNBA copolymer exhibited tun-

able LCST-type phase transition with respect to copolymer

compositions. Upon UV light irradiation, Tcp of the copolymer

increased due to the photocleavage of PNBA segments result-

ing in the formation of more hydrophilic P(OEtOxA)-ran-PAA

compared to that of P(OEtOxA)-ran-PNBA copolymer.

[

Fig. 8(C)]. Afterwards it remained constant and no further

reduction of emission intensity of NR was observed [Fig.

(C)] upon increasing of temperature indicating that some of

8

the loaded NR was still remain encapsulated in the collapsed

micelles (Scheme 3). These results further proved that the

micelles were shrunk at above cloud point. Thus, one can

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P(OEtOxA)-ran-PNBA copolymer indeed self-aggregated into

19 C. J. F. Rijcken, O. Soga, W. E. Hennink, C. F. Van Nostrum,

J. Controlled Release 2007, 120, 131–148.

well-dispersed spherical micelles in H O at 20 8C. Upon UV

2

0 L. Li, K. Raghupathi, C. Song, P. Prasad, S. Thayumanavan,

light irradiation, the amphiphilic P(OEtOxA)-ran-PNBA con-

verted into fully hydrophilic P(OEtOxA)-ran-PAA, causing the

disruption of micelles in water. Additionally, above LCST, the

hydrophilic P(OEtOxA) segments of corona are converted

into hydrophobic segments and it collapsed over micellar

core, resulting in the shrinkage of the micelles into smaller

size. Finally, as a proof concept, NR was successfully encap-

sulated into the P(OEtOxA)-ran-PNBA micellar core, and its

light- and temperature-induced release was clearly demon-

strated. This multiresponsive copolymer assembly can be

potentially employed in highly important areas such as con-

trolled release of drugs and dyes, biosensors and

nanoreactors.

Chem. Commun. 2014, 50, 13417–13432.

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ACKNOWLEDGMENTS

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9 P. Schattling, F. D. Jochum, P. Theato, Polym. Chem. 2014,

S. Jana thanks IACS for providing fellowship. Thank are also due

to CSIR, India, for the fellowship to A. Bose. We also thank

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research.

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Article Doi

Photocleavable and tunable thermoresponsive amphiphilic random copolymer: Self-assembly into micelles, dye encapsulation, and triggered release

DOI: 10.1002/pola.28537

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Article abstract of DOI:10.1002/pola.28537

Full text of DOI:10.1002/pola.28537

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