ph-switchable polymer nanostructures for controlled release

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pH-switchable polymer nanostructures for controlled release†

Kay E. B. Doncom,a Claire F. Hansell,a Patrick Theatob and Rachel K. O’Reilly*a

Received 20th July 2012, Accepted 8th August 2012

DOI: 10.1039/c2py20545a

A diblock copolymer consisting of poly(methyl acrylate) (PMA) and poly(pentafluorophenyl acrylate)

(PPFPA) was synthesized by RAFT polymerization methods. The PPFPA block was then substituted

with N,N-diisopropylethylenediamine and the end group modified with one of two hydrophilic groups

to form pH-responsive copolymers. The self-assembly properties of these polymers were investigated

and shown by TEM and DLS to form micelles at acidic pH and vesicles at basic pH. The encapsulation

and controlled release of a hydrophilic dye molecule, Rhodamine B, was demonstrated using

fluorescence spectroscopy.

Introduction

The ability of amphiphilic block copolymers to self-assemble in

selective solvents, particularly water, has been of great interest to

scientists and has been widely studied in academia. These

amphiphiles self-assemble in order to minimize any unfavourable

interactions between the hydrophobic block and the aqueous

environment.1 Many morphologies are possible, from the

conventional spherical micelles,2 rods,3 cylindrical micelles4 and

vesicles,5–7 to the more exotic hamburger micelles8 and Janus

particle micelles.9,10 The structure of the particle formed is related

to the interfacial curvature favored by the amphiphile and the

effect this has on the packing of the polymer chains.1 This can be

predicted from a dimensionless factor known as the packing

parameter, p, which when simplified, is related to the amphiphilic

balance, or the ratio of hydrophobic to hydrophilic blocks, of the

block copolymer. For example, a micelle is formed when p# 1/3 ,

and vesicles are favoured when ½ # p # 1. Therefore changing

the length of the hydrophilic block will cause a change in the

packing parameter and in the morphology formed upon self-

assembly.

In recent years particular attention has been paid to stimuli

responsive polymers, which undergo a change in hydrophilicity

in response to external stimuli, such as light,11–14 temperature,15–23

pH,24–31 or a combination of stimuli.32–37 Copolymers made up of

one or more of these responsive blocks will undergo a phase

transition in response to a specific stimulus. This can result in a

morphology change such as from unimers to micelles,23,37–40

micelles to vesicles,1,15,16,41–43 or rod–coil transitions14,44 by

altering the amphiphilic balance of the copolymer and therefore

aUniversity of Warwick, Department of Chemistry, Gibbet Hill Road,Coventry, CV7 4AL, UK. E-mail: [email protected] for Technical and Macromolecular Chemistry, University ofHamburg, Bundesstrasse 45, D-20146, Hamburg, Germany

† Electronic supplementary information (ESI) available: Furthercharacterization of polymers and self-assembled structures. See DOI:10.1039/c2py20545a

This journal is ª The Royal Society of Chemistry 2012

its packing parameter. Within this area of research particular

interest has been paid to the potential ability of these responsive

amphiphilic polymers to encapsulate a small molecule and

release it in a controlled manner upon application of the specific

stimulus.28,29,45–47 This ability could have the potential to be used

in the medical or pharmaceutical industries, such as in targeted

drug delivery applications.

Controlled radical polymerization techniques such as Atom

Transfer Radical Polymerization (ATRP),48 Nitroxide Mediated

Polymerization (NMP)49 and Reversible Addition Fragmenta-

tion chain Transfer (RAFT) polymerization provide a facile

route to the synthesis of amphiphilic polymers as they allow the

formation of polymers with controlled architecture.50 Of these

techniques, RAFT provides an excellent route to the formation

of these ‘‘smart’’ polymers as it produces well-defined polymers,

with narrow polydispersities and predictable and controllable

molecular weight.51–53 RAFT also has a high tolerance for

functional groups within the growing polymer chain and retains

good control over end group fidelity, an important feature when

well-defined end groups are required. Functionality at the a end

of a polymer chain can be introduced pre-polymerization by

using a chain transfer agent containing the desired group. Post-

polymerization modification of the thiocarbonylthio group of

the chain transfer agent enables the introduction of a desired

functionality at the u chain end.54–59

Functionality within the polymer chain can be achieved by

directly polymerizing the desired monomer. However, for

monomers which may prove more difficult to directly polymerize

with good control an alternative route is through post poly-

merization functionalization of a scaffold polymer, for example

activated esters. Pentafluorophenyl acrylate is a good example of

an activated ester that can be polymerized by RAFT and has

been shown to be easily modified with both alcohols and

amines.60–66

Previous work within our group has shown that a diblock

copolymer consisting of a hydrophobic block, the temperature

responsive block PNIPAM and a charged hydrophilic RAFT

Polym. Chem., 2012, 3, 3007–3015 | 3007

http://dx.doi.org/10.1039/c2py20545a






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end group can undergo a morphology transition from micelle to

vesicle in response to a change in temperature.15,16 This switching

behaviour was shown to be fully reversible and reproducible,

however, the time required for switching was slow. To improve

the utility of such morphology-switching materials we have

switched our focus to explore an alternative stimulus, namely

pH. Herein we report a new diblock copolymer containing a

hydrophobic block, a pH responsive block and a hydrophilic end

group. We investigate the self-assembly behaviour of this poly-

mer and show that it undergoes a morphology transition upon

decreasing the pH below the pKa of the responsive polymer. We

also show that the self-assembled structures are capable of

trapping a hydrophilic dye molecule and releasing it in a

controlled manner upon application of the stimulus.

Experimental

Materials

N,N-dimethylformamide (DMF 99.9%), 1,4-dioxane, N,N-diiso-

propylethylenediamine and all other chemicals were used as

received from Aldrich and Tokyo Chemical Industry unless

otherwise stated. AIBN [2,20-azobis(2-methylpropionitrile)] was

recrystallized twice frommethanol and stored in the dark at 4 �C.Methyl acrylate (MA) was passed over a short column of alumina

immediately prior to use in order to remove the inhibitor. Pen-

tafluorophenyl acrylate (PFPA) was synthesized according to

literature procedures.60 Triethylene glycol methyl ether acrylate

was synthesized according to literature procedures.67

Characterization

Nuclear magnetic resonance (1H and 13C NMR) experiments

were recorded at 400 or 500 MHz in CDCl3 or MeOD on a

Bruker DPX-400 or Bruker AM500 spectrometer. 19F NMR

spectra were recorded at 300 MHz in CDCl3 or MeOD on a

Bruker Avance 300 spectrometer. Chemical shifts are reported in

parts per million relative to CHCl3 (7.26 ppm for 1H and 77.0

ppm for 13C) or MeOD (4.84 ppm for 1H and 49.0 ppm for 13C).

Size exclusion chromatography (SEC) measurements were

obtained in either HPLC grade CHCl3 or DMF containing 0. 1

MNH4BF4 with a flow rate of 1 mL min�1, on a set of two PLgel

5 mm Mixed D columns plus a guard column. Cirrus SEC soft-

ware was used to analyze the data using poly(methyl methacry-

late) (PMMA) standards. Hydrodynamic diameters (Dh) and size

distributions of the self-assembled structures in aqueous solu-

tions were determined by dynamic light scattering (DLS). The

DLS instrumentation consisted of a Malvern Zetasizer NanoS

instrument operating at 25 �C with a 4 mW He–Ne 633 nm laser

module. Measurements were made at a detection angle of 173�

(back scattering) and Malvern DTS software was utilized to

analyze the data. All measurements were run at least three times

with a minimum of 10 runs per measurement. TEM measure-

ments were made by drop deposition of 4 mL solution onto an

oxygen plasma treated carbon-coated copper grid. Analysis was

performed on a JEOL TEM 2011 operating at 200 keV. Number

average particle diameters (Dav) were generated from the analysis

of a minimum of 50 particles from at least three different

micrographs. Fluorescence measurements were recorded on a

Perkin Elmer LS 55 spectrometer. Infrared spectrometry was

3008 | Polym. Chem., 2012, 3, 3007–3015

recorded on a Perkin Elmer Spectrum 100 FT-IR ATR unit.

Mass spectra were recorded on a Bruker Esquire 2000 ESI

spectrometer. Dialysis tubing was bought from Spectrum labs

with a molecular weight cut off 3.5 kDa.

Formation of the diblock copolymer

MA (4.00 g, 0.93 mmol, 50 equiv.) CTA 1 (ref. 68) (0.36 g, 46.5

mmol) and AIBN (15.3 mg, 0.09 mmol, 0.10 equiv.) were dis-

solved in 1,4-dioxane (2 : 1 volume compared to monomer) and

placed in an oven-dried ampoule under the flow of nitrogen with

a stirrer bar. The ampoule was degassed by at least three freeze–

pump–thaw cycles and released to and sealed under nitrogen.

The polymerization mixture was then heated at 65 �C for 2 hours

20 minutes to afford 2, conversion ¼ 73% (see Scheme 1). The

polymer was purified by precipitation into a stirred solution of

cold MeOH : H2O (10 : 1) three times, followed by dissolution in

THF, drying over anhydrous MgSO4, removal of the THF and

drying in vacuo to yield a yellow oily polymer. Mn (1H NMR) ¼

3.8 kDa, Mn (CHCl3 SEC) ¼ 2.6 kDa, Mw/Mn ¼ 1.07. 1H NMR

(400 MHz, CDCl3): d 0.88 (t, 3H, J ¼ 6.9 Hz, CH2CH3 of CTA

end group), 1.20–1.38 (br m, 20H, (CH2)10CH3 of CTA end

group), 1.40–2.10 (br m, 80H, CHCH2 of polymer backbone),

2.24–2.40 (br s, 40H, CHCH2 of polymer backbone), 3.34 (t, 2H,

J¼ 7.2 Hz, SCSSCH2 of CTA end group), 3.60–3.70 (br s, 120H,

OCH3 of PMA side chain), 4.88 (q, 1H, J¼ 7.6 Hz, CH3CHPh of

CTA end group), 7.12–7.28 (m, 5H, ArH in CTA end group). 13C

NMR (125 MHz, CDCl3): d 221.4, 175.8–175.6, 174.8–174.2,

170.4, 146.2, 146.2, 128.4, 126.9, 126.2, 52.9, 51.7, 50.5, 50.4,

50.0, 41.3–41.1, 37.5, 36.0–34.1, 31.9, 29.6, 29.5, 29.4, 29.3, 29.0,

28.9, 27.8, 23.0, 22.6, 22.5, 22.4, 22.2, 21.8, 14.1. FTIR nmax/cm�1

2953 and 2854 (alkane C–H stretch), 1729 (C]O ester stretch),

1435 and 1378 (C]C aromatic stretch).

Polymer 6 was synthesized in a similar manner, [CTA] : [M] ¼1 : 40, time ¼ 1 hour 35 minutes, conversion ¼ 50%. Mn (1H

NMR) ¼ 2.1 kDa, Mn (DMF SEC) ¼ 2.6 kDa, Mw/Mn ¼ 1.11.1H NMR (400 MHz, CDCl3): d 0.88 (t, 3H, J ¼ 6.7 Hz, CH2CH3

of CTA end group), 1.18–1.34 (br m, 20H, (CH2)10CH3 of CTA

end group), 1.40–2.10 (br m, 40H, CHCH2 of polymer back-

bone), 2.24–2.40 (br s, 20H, CHCH2 of polymer backbone), 3.34

(t, 2H, J¼ 7.4 Hz, SCSSCH2 of CTA end group), 3.60–3.70 (br s,

60H, OCH3 of PMA side chain), 4.88 (q, 1H, J ¼ 7.5 Hz,

CH3CHPh of CTA end group), 7.12–7.28 (m, 5H, ArH in CTA

end group). 13C NMR (125 MHz, CDCl3): d 221.4, 175.8, 175.6,

174.8, 174.3, 174.2, 170.4, 146.2, 128.4, 126.9, 126.2, 52.9, 51.7,

50.5, 50.4, 49.9, 41.3–41.1, 37.5, 36.0–34.0, 31.9, 29.6, 29.49, 29.4,

29.3, 29.0, 28.8, 27.7, 23.0, 22.6, 22.6, 22.4, 22.2, 21.7, 14.1. FTIR

nmax/cm�1 2953 and 2854 (alkane C–H stretch), 1729 (C]O ester

stretch), 1435 and 1378 (C]C aromatic stretch).

PFPA (9.21 g, 38.7 mmol, 120 equiv.), homopolymer 2 (1.23 g,

3.2 mmol) and AIBN (10.5 mg, 0.66 mmol, 0.2 equiv.) were

dissolved in 1,4-dioxane (1 : 1 volume compared to monomer)

and placed in an oven-dried ampoule under the flow of nitrogen

with a stirrer bar. The ampoule was degassed at least three times

and released to and sealed under nitrogen. The polymerization

mixture was then heated at 65 �C for 1 hour 45 minutes to afford

diblock copolymer 3, conversion ¼ 76%. The polymer was

purified by precipitation into cold hexanes three times and dried

in vacuo to yield a yellow powder.Mn (1HNMR)¼ 27.5 kDa,Mn



Scheme 1 Synthetic route for polymers 2–9.

‡ Although not ideal due to the potential for transamidation,N,N-dimethylformamide was utilized as the solvent due to the limitedsolubility of the charged tertiary amine acrylate in other organic solvents.

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(CHCl3 SEC) ¼ 7.7 kDa, Mw/Mn ¼ 1.29. 1H NMR (400 MHz,

CDCl3): d 0.88 (t, 3H, J ¼ 6.8 Hz, CH2CH3 of CTA end group),

1.20–1.34 (br m, 20H, (CH2)10CH3 of CTA end group), 1.40–2.40

(br m, 280H, CHCH2 of polymer backbone), 2.40–2.58 (br s,

40H, CHCH2 of polymer backbone), 3.0–3.15 (br s, 100H,

CHCH2 of polymer backbone), 3.34 (m, 2H, SCSSCH2 of CTA

end group), 3.60–3.70 (br s, 120H, OCH3 of PMA side chain),

7.12–7.28 (m, 5H, ArH in CTA end group). 13C NMR (125MHz,

CDCl3): d 174.9, 170.1, 170.0, 169.8, 169.7, 142.0, 141.9, 140.8,

140.0, 139.9, 138.9, 138.8, 136.7, 128.4, 127.0, 126.9, 126.2, 124.4,

51.7, 41.3, 41.1–39.9, 36.2–33.0, 32.9, 32.8, 30.3, 29.6, 29.5, 29.4,

29.3, 29.0, 28.9, 25.6, 22.7, 14.0. 19F NMR (400 MHz, CDCl3):

d �162.8 (br s, 2F, ArF in polymer side chain), �157.3 (br s, 1F,

ArF in polymer side chain),�153.8 (br s, 2F, ArF in polymer side

chain). FTIR nmax/cm�1 2956 (alkane C–H stretch), 1783 and

1737 (C]O ester stretch), 1517 and 1471 (C–F stretch), 1453

(C]C aromatic stretch).

Polymer 7 was synthesized in a similar manner, [CTA] : [M] ¼1 : 40, time ¼ 1 hour 50 minutes, conversion ¼ 87%. Mn (1H

NMR) ¼ 11.8 kDa, Mn (DMF SEC) ¼ 8.7 kDa, Mw/Mn ¼ 1.13.1H NMR (400 MHz, CDCl3): d 0.88 (t, 3H, J¼ 6.9 Hz, CH2CH3

of CTA end group), 1.20–1.38 (br m, 20H, (CH2)10CH3 of CTA

end group), 1.40–2.40 (br m, 140H, CHCH2 of polymer back-

bone), 2.40–2.50 (br s, 20H, CHCH2 of polymer backbone), 3.0–

3.15 (br s, 50H, CHCH2 of polymer backbone), 3.34 (m, 2H,

SCSSCH2 of CTA end group), 3.60–3.70 (br s, 60H, OCH3 of

PMA side chain), 7.12–7.28 (m, 5H, ArH in CTA end group). 19F

NMR (400 MHz, CDCl3): d �162.8 (br s, 2F, ArF in polymer

side chain), �157.3 (br s, 1F, ArF in polymer side chain), �153.8

(br s, 2F, ArF in polymer side chain). 13C NMR (125 MHz,

CDCl3): d 174.9, 170.1, 169.8, 169.7, 169.5, 169.4, 142.0, 141.9,

140.8, 139.99, 139.9, 138.9, 136.9, 128.5, 127.0, 126.3, 124.4, 51.7,


41.3–40.0, 36.1–34.7, 31.9, 29.6, 29.6, 29.4, 29.4, 29.1, 28.9, 22.7,

14.1. FTIR nmax/cm�1 2955 (alkane C–H stretch), 1783 and 1737

(C]O ester stretch), 1516 and 1471 (C–F stretch), 1450 (C]C

aromatic stretch).

Synthesis of the charged tertiary amine acrylate

Dimethylaminoethyl acrylate (DMAEA) (5.00 mL, 0.03 mol, 1

equiv.) was dissolved in petroleum ether (100 mL). Methyl

iodide (20.5 mL, 0.33 mol, 10 equiv.) was added and left to stir

for 1 hour. The solution was then filtered and the solid dried to

give a white solid (8.50 g, 91%). 1H NMR (400 MHz, D2O): d

3.11 (s, 9H, N+(CH3)3), 3.67 (m, 2H,CH2CH2N), 4.53 (m, 2H,

COOCH2), 5.92 (dd, 1H,2J ¼ 1.2 Hz, 3J ¼ 14.0 Hz, CHH]

CH), 6.11 (m, 1H, CHH]CH), 6.35 (dd, 1H,2J ¼ 1.2 Hz, 3J ¼23.2 Hz, CHH]CH). 13C NMR (125 MHz, D2O): d 54.6, 59.1,

66.1, 128.8, 132.9. FTIR nmax/cm�1 3020 (alkene C–H stretch),

3002 and 2949 (alkane C–H stretch), 1731 (C]O acrylate

stretch), 1621 (C]C alkene stretch), 1267 and 1278 (C–O

stretch), 1061 (C–N stretch). ESI MS: expected 158.12, found

158.12.

Substitution of the PFPA and end group modification

The substitution of the PPFPA scaffold and subsequent end

group modification proceeds via a one-pot, two step method, the

general procedure for which is as follows.

The diblock copolymer was dissolved in DMF‡ at a concen-

tration of 150 mg mL�1 and placed in an oven-dried ampoule.

Polym. Chem., 2012, 3, 3007–3015 | 3009


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The ampoule was degassed at least three times and released to

and sealed under nitrogen. In a separate oven-dried ampoule

N,N-diisopropylethylenediamine (1.5 equiv. per PFPA) was

dissolved in DMF and the ampoule was degassed by three

freeze–pump–thaw cycles and released to and sealed under

nitrogen. The amine solution was transferred to the polymer

solution using air sensitive techniques. The solution was stirred

at room temperature overnight. 19F NMR was used to confirm

the full modification of pentafluorophenyl groups. In order to

modify the end group of the polymer, the desired end group

acrylate (100 equiv.), PBu3 (20 equiv.) and hexylamine (20 equiv.)

were separately dissolved in DMF and placed into individual

oven-dried ampoules. These three ampoules were then degassed

and released to and sealed under nitrogen. Air sensitive tech-

niques were used to transfer, firstly, the acrylate solution into the

polymer solution, followed by the PBu3 solution. After stirring

for 10 minutes, air sensitive techniques were used to transfer the

hexylamine solution into the polymer solution. The polymer

solution was then stirred overnight. The polymer was purified by

exhaustive dialysis against water, incorporating both acidic and

basic water changes. The polymer was recovered by lyophiliza-

tion to yield diblock copolymer 4, 5, 8 or 9. Full side chain

conversion was observed and end group modification was

calculated to be 100% by 1H NMR spectroscopy in both cases.

Polymer 4.Mn (1HNMR)¼ 23.9 kDa,Mn (DMF SEC)¼ 23.1

kDa, Mw/Mn ¼ 1.19. 1H NMR (400 MHz, MeOD): d 1.11–2.50

(br m, 420H, CHCH2 of polymer backbone), 1.35–1.50 (br s,

1200H, N(CH(CH3)2)2 of DIPEA side chain), 2.65 (t, 2H, J¼ 7.2

Hz, SCH2CH2COO of end group), 2.90 (br m, 2H,

SCH2CH2COO of end group), 3.16–3.42 (br s, 200H,

NHCH2CH2N of DIPEA side chain), 3.40–3.90 (br m, 520H,

NHCH2CH2N and N(CH(CH3)2)2 of DIPEA side chain and

OCH3 of PMA side chain), 4.55 (br, 2H, COOCH2CH2N of end

group), 7.10–7.30 (m, 5H, ArH of end group). 13C NMR (125

MHz, MeOD): d 176.9, 176.7, 176.6, 129.6, 128.2, 128.2, 68.9,

52.4, 50.8, 46.0, 43.7, 42.7, 42.1, 35.9, 21.2. FTIR nmax/cm�1:

3303 (N–H amide stretch), 2964 (alkane C–H stretch), 1737 (C]

O ester stretch), 1646 (C]O amide stretch), 1536 (N–H amide

bend), 1361 and 1185 (C–N stretch).

Polymer 5. Mn (1HNMR)¼ 23.9 kDa,Mn (DMF SEC)¼ 23.1

kDa,Mw/Mn¼ 1.19. 1HNMR (400MHz,CDCl3): d 0.90–1.11 (br

s, 1200H, N(CH(CH3)2)2 of DIPEA side chain) 1.20–2.40 (br m,

420H, CHCH2 of polymer backbone), 2.40–2.50 (br s, 200H,

NHCH2CH2NofDIPEAside chain), 2.75 (m,4H,SCH2CH2COO

of end group), 2.90–3.30 (br m, 300H, NHCH2CH2N and

N(CH(CH3)2)2 of DIPEA side chain), 3.39 (br s, 3H, OCH3 of end

group), 3.47–3.56 (m, 8H, (OCH2CH2O)2 of end group), 3.60–3.69

(br s, 120H, OCH3 of PMA side chain), 3.69–3.72 (m, 2H,

COOCH2CH2O of end group), 4.20–4.27 (m, 2H, COOCH2CH2O

of end group), 6.30–7.00 (br s, 100H, CHNHC of DIPEA side

chain), 7.10–7.30 (m,5H,ArHof endgroup). 13CNMR(125MHz,

CDCl3): d 174.9, 128.4, 127.0, 126.9, 126.2, 71.9, 70.6, 69.1, 69.0,

63.8, 59.0, 51.7, 48.7, 48.7, 45.3, 44.3, 42.7, 42.7, 41.3, 40.0, 35.1,

35.0, 34.9, 32.1, 31.9, 29.6, 29.3, 23.1, 21.3, 20.8, 14.1. FTIR nmax/

cm�1: 3294 (N–H amide stretch), 2964 (alkane C–H stretch), 1737

(C]Oester stretch), 1648 (C]Oamide stretch), 1536 (N–Hamide

bend), 1361 and 1185 (C–N stretch).

3010 | Polym. Chem., 2012, 3, 3007–3015


kDa, Mw/Mn ¼ 1.14. 1H NMR (400 MHz, MeOD): d 0.90–1.10

(br s, 500H, N(CH(CH3)2)2 of DIPEA side chain) 1.20–2.40 (br

m, 210H, CHCH2 of polymer backbone), 2.40–2.52 (br s, 100H,

NHCH2CH2N of DIPEA side chain), 2.68 (m, 2H,

SCH2CH2COO of end group), 2.78 (br m, 2H, SCH2CH2COO of

end group), 2.90–3.20 (br m, 200H, NHCH2CH2N and

N(CH(CH3)2)2 of DIPEA side chain), 3.50–3.62 (br s, 63H,

OCH3 of PMA side chain), 4.55 (br, 2H, COOCH2CH2N of end

group), 7.10–7.30 (m, 5H, ArH of end group). 13C NMR (125

MHz, MeOD): d 176.9, 176.6, 129.6, 128.2, 127.4, 52.5, 50.8,

46.0, 43.7, 42.8, 42.2, 35.9, 21.2. FTIR nmax/cm�1: 3304 (N–H

amide stretch), 2966 (alkane C–H stretch), 1737 C]O (ester

stretch), 1646 (C]O amide stretch), 1533 (N–H amide bend),

1383 and 1185 (C–N stretch).


kDa, Mw/Mn ¼ 1.11. 1H NMR (400 MHz, CDCl3): d 0.90–1.10

(br s, 500H, N(CH(CH3)2)2 of DIPEA side chain) 1.20–2.40 (br

m, 210H, CHCH2 of polymer backbone), 2.40–2.50 (br s, 100H,

NHCH2CH2N of DIPEA side chain), 2.75 (m, 4H,

SCH2CH2COO of end group), 2.90–3.20 (br m, 200H,

NHCH2CH2N and N(CH(CH3)2)2 of DIPEA side chain), 3.39

(br s, 3H, OCH3 of end group), 3.47–3.56 (m, 8H, (OCH2CH2O)2of end group), 3.60–3.69 (br s, 63H, OCH3 of PMA side chain),

3.69–3.72 (m, 2H, COOCH2CH2O of end group), 4.20–4.27 (m,

2H, COOCH2CH2O of end group), 7.10–7.30 (m, 5H, ArH of

end group). 13C NMR (125 MHz, CDCl3): d 174.9, 128.4, 127.0,

126.9, 126.2, 71.9, 70.6, 69.1, 69.0, 63.8, 59.0, 51.7, 48.7, 48.7,

45.3, 44.3, 42.7, 42.7, 41.3, 40.0, 35.1, 34.9, 32.1, 31.9, 29.6, 29.3,

23.1, 21.3, 20.8, 14.1. FTIR nmax/cm�1: 3295 (N–H amide

stretch), 2965 (alkane C–H stretch), 1737 (C]O ester stretch),

1647 (C]O amide stretch), 1535 (N–H amide bend), 1361 and

1185 (C–N stretch).

Self assembly techniques

Solvent switch. A general procedure for solvent switch is given.

The polymer was dissolved in DMF to a concentration double of

that required and stirred overnight. 18.2 MU cm�1 water was

added at 0.6 mL min�1, after which the opaque solution was

dialyzed against 18.2 MU cm�1 water, incorporating at least 6

water changes. The final concentration of the self-assembled

solution was calculated by measuring the final volume.

Direct dissolution. The polymer was dissolved in acidic water

(below pH 2.5) and was stirred overnight.

Size-switching studies. The polymer was dissolved at a

concentration of 0.25 mg mL�1 in acidic water (<pH 2.5). To

achieve the transition from micelle to vesicle, the pH was slowly

increased until a slight blue tint was seen and then stirred to allow

the particles to stabilize. The pH of the solution was dropped in

order to achieve the morphology change from vesicle to micelle.

The reversibility of the response was tested by repeating the pH

switch cycle.

Release studies. The polymer was dissolved in DMF at 2 mg

mL�1 after which Rhodamine B was added to a concentration of



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0.2 mg mL�1 and the solution was stirred overnight. 18.2 MU

cm�1 water was added at a speed of 0.6 mLmin�1. After addition

the solution was dialyzed against 200 mL of 18.2 MU cm�1

water. After leaving for at least 6 hours to allow the system to

equilibrate, the dialyzate was tested for fluorescence at an exci-

tation wavelength of 540 nm and the emission at 575 nm recor-

ded. After two water changes, where the system showed no

fluorescence, the solution was removed from the dialysis bag, the

pH reduced to approximately 2.5 and then dialyzed against

acidic water. Again, the system was left to reach equilibrium each

time the water was changed and the fluorescence recorded.

Fig. 1 SEC traces showing the chain extension of 2 with PFPA to form

block copolymer, 3.

Results and discussions

Block copolymer synthesis

Our goal was to create a diblock copolymer consisting of a

hydrophobic block, a responsive block which would change its

hydrophilicity in response to a change in pH, and a hydrophilic

head group that would direct self-assembly. There are many

other pH-responsive polymers that have been widely investigated

within the literature, mainly based on 2-(diethylamino)ethyl

methacrylate69–71 and 2-(dimethylamino)ethyl methacrylate,71

and the self-assembly and responsive behaviour of polymers of

these monomers have been studied. The polymer, poly(2-(N,N-

diisopropylamino) ethyl acrylate), investigated within this report

was chosen since it has been largely unexplored within the liter-

ature and it has been reported to be more stable than the ethyl-

and methylamine versions.72 Another reason this particular

monomer was chosen is due to a reportedly lower pKa for the

methacrylate version than that for the ethylamine or methyl-

amine equivalent.71 The higher pKas of the methyl- and

ethylamine equivalents render them hydrophilic at neutral pH,

whereas 2-(N,N-diisopropylamino)ethyl methacrylate

homopolymer was found to have a lower pKa, (ca. 6.0) meaning

it is hydrophobic at neutral pH and for our self-assembly

objectives this is desirable. To the best of our knowledge there are

no accounts of the desired monomer, 2-(N,N-diisopropylamino)

ethyl acrylate, being polymerized in the literature. The methac-

rylate version, 2-(N,N-diisopropylamino)ethyl methacrylate, has

been polymerized by ATRP72–74 and RAFT previously, although

in the case of RAFT polymerization the formation of diblock

copolymers led to a loss of control, shown by broad poly-

dispersities (Mw/Mn > 1.4).75–77 These polymers have potential in

drug delivery due to their pH responsivity.74 Attempts within our

group to directly polymerize 2-(N,N-diisopropylamino)ethyl

acrylate have been unsuccessful (see ESI Tables S1 and S2†).

Therefore in order to obtain a diblock copolymer containing this

functionality, a different route was followed. A scaffold polymer

comprising of poly(methyl acrylate) and poly(pentafluorophenyl

acrylate) was instead synthesized. The activated ester penta-

fluorophenyl acrylate was chosen as the resulting polymer could

then be easily substituted with amines61,62 such as N,N-diiso-

propylethylene diamine, resulting in the desired polymer

functionality.

The chain transfer agent (CTA) employed has been reported

previously.68 CTA 1 (see Scheme 1) was used to polymerize

methyl acrylate to form a block, 2,Mn (1H NMR)¼ 3.8 kDa,Mn

(CHCl3 SEC)¼ 2.5 kDa andMw/Mn¼ 1.06. This was then chain


extended with pentafluorophenyl acrylate to form the diblock

copolymer, 3, as a yellow solid, with an activated ester block

length of 100, Mn (1H NMR) ¼ 27.5 kDa, Mn (CHCl3 SEC) ¼7.7 kDa and Mw/Mn ¼ 1.29. The disparity between the Mn

calculated from NMR and the Mn given by SEC is due to the

solvophobicity of the polymer causing interactions with the SEC

column and the structural difference between the PMMA stan-

dards and the diblock 3. The efficient chain extension can be seen

by SEC analysis as shown in Fig. 1. A small amount of tailing is

observed for the reactive diblock copolymers. However, once the

PFPA block has been substituted, the polydispersity decreases

and tailing is not as pronounced (see ESI Fig. S4 and S7†).

Substitution of the PFPA groups and end group modification

In order to easily form two polymers (4 and 5) which bear the

same polymer backbone but different end groups, previously

established chemistries were used to substitute the penta-

fluorophenyl acrylate block61 and modify the end group54 at the

same time in a one-pot, two step method. Firstly, the PFPA

block was substituted with N,N-diisopropylethylenediamine and

the conversion of all the ester groups was confirmed by 19F NMR

spectroscopy. The disappearance of the broad polymer signals

at �153.8, �157.3 and �162.8 ppm and appearance of sharp

pentafluorophenol signals at �162.9 and �165.7 ppm was

observed, indicating the complete conversion of the activated

ester groups (see ESI Fig. S2†). The complete conversion was

also confirmed by analysis of the FT-IR spectra of the polymers.

The PFPA C]O ester stretch at 1783 cm�1 disappeared and was

replaced by a C]O stretch at 1646 cm�1, relating to the amide

group formed, with the MA ester stretch at 1737 cm�1 remaining

unchanged (see ESI Fig. S3†).

Subsequent addition of PBu3, hexylamine and the charged

acrylate monomer afforded the end group modification of the

polymer via thiol–ene chemistries. The trithiocarbonate group of

the RAFT end group was observed to have been removed by the

absence of a UV signal in the SEC analysis. The polymers were

purified by dialysis first against acidic then basic water and after

lyophilization the now white polymers 4 and 5were collected and

the full substitution of the PFPA block with the amine was again

confirmed by the appearance of new signals at 3.20, 3.60 and 3.80

ppm in the NMR relating to the NHCH2CH2 and the

Polym. Chem., 2012, 3, 3007–3015 | 3011


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NHCH2CH2 and NCH(CH3)2 respectively. These peaks inte-

grate as expected when set against known signals, such as the

methyl acrylate side chain signals, which would not have been

affected by the substitution or end group modification processes.

The incorporation of the end group was observed by 1H NMR

spectroscopy. In the case of polymer 4, which bears the charged

tertiary amine end group, the appearance of new signals at 4.50

and 2.80 ppm for the CH2 next to the sulfur and the CH2 next to

the charged tertiary amine confirmed the successful end group

modification. In the case of polymer 5, which bears a triethylene

glycol end group, the CH3 signal of the TEGA end group is

clearly observable at 3.7 ppm as is the signal at 4.50 ppm which

relates to the CH2 next to the carbonyl group. The dispersity of

both the polymers were not negatively affected by the substitu-

tion as confirmed by SEC, 4: Mn (DMF SEC) ¼ 23.1 kDa and

Mw/Mn ¼ 1.19; 5: Mn (DMF SEC) ¼ 21.5 kDa and Mw/Mn ¼1.21).

Self-assembly properties

To investigate the self-assembly properties of these diblock

copolymers a solvent switch strategy was employed.78,79 The

polymers were dissolved in DMF at a concentration double to

that desired and then water was added slowly to achieve the

desired concentration, followed by exhaustive dialysis against

18.2 MU cm�1 water. For the charged polymer 4, a slightly

turbid solution with a pH of 7.4 and concentration of 0.16 mg

mL�1 was obtained after exhaustive dialysis. DLS measurements

showed the presence of large structures, Dh (by number) ¼ 340

nm with a dispersity, Ð, of 0.204. TEM analysis by drop depo-

sition onto a formvar grid, followed by staining with uranyl

acetate confirmed the presence of these large structures with an

average size of 353 nm (determined by counting at least 50

particles, see Fig. 2). No shrinkage of the particles relative to

Fig. 2 (Top) Schematic of morphology change of 4 with pH. (Bottom left)

uranyl acetate; (middle) DLS plot showing change in size with change in pH;

with uranyl acetate. Scale bars ¼ 200 nm.

3012 | Polym. Chem., 2012, 3, 3007–3015

their hydrodynamic diameters was observed in this case. This

perhaps is a coincidence or could be a result of the charged end

groups repelling each other, suggesting that the structure simply

collapses as it dries on the TEM substrate. We propose that these

nanostructures are vesicular in nature given the size of these

particles and also the predicted packing parameter based on the

amphiphile structure. To investigate the pH responsivity of

polymer 4 a small amount of the solution was taken and the pH

adjusted to 1.75 with dilute HCl, ca. 0.2 mL. Immediately the

turbidity disappeared and after stirring overnight smaller parti-

cles were observed by DLS analysis. These particles had a size (by

number) of 35.9 nm and a rather high Ð of 0.414. This large

dispersity is due to the presence of a larger population in the

intensity data, likely to be caused by the aggregation of the

micelles. This solution was further analyzed by TEMwith uranyl

acetate staining and spherical micelles with an average size of

31 nm were observed. These micelles seemed to be aggregated in

parts on the TEM grid, which supports our observation of

aggregation in the DLS results, see Fig. 2.

Polymer 5 was also self-assembled in a similar manner to

polymer 4 to give a slightly turbid solution at a concentration of

0.12 mg mL�1 at a pH of 7.8. Analysis by DLS showed large

structures with a size (by number) of 191 nm and a Ð of 0.074.

The presence of large structures was confirmed by TEM analysis,

with an average particle size of 126 nm. This is smaller than seen

in the DLS and we attribute this to either a staining artefact or

the drying and collapse of the vesicle on the TEM support. Once

again we propose that these nanostructures are vesicular in

nature. The pH of this solution was reduced to 3.7 with dilute

HCl (ca. 0.2 mL), which resulted in smaller structures with a Dh

by number of 45 nm observed in the DLS and analysis by TEM

confirming the presence of micelles with an average size of 34 nm,

see Fig. 3. The solutions had to be left stirring at least overnight

in order for the smaller structures to equilibrate. If left for less

Representative TEM image of 4 self-assembled at pH 1.75, stained with

(right) representative TEM image of 4 self-assembled at pH 7.4, stained



Fig. 3 (Left) Representative TEM of 5 self-assembled at acidic pH, stained with phosphotungstic acid; (middle) DLS graph showing the change in size

of 5 with pH; (right) representative TEM of 5 self-assembled at basic pH, stained with uranyl acetate. Scale bars ¼ 200 nm.

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time then multiple sizes were seen during DLS analysis. Since

such a small volume of acid was added to lower the pH and

induce the morphology change, no significant change in polymer

concentration occurred.

Since these self-assembled structures were observed to require

relatively long times to stabilize after a morphology transition

had occurred, we hypothesized that a smaller block length may

afford a faster morphology transition. Therefore a new PPFPA–

PMA scaffold, 7, was constructed. This new scaffold was

substituted with N,N-diisopropylethylenediamine and the end

groupmodified in the same manner as before, to form polymers 8

(Mn (DMF SEC) ¼ 14.2 kDa, and Mw/Mn ¼ 1.14) and 9 (Mn

(DMF SEC) ¼ 14.9 kDa and Mw/Mn ¼ 1.12). The successful

incorporation of the different end groups into the polymers 8 and

9 was once again confirmed by 1H NMR spectroscopy. The self-

assembly of these new polymers was investigated. Due to the

shorter hydrophobic block lengths in polymers 8 and 9, direct

dissolution was utilized rather than solvent switch. Polymer 8

was dissolved in acidic water at a pH of 2.25. After stirring, the

solution was analyzed by DLS and the presence of small struc-

tures with a Dh of 37 nm, Ð ¼ 0.39 was observed. Then dilute

NaOH was used to carefully raise the pH of the solution to 8.5,

above the pKa of the polymer, resulting in a turbid solution that

showed large structures in the DLS, with a Dh ¼ 97 nm and

Ð ¼ 0.101. This pH switching cycle was repeated three times,

Fig. 4 Graph showing the increase and decrease in size with change in

pH. The size change is repeatable and reversible.


with fully reversible and reproducible results, see Fig. 4. The

transition in both directions took only a short amount of time to

stabilize, typically 10 to 15 minutes, showing that the smaller

block lengths allow the morphology transition to happen more

quickly. Similar results were seen for polymer 9, see ESI

Fig. S13.†

Encapsulation and release of hydrophilic dye

Since the polymers form vesicles in neutral or basic environ-

ments, encapsulation of a hydrophilic species and release upon

acidifying the solution should be possible. In order to clearly see

any release, a hydrophilic fluorescent dye, Rhodamine B, was

chosen to be encapsulated in the polymer nanostructures. Poly-

mer 8 was self-assembled using solvent switch methods at a

concentration of 1.0 mg mL�1 in the presence of the Rhodamine

B at a concentration of 0.2 mg mL�1. The solution was then

dialyzed against a known volume of water and following equil-

ibration the water was changed and a sample taken for fluores-

cence analysis. This was repeated until no more Rhodamine B

was detected in the surrounding dialysis water. At this point the

pH of the solution inside the dialysis bag was measured as 7.5

and had a significant fluorescence response, showing that there

was Rhodamine B present, trapped within the interior water pool

of the vesicles. The pH of the polymer solution was then dropped

to pH 2.5 and stirred overnight, at which point the solution was

dialyzed against acidic water. Again the water was changed after

equilibration time and the dialyzate tested. There was a response

in the dialysis water immediately after the pH change, showing

that Rhodamine was released upon morphology change. This

demonstrated that the vesicles were able to encapsulate the

hydrophilic dye and release it in response to pH, see Fig. 5.

Conclusions

Polymer scaffolds bearing activated ester pentafluorophenyl

acrylate (PFPA) groups were successfully synthesized by RAFT

methods. The PFPA groups were easily substituted with N,N-

diisopropylethylene diamine and the RAFT end group modified

with either a charged tertiary amine acrylate or triethylene glycol

methyl ether acrylate, to give pH-responsive block copolymers

with the same backbone but different end groups. These poly-

mers were all found to self-assemble in aqueous solution at basic

Polym. Chem., 2012, 3, 3007–3015 | 3013


Fig. 5 Fluorescence graph of the dialyzate showing the release of

Rhodamine B upon lowering of pH. Solid line ¼ pH 7.5, dashed line ¼pH 2.5.

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pH to form vesicles and all exhibited a morphology transition to

a micelle upon lowering the pH. The larger block copolymers

took longer to stabilize after a morphology switch than the

smaller block copolymers. In addition the encapsulation and

controlled release of a hydrophilic dye, Rhodamine B, was

demonstrated.

Acknowledgements

The authors wish to thank the University of Warwick and

EPSRC for funding. The SEC equipment used in this research

was obtained through Birmingham Science City: Innovative

Uses for Advanced Materials in the Modern World with support

from Advantage West Midlands (AWM) and part funded by the

European Regional Development Fund (ERDF). Also thanks to

Mr Ian Portman-Hands (University of Warwick) for help with

TEM characterization.

Notes and references

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