A new design of cleavable acetal-containing amphiphilic block copolymers triggered by light

Article abstract of DOI:10.1002/pola.29062

We report a new design of photolabile acetal-containing amphiphilic block copolymers. Acetals as protecting groups for carbonyls or diols can be hydrolyzed under acidic condition but very stable with respect to hydrolysis at pH > 7. When combining light-capturing chromophores with acetals, the hydrolysis of acetals can be activated by light to design dual responsive acetal-containing polymers. Using acetalization reaction of 2,3-dihydroxypropyl methacrylate with benzaldehyde derivatives, two new acetal-containing photolyzable monomers have been designed. Comparable to commonly used photolabile monomers containing nitrobenzyl esters, the two acetal-containing monomers are easy to polymerize using atom transfer radical polymerization with excellent molecular weight and dispersity control. We studied the cleavage kinetics and mechanism of acetal groups in both monomers and polyethylene oxide (PEO)-containing amphiphilic block copolymers using ¹H NMR and UV–vis spectroscopy. o-Nitrobenzaldehyde acetal showed a Norrish Type II rearrangement to form benzoic ester; while, 2,5-dimethoxy benzaldehyde acetal was photolabile to completely release 2,3-dihydroxypropyl methacrylate. The photocleavage of acetals is a zero-order reaction in regardless of molecular states of acetals; while, the acid-cleavage of acetals proves to be a first-order kinetics and the cleavage becomes much slower for polymers. The self-assembly of acetal-containing amphiphilic block copolymers and the acid-/light-controlled dissociation of their vesicles have been investigated. We demonstrate that those acetal-containing polymers are potentially useful as smart drug delivery systems where the release kinetics of payloads is tunable using light and pH as triggers.

Full text of DOI:10.1002/pola.29062

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ARTICLE
ARTICLE
POLYMER SCIENCE
A New Design of Cleavable Acetal-Containing Amphiphilic Block
Copolymers Triggered by Light
1
,2
1
3
1,4
Yu Huang, Srinivas Thanneeru, Qian Zhang, Jie He
1
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269
2
College of Pharmacy, Ningxia Medical University, 750004, Yinchuan, Ningxia, People’s Republic of China
Department of Applied Chemistry, School of Sciences, Xi’an University of Technology, 710048, Xi’an, Shaanxi, People’s
3
Republic of China
4
Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, Connecticut 06269
Correspondence to: J. He (E-mail: jie.he@uconn.edu)
Received 8 March 2018; accepted 9 May 2018; published online in Wiley Online Library
DOI: 10.1002/pola.29062
ABSTRACT: We report
a
new design of photolabile acetal-
Norrish Type II rearrangement to form benzoic ester; while, 2,5-
dimethoxy benzaldehyde acetal was photolabile to completely
release 2,3-dihydroxypropyl methacrylate. The photocleavage of
acetals is a zero-order reaction in regardless of molecular states
of acetals; while, the acid-cleavage of acetals proves to be a first-
order kinetics and the cleavage becomes much slower for poly-
mers. The self-assembly of acetal-containing amphiphilic block
copolymers and the acid-/light-controlled dissociation of their
vesicles have been investigated. We demonstrate that those
acetal-containing polymers are potentially useful as smart drug
delivery systems where the release kinetics of payloads is tun-
containing amphiphilic block copolymers. Acetals as protecting
groups for carbonyls or diols can be hydrolyzed under acidic
condition but very stable with respect to hydrolysis at pH > 7.
When combining light-capturing chromophores with acetals, the
hydrolysis of acetals can be activated by light to design dual
responsive acetal-containing polymers. Using acetalization reac-
tion of 2,3-dihydroxypropyl methacrylate with benzaldehyde
derivatives, two new acetal-containing photolyzable monomers
have been designed. Comparable to commonly used photolabile
monomers containing nitrobenzyl esters, the two acetal-
containing monomers are easy to polymerize using atom trans-
fer radical polymerization with excellent molecular weight and
dispersity control. We studied the cleavage kinetics and mecha-
able using light and pH as triggers. V
2018 Wiley Periodicals, Inc.
C
J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1815–1824
nism of acetal groups in both monomers and polyethylene oxide
1
KEYWORDS: acetal; nitrobenzyl esters; photolysis; photorespon-
(
PEO)-containing amphiphilic block copolymers using H NMR
sive polymers; responsive micelles
and UV–vis spectroscopy. o-Nitrobenzaldehyde acetal showed a
INTRODUCTION There is a tremendous interest in designing
type II intramolecular rearrangement to yield o-nitrosobenzalde-
17,19
new photoresponsive polymers whose physical or chemical prop-
hyde and a carboxylic acid.
Therefore, when incorporating o-
1–5
erties can be changed upon light exposure. Since light is a non-
invasive stimulus and it shows excellent spatiotemporal control,
photoresponsive polymers have received considerable attention
nitrobenzyl esters as side moieties, photocleavage of the o-nitro-
benzyl esters can result in the change in the hydrophobicity of
polymers because of the removal of hydrophobic o-nitrosobenzal-
2,6,7
17
for biomedical applications such as drug delivery.
The design
dehyde and the remaining hydrophilic carboxylic acid. Zhao
of photoresponsive polymers relies on chromophores to capture
and coworkers reported a few examples to design photorespon-
sive polymer micelles using amphiphilic diblock copolymers (di-
8–16
light and undergo photochemical reactions.
Those chromo-
13,14
phores can respond to light by means of either reversible isomer-
BCPs) containing photolabile protecting groups.
The main
8–12
ization (e.g., azobenzene, spiropyran, and cinnamic ester)
or
strategy is to design photoresponsive (meth)acrylate monomers
using esterification of (meth)acrylic acid and o-nitrobenzyl (or
other benzyl-based) alcohols. However, there are profound chal-
lenges to polymerize o-nitrobenzyl (or other benzyl-based) con-
taining (meth)acrylate monomers using controlled radical
polymerization. For example, Gohy and coworkers showed that o-
irreversible photolysis (e.g., o-nitrobenzyl and other benzyl-based
13–18
esters).
Among various photoresponsive chromophores,
o-nitrobenzyl ester as a photolabile protecting group is the most
commonly used in responsive polymers. The photolysis of o-
nitrobenzyl carboxylic ester usually goes through a Norrish
Additional Supporting Information may be found in the online version of this article.
2018 Wiley Periodicals, Inc.
V
C
J OJ OU UR RN NA AL LO OF FP PO OL LY YMM E ER RS SC CI EI ENN C CE E, ,P PAA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY 22 00 11 88 ,, 55 66 ,, 11 81 55 –– 11 88 22 44
1 18 81 15 5

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
AA RR TT II CC LL EE
WW WW WW . .PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
nitrobenzyl acrylate cannot polymerize using controlled radical
polymerization and o-nitrobenzyl methacrylate shows somewhat
controlled polymerization using atom transfer radical polymeri-
20,21
zation (ATRP) at a low conversion (below 30%).
The lack of
control in polymerization was due to the radical inhibition effect
from nitrobenzyl moieties, although there are recent reports on
the controlled polymerization of o-nitrobenzyl methacrylates
using photoinduced electron/energy transfer reversible addi-
22
tion–fragmentation chain transfer and single electron transfer-
21
living radical polymerization.
We herein present a new design of light and pH dual
responsive polymers containing photolabile acetals. Acetals
are commonly used protecting groups for carbonyls or
diols. They can be hydrolyzed under acidic condition
SCHEME 1 Illustration of light or pH triggered cleavage of
acetal-containing amphiphilic di-BCPs. [Color figure can be
viewed at wileyonlinelibrary.com]
(
pH < 7) but they are very stable with respect to hydrolysis
under reduced pressure. The product was used for further
synthesis of acetal monomers without further purification.
2
3–27
at pH > 7.
There are examples showing acetals of sali-
cylaldehyde and coumarin derivatives to be excellent photo-
labile protection groups, comparable to benzyl-based
0
.8 g of 2, 3-dihydroxypropyl methacrylate (5 mmol) and
0.76 g of o-nitrobenzaldehyde (5 mmol) were dissolved in
0 mL of cyclohexane containing 0.03 g of p-toluenesulfonic
2
8,29
esters.
Therefore, those acetals are ideal chromophores
4
to combine dual responsiveness, that is, light and pH, to a
homopolymer. In the current contribution, we synthesized
two photoresponsive acetal-containing methacrylate mono-
mers using acetalization reaction of 2,3-dihydroxypropyl
methacrylate with o-nitrobenzaldehyde and 2,5-dimethoxy
benzaldehyde. Scheme 1 illustrates the design of di-BCPs
and their cleavage to drive the dissociation of micellar
aggregates. Although the two acetal monomers have bulky
side groups, both of them are easy to polymerize using a
conventional ATRP catalytic system CuBr/PMDETA
acid as catalyst. The reaction mixture was refluxed overnight
in a round-bottom flask equipped with a Dean Stark trap to
remove water from the mixture. After the reaction mixture
was cooled to room temperature, the solvent was removed
using a rotary evaporator. The crude oil product was dissolved
in 100 mL ethyl acetate and successively washed with satu-
rated NaHCO3 solution (3 3 50 mL), water (50 mL), and
brine (50 mL). The organic layer was collected and dried by
anhydrous sodium sulfate. After removal of ethyl acetate, the
crude product was purified by column chromatography (ethyl
0 00 00
(
N,N,N ,N ,N -pentamethyldiethylenetriamine) and a poly(-
acetate:hexane 5 1:3) to obtain NBDPMA as an oil liquid
ethylene oxide) (PEO) macroinitiator. All amphiphilic di-
BCPs show a controllable acetal-containing block length
and a low dispersity index of <1.2. The photocleavage of
acetal proves to be a zero-order reaction in regardless of
the molecular or aggregation states of acetals. The potential
application of acetal-containing polymers has been demon-
strated in photo- and pH-dual triggered release where the
release profile of payloads is highly controllable through
triggers.
1
(note, it is a mixture of diastereomers, 0.51 g, yield 55%). H
NMR (CDCl , see Supporting Information Fig. S1): 1.91–1.98
3
(m, CH C, 3H), 3.88–3.96, 4.00–4.16 (m, OCH , 2H), 4.24–4.26,
3
2
4
5
6
.31–4.33 (m, COOCH
.67, 5.62–5.63 (t, CH @C, 1H), 6.07, 6.17 (s, CH @C, 1H),
.47, 6.63 (s, ArCH, 1H), 7.48–7.53 (m, Ar-H, 1H), 7.6–7.65
2
, 2H), 4.43–4.55 (m, OCH, 1H), 5.56–
2
2
(m, Ar-H, 1H), 7.78–7.93 (m, Ar-H, 2H).
Synthesis of 2,5-Dimethoxybenzylidenedioxypropyl
Methacrylate (DMBPMA)
5
2
2
.8 g of 2,3-dihydroxypropylmethacylate (36 mmol) and 5 g of
,5-dimethoxy benzaldehyde (30 mmol) were dissolved in
00 mL cyclohexane containing 0.3 g of p-toluenesulfonic acid.
EXPERIMENTAL
Synthesis of Acetal-Containing Monomers and Di-BCPs
Synthesis of 2,3-(2-Nitrobenzylidenedioxy)Propyl
Methacrylate (NBDPMA)
The reaction mixture was refluxed in a round-bottom flask
equipped with a Dean Stark trap. After the reaction mixture was
cooled to room temperature, the solvent was removed using a
rotary evaporator. The crude oil product was solved in 300 mL
ethyl acetate and successively washed with saturated NaHCO3
solution (3 3 100 mL), water (100 mL), and brine (100 mL). The
organic layer was then collected and dried by anhydrous sodium
sulfate. After removal of ethyl acetate, the crude product was
purified by column chromatography (ethyl acetate:hexane 5 1:4)
to obtain the DMBPMA as a colorless oil (note, it is a mixture of
2,3-Dihydroxypropyl methacrylate was synthesized through
hydrolysis of glycidyl methacrylate (GMA, 97%, Sigma) in the
presence of dilute sulfuric acid. Briefly, 14.49 g of GMA was
dissolved in 25 mL of tetrahydrofuran (THF). After the THF
solution was cooled down by ice/water bath, 125 mL of
H SO (2 M) was added dropwise over 30 min. The mixture
2
4
was then stirred at room temperature for 2 h. After the
removal of THF, the mixture was extracted with dichlorome-
thane (5 3 100 mL). The organic layer was combined and
dried by anhydrous sodium sulfate. 2, 3-Dihydroxypropyl
methacrylate was obtained after removing dichloromethane
1
diastereomers, 6.1 g, 66%). H NMR (CDCl ): 1.94–1.98 (m, CH ,
3H), 3.77, 3.78 (s, MeO, 3H), 3.81, 3.82 (s, MeO, 3H), 3.77–3.89,
4.00–4.16 (m, OCH , 2H), 4.27–4.37 (m, COOCH , 2H), 4.46–4.60
3
3
2
2
1
81 18 61 6
JJ OO UU RR NN AA LL OO FF PP OO LL YY MM EE RR SS CC II EE NN C EE ,, PP AA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM I ISS TT RR YY 2 20 01 18 8, ,5 56 6, ,1 18 81 15 5– –1 18 82 24 4

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
WW WW WW .. PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
AA RR TT II CC LL EE
(
1
7
m, OCH, 1H), 5.58–5.62 (m, CH @C, 1H), 6.14–6.18 (m, CH @C,
directly. The solution was incubated at 60 8C for 2 h before
NMR measurement. To measure the kinetics of photocleav-
age, 8.5 mL of the vesicular aqueous solution was used for
irradiation. 0.5 mL of the solution was sampled at different
irradiation times. For each NMR measurements, 50 lL of
2
2
H), 6.16, 6.28 (s, ArCH, 1H), 6.83–6.90 (m, Ar-H, 2H), 7.09–7.10,
13
.16–7.17 (d, Ar-H, 1H). C NMR (CDCl , see Supporting Infor-
3
mation Fig. S2): 18.43 (CH ), 55.90, 56.46 (MeO), 64.56, 64.72
3
(OOCH ), 67.47, 67.52 (OCH ), 73.92, 74.12 (OCH), 99.58, 99.78
2 2
(ArCH), 112.30, 112.38, 112.50, 112.55, 115.61, 115.87 (Ar),
D O was added for deuterium lock. For all experiments, we
2
1
26.33 (CH @), 129.14 (Ar), 136 (C@), 152.08, 153.83 (Ar),
measured the light scattering intensity of each samples as
well on an ALV/CGS-3 MD dynamic light scattering (DLS)
system.
2
167.23 (C@O).
Synthesis of Acetal-Containing Amphiphilic Di-BCPs
Using DMBPMA to prepare PEO114-b-PDMBPMA67 as an
example, CuBr (29 mg, 0.2 mmol) and DMBPMA (308 mg, 1
mmol) were dissolved in 3 mL of anisole. The mixture was
degassed and recharged with nitrogen, followed by adding
PMDETA (69 mg, 0.4 mmol) into the mixture. After stirred
UV–Vis Measurement on Cleavage Kinetics
For photocleavage experiments, very diluted monomer or
polymer solution was prepared in 2.5 mL of methanol and
water mixture (80:20, vol). The UV–vis spectra of the solu-
tion were recorded with different irradiation times at room
temperature. In acid-triggered cleavage experiments, the
same solution was used but the pH of the solution was
tuned by adding HCl solution (1 mM). All UV–vis spectra
were collected on a Cary 60 UV–vis spectrophotometer
equipped with a temperature controller. The absorbance at
and bubbled with N for 10 min, the macroinitiator PEO114-
2
1
1
Br (500 mg, 0.1 mmol, 5 kg/mol) in 1 mL of anisole was
added into the above solution. The mixture was further bub-
bled with nitrogen at room temperature for another 15 min.
The solution was placed in an oil bath preheated at 65 8C.
The polymerization was stopped after 7 h by diluting with
excess THF. The mixture was then passed through a neutral
Al O column to remove the catalyst. The solution was con-
295 nm was used to fit the reaction kinetics.
Encapsulation and Photo-/Acid-Controlled Release
We used Rhodamine B (RB) or ibuprofen sodium as model
compounds for photo-/acid-controlled release studies. To
2
3
centrated under reduced pressure and the polymer was pre-
cipitated in hexane three times. The yielded polymer has a
load RB and ibuprofen sodium,
PDMBPMA67 polymer was first dissolved in 1.5 mL DMF.
.5 mL of DMF/water (40:60, vol) solution containing 50 mg
5 mg of PEO114-b-
number average molecular weight (M ) of 16.5 kg/mol and a
n
dispersity index of 1.09 measured by gel permeation chro-
matography (GPC) calibrated by polystyrene. The average
number of repeat units of the PDMBPMA block was esti-
1
of RB or ibuprofen sodium was added into the polymer solu-
tion at an addition rate of 75 mL/min using a syringe pump.
After stirred for another 2 h, the solution was transferred
into a dialysis bag and dialyzed against water for 72 h.
Water was changed every 6–8 h. The obtained vesicular
solution was stored in dark at 5 8C. The concentration of
encapsulated RB or ibuprofen sodium was calculated using
their standard curves.
1
mated from H NMR measurement using PEO as an internal
standard. The chain length of the hydrophobic PDMBPMA
block can be varied by the ratio of PEO114-Br and DMBPMA
monomer. Two more di-BCPs were further prepared as
PEO114-b-PDMBPMA34 and PEO114-b-PDMBPMA146
.
Preparation of Polymer Vesicles
1
0 mg of PEO114-b-PDMBPMA67 was first dissolved in 1.5 mL
RB-loaded polymer vesicles were used to study acid-
controlled release. 100 lL of RB-loaded polymer vesicles
was added into a dialysis bag immersed into 1.5 mL of ace-
tate buffer (pH 3.6) in a micro quartz cuvette. The fluores-
cence spectra of RB were recorded every 30 min on a Cary
Eclipse Fluorescence Spectrophotometer. As a control experi-
ment, the RB release experiments were carried out in
of dimethylformamide (DMF) and stirred for 2 h at room tem-
perature. 1.5 mL of DMF/water (40:60, vol) solution was
added into the above polymer solution at an addition rate of
7
2
5 mL/min through a syringe pump. After stirred for another
h, the polymer solution was transferred to a dialysis bag
(
molecular weight cut-off of 6000–8000 g/mol) and dialyzed
against water to remove residual DMF. The final vesicle
solution was diluted to 2 mg/mL and stored in a refrigerator.
1.5 mL phosphate buffer (pH 7.4). The concentration of RB
was determined using the standard curve of RB under the
same conditions. Similarly, ibuprofen sodium loaded polymer
vesicles were used in photo-controlled release experiments
and the release amount of ibuprofen sodium was determined
by liquid chromatography–mass spectrometry (LC/MS,
Applied Biosystems 4000 Q Trap LC/MS system).
1
Proton Nuclear Magnetic Resonance ( H NMR)
Measurements on Cleavage Mechanism
All H NMR experiments were carried out on a Bruker
Avance 300 MHz spectrometer. Monomers or polymers were
1
first dissolved in CDCl3 or d -DMSO at a concentration of
6
4
mg/mL. The photocleavage of acetals was triggered by UV
RESULTS AND DISCUSSION
light (OmniCure Series 1500 UV lamp, 100 W high pressure
mercury vapor lamp). For acid cleavage experiments, mono-
mers, or polymers were dissolved in 0.8 mL of d -DMSO at a
6
concentration of 4 mg/mL. 80 lL of HCl solution (1 mM)
was added into the above solution. The pH values presented
in our studies were calculated from the proton concentration
Synthesis of Acetal-Containing Monomers and Di-BCPs
Acetal-containing monomers were synthesized using acetali-
zation reaction of 2,3-dihydroxypropyl methacrylate with
o-nitrobenzaldehyde and 2,5-dimethoxy benzaldehyde (Scheme
2), for NBDPMA and DMBPMA, respectively. The acetalization
J OJ OU UR RN NA AL LO OF FP PO OL LY YMM E ER RS SC CI EI ENN C CE E, ,P PAA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY 22 00 11 88 ,, 55 66 ,, 11 81 55 –– 11 88 22 44
1 18 81 17 7

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
AA RR TT II CC LL EE
WW WW WW . .PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
SCHEME 2 (a) Synthetic routes of the two acetal-containing monomers, DMBPMA and NBDPMA. (b) Synthesis of di-BCPs of PEO
and PDMBPMA using ATRP.
reaction was catalyzed by p-toluenesulfonic acid. A Dean Stark
trap is necessary for continuous removal of water from the mix-
ture to increase the conversion of aldehydes. The yield of both
monomers is around 60% (see Supporting Information Figs. S1
and S2 for the NMR spectra of the two monomers).
Cleavage Reaction of Acetal Groups in Monomers
and Polymers
Among various photolabile groups, o-nitrobenzyl group has
been extensively studied for photoresponsive polymers.
The o-nitrobenzyl photolabile group usually goes through a
1
7,31
Norrish Type II mechanism to break N@O bonds and form
The amphiphilic di-BCPs were prepared through ATRP. The PEO-
Br macroinitiator was synthesized by the esterification reaction
of monomethoxy PEO (5 kg/mol) with 2-bromoisobutyryl bro-
32,33
C@O bonds as COOH groups typically.
Our initial trial is
11,30
mide.
Subsequently, di-BCPs were made using a CuBr/
PMDETA ATRP catalytic system at 65 8C. Both NBDPMA and
DMBPMA monomers showed high conversion using the
CuBr/PMDETA catalyst. Three di-BCPs with different block
lengths were prepared, that is PEO114-b-PDMBPMA , PEO114-b-
34
PDMBPMA67 and PEO114-b-PDMBPMA146 (Table 1). One di-BCP
of NBDPMA, that is PEO114-b-PNBDPMA166, was also synthesized
(see Supporting Information Fig. S3 for its NMR spectrum and
GPC elution curve). Unlike to o-nitrobenzyl ester containing
20,21
monomers,
the two acetal-containing monomers are poly-
merizable without any special ATRP catalytic system. All di-BCPs
1
have a low dispersity index of ꢀ1.1. Figure 1 shows the H NMR
spectrum in d -DMSO and the GPC elution curve of PEO -b-
6
114
PDMBPMA67 as an example. Using the molecular weight of the
hydrophilic PEO block, the relative block length of PDMBPMA
could readily be estimated by comparing the integrals of peak g
(
CH of PEO) and peak b (CH of acetal groups). From GPC mea-
2
surement, the polymer has a number average molecular weight
(
M ) of 16.5 kg/mol and a dispersity index of 1.09. Although the
n
DMBPMA monomer is not stable even when stored at 4 8C, the
di-BCPs of PEO-b-PDMBPMA and PEO-b-PNBDPMA are fairly sta-
ble at room temperature. No change is measureable by H NMR
after stored for one month.
1
1
FIGURE 1 Characterization of PEO114-b-PDMBPMA67, (a)
NMR spectrum in d
H
6
-DMSO and (b) its GPC elution curve in THF.
1
81 18 81 8
JJ OO UU RR NN AA LL OO FF PP OO LL YY MM EE RR SS CC II EE NN C EE ,, PP AA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM I ISS TT RR YY 2 20 01 18 8, ,5 56 6, ,1 18 81 15 5– –1 18 82 24 4

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
WW WW WW .. PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
AA RR TT II CC LL EE
TABLE 1 Molecular Weights and Dispersity Indexes of Acetal-
and oxidation of those aromatic products during photolysis, in
consistence with H NMR results.
1
Containing Di-BCPs
M
n,NMR
M
n,GPC
Dispersity
Index
Using the absorbance at 295 nm, we further fitted the reaction
kinetics of both photo- and acid-cleavage reactions [Fig. 3(b,d)].
The photocleavage of acetal was fitted as a zero-order reaction
at which A/A (A and A are the absorbance at 295 nm at any
Samples
(kg/mol)
(kg/mol)
PEO114-b-PDMBPMA34
PEO114-b-PDMBPMA67
PEO114-b-PDMBPMA146
PEO114-b-PNBDPMA166
15.4
25.6
49.9
53.6
11.9
16.3
19.4
27.3
1.07
1.09
1.16
1.13
0
0
given reaction time and the initial absorbance) presents a linear
decrease with irradiation time. The apparent rate constant
21
normalized by the initial concentration is 0.0263 min using
0
A/A 5 1 – k 3t. The acid-cleavage reaction of DMBPMA was
0
best fitted as a first-order reaction where ln(A/A ) linearly
to synthesize NBDPMA with photolabile acetal using o-nitro-
0
decreased with the cleavage time. The rate constant for acid-
benzyl aldehyde. The photocleavage reaction of NBDPMA
2
1
1
24
1
cleavage reaction is 0.183 min at [H ] 5 10 M, 60 8C.
was studied using H NMR spectroscopy when subjected to
UV light at 365 nm (4 W, fluorescent lamp). A Norrish Type
II rearrangement was observed for NBDPMA to form o-
nitrosobenzoic ester (see Supporting Information Fig. S4). No
aldehyde was observed and new peaks appeared above
To examine whether the acetal-containing polymers undergo
similar cleavage reactions, the cleavage kinetics of PEO114-b-
PDMBPMA67 was also measured in methanol containing 20 vol
%
of water (Fig. 4). Note that, the polymer is insoluble in the
8
ppm assigned to protons at the aromatic ring of o-nitroso-
solvent. To prepare the solution for UV–vis measurement, the
vesicular solution of PEO114-b-PDMBPMA67 in water was used
to dilute and balance with methanol. In case of photo-cleavage
reaction, the absorption peak at 353 nm showed an increase
over a short period of irradiation time; then the peak showed a
decrease in intensity with an obvious red-shift. The oxidation
or possible polymerization of phenol products likely occurred
for polymer. The apparent rate constant of polymer photo-
benzoic moieties. However, o-nitrosobenzoic ester will not
significantly change the hydrophobicity of NBDPMA groups.
Subsequent hydrolysis of o-nitrosobenzoic esters is neces-
sary for the complete cleavage to yield hydrophilic diols.
Acetals of salicylaldehyde and coumarin derivatives were
reported to be excellent photolabile protection groups for
2
8,29
diols in literatures.
Taking this inspiration, the acetal
2
1
monomer DMBPMA was designed using 2,5-dimethoxyben-
zaldehyde which shows a complete photocleavage reaction
cleavage reaction is 0.0233 min , very close to that of the
DMBPMA monomer. For the acid-cleavage reaction, much
slower reaction rate was observed. The rate from the first-
1
to yield diols. H NMR spectra of DMBPMA before and after
2
3
21
photocleavage reaction are exhibited in Figure 2. After
exposed to UV light (100 W high pressure mercury vapor
lamp) for 1 h, a complete photocleavage of dimethoxybenzal-
dehyde was seen. The resonance peak b of the acetal group
at 5.95 and 6.07 ppm (a mixture of diastereomers) disap-
peared. The shift of aromatic protons from 6.9 to 7.2 ppm
and the new aldehyde peaks at 10.3 ppm confirmed the for-
mation of aldehyde. The formation of methanol was also
seen (the peak at 3.2 ppm) after photocleavage, likely due to
the deprotection of o-methoxy. As a comparison, similar
results were seen to cleave acetal and yield diols in acid-
cleavage reaction (see Supporting Information Fig. S5); while
no methanol was observed.
order reaction fitting is 3.87 3 10 min for the polymer.
Even the concentration of the polymer used for UV–vis mea-
surement is very low (10–20 lg/mL), the hydrophobicity of
the PDMBPMA block obviously shielded water and acid from
the hydrophobic domain which slows down the acid-cleavage
reaction of acetal.
UV–vis spectroscopy was used to monitor the cleavage kinetics
of DMBPMA (Fig. 3). The UV–vis experiments were carried out
in methanol containing 20 vol % of water to avoid the absor-
bance overlap with the solvent. DMBPMA has three UV–vis
absorption peaks at 258, 295, and 353 nm. Its maximum
absorbance is 295 nm assigned to p!p* transition of the ben-
zenoid ring which also enables the photocleavage under UV
light. The decrease in the absorbance at 295 nm indicates the
cleavage of acetal upon exposure to UV light or lowering the
pH of the solution. When comparing the absorption feature
after cleavage, the product from acid-cleavage reaction showed
higher absorbance at 258 and 353 nm; while both peaks of the
product from photo-cleavage decreased with a blue-shift in
absorption wavelength. This is indicative of the decomposition
1
FIGURE 2 H NMR spectra of DMBPMA monomer before (black,
bottom) and after (red, top) photo irradiation for 1 h at room tem-
perature. [Color figure can be viewed at wileyonlinelibrary.com]
J OJ OU UR RN NA AL LO OF FP PO OL LY YMM E ER RS SC CI EI ENN C CE E, ,P PAA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY 22 00 11 88 ,, 55 66 ,, 11 81 55 –– 11 88 22 44
1 18 81 19 9

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
AA RR TT II CC LL EE
WW WW WW . .PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
FIGURE 3 Cleavage reaction of DMBPMA monomer in methanol containing 20 vol % of water. (a) UV–vis spectra at different irra-
diation time. The absorption spectra were collected every 2 min. (b) Kinetic fitting of the photocleavage reaction using the absor-
1
24
bance at 295 nm. (c) UV spectra of DMBPMA collected at [H ] 5 10 M, 60 8C. The absorption spectra were collected every 30 s.
(
d) Kinetic fitting of the pH-cleavage reaction using absorbance at 295 nm. [Color figure can be viewed at wileyonlinelibrary.com]
1
We used H NMR spectroscopy to confirm the product differ-
ence in photo- and acid-cleavage reactions of polymers. For
acid-cleavage reaction, the di-BCP of PEO114-b-PDMBPMA67
was dissolved in d -DMSO (2 mg/mL). After adding acid, the
NMR sample was incubated at 60 8C for 2 h to reach the
complete hydrolysis of acetals as shown in Figure 5. The
6
FIGURE 4 Cleavage reaction of the di-BCP, PEO114-b-PDMBPMA67 in methanol containing 20 vol % of water. (a) UV–vis spectra
under irradiation of UV light at 295 nm. The absorption spectra were collected at 0, 100, 200, 300, 400, 600, 800, 1000, 1200, 1400,
1600, and 1800 s from top to bottom. (b) Kinetic fitting of the photocleavage reaction using absorbance at 295 nm. (c) UV spectra
of PEO114-b-PDMBPMA67 collected at pH 4, 60 8C. The absorption spectra were collected every 15 min. (d) Kinetic fitting of the pH-
cleavage reaction using absorbance at 295 nm. [Color figure can be viewed at wileyonlinelibrary.com]
1
81 28 02 0
JJ OO UU RR NN AA LL OO FF PP OO LL YY MM EE RR SS CC II EE NN C EE ,, PP AA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM I ISS TT RR YY 2 20 01 18 8, ,5 56 6, ,1 18 81 15 5– –1 18 82 24 4

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
WW WW WW .. PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
AA RR TT II CC LL EE
disappearance of the peak a at 6 ppm which is assigned to
CH of the acetal group is indicative of the cleavage reaction.
The cleavage product was confirmed from the peak c at
10.3 ppm, attributed to the aldehyde proton of 2,5-
dimethoxybenzaldehyde.
1
Figure
6
shows the
H NMR spectra of PEO114-b-
PDMBPMA67 in the course of photocleavage reaction at dif-
ferent irradiation times. After exposed to UV light for 15
min, a small peak at 3.2 ppm assigned to methanol appeared
while no apparent differences were seen for other resonance
peaks. The methanol peak became more pronounced with
increasing irradiation time. This was due to the demethyla-
tion of o-methoxy or m-methoxy groups under irradiation.
The cleavage of o-methoxy group to form phenol hydroxyl
group likely can promote the cleavage of acetal as a proton
source. After irradiation for 90 min, a new peak appeared at
1
0.3 ppm which can be assigned to aldehyde, along with
1
FIGURE 5 H NMR spectra of PEO114-b-PDMBPMA67 before
new broad multiplet at 7.2 ppm. This suggests the formation
of aldehyde as a cleavage product. However, there is a new
peak appeared at 8.1 ppm which was not observed in acid-
(
black, bottom) and after (red, top) the addition of HCl in d
DMSO. The sample for pH-cleavage was incubated at 60 8C for
h. [Color figure can be viewed at wileyonlinelibrary.com]
6
-
2
1
1
FIGURE 6 Photocleavage of PEO114-b-PDMBPMA67 monitored by H NMR in d
6
-DMSO. H NMR spectra of the polymer were col-
lected after photo irradiation for 0, 15, 30, 60, 90, 120, 150, and 180 min (from bottom to top) at room temperature. [Color figure
can be viewed at wileyonlinelibrary.com]
J OJ OU UR RN NA AL LO OF FP PO OL LY YMM E ER RS SC CI EI ENN C CE E, ,P PAA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY 22 00 11 88 ,, 55 66 ,, 11 81 55 –– 11 88 22 44
1 18 82 21 1

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
AA RR TT II CC LL EE
WW WW WW . .PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
FIGURE 7 Self-assembly of PEO114-b-PDMBPMA67 and its photoresponsiveness. (a) A representative SEM image of vesicles of
PEO114-b-PDMBPMA67 assembled in water. (b) A SEM image of vesicular solution after light irradiation for 120 min. (c) Images of
vesicular solutions (from left to right): acid cleavage after 24 h (image 1), the origin solution storage in dark (image 2), the solu-
tions after light irradiation for 30 min (image 3), 60 min (image 4), 90 min (image 5), and 120 min (image 6). The concentration of
vesicles is 1.5 mg/mL in water for those experiments. (d) Plotting normalized light scattering intensity (measured at 908)versus irra-
diation time to show the dissociation of vesicles. [Color figure can be viewed at wileyonlinelibrary.com]
cleavage reaction. Therefore, the photocleavage of the di-BCP
of PEO114-b-PDMBPMA67 is proposed to be a two-step reac-
tion as shown in Figure 6. The first step is the demethylation
of the polymer to form o-hydroxyl benzaldehyde acetal, m-
hydroxyl benzaldehyde acetal, or 2,5-dihydroxyl benzalde-
hyde acetal. The second step is the acetal cleavage of the of
benzaldehyde acetal to generate hydrophilic dihydroxypropyl
moieties with free diols.
measured from SEM images. The average hydrodynamic
diameter of polymer vesicles is 504 nm determined by DLS
(Supporting Information Fig. S7), in close agreement with
our SEM observation.
Since the formation of vesicles is driven by the amphiphilic-
ity of the di-BCPs, the cleavage of acetal groups either under
photo irradiation or acid triggered hydrolysis would cause
the shift of hydrophobic-to-hydrophilic balance. The com-
plete cleavage of acetal groups can lead to the disruption of
polymer vesicles. We investigated the photo- and pH-
responsiveness of polymer vesicles in aqueous solution. First
of all, the change in apparent transmittance is shown in Fig-
ure 7(c). The polymer vesicle solution (1.5 mg/mL) is quite
turbid. When incubating the vesicle solution at pH 4, 60 8C
for 24 h, the solution became transparent because of the
acid-cleavage reaction of acetals. Similarly, when exposed to
UV light, the apparent transparence of the solution increased
over the irradiation time, although the solution became
slightly yellow due to the formation of quinone and other
oxidized by-products. The change of transparence can be fol-
lowed by the difference in scattering intensity. Figure 7(d)
presents the change in normalized scattering intensity of the
Photo- and pH-Responsiveness of Polymer Vesicles
Acetal-containing polymers having fairly rigid hydrophobic
side chains of 2,5-dimethoxybenzaldehyde acetal can self-
assemble in water to form vesicles. Using the amphiphilic di-
BCP of PEO114-b-PDMBPMA67 as an example, the self-
assembly was triggered by adding water to its DMF solution
(
6.7 mg/mL), followed by dialysis against water. The self-
assembled nanostructures of PEO114-b-PDMBPMA67 were
examined by scanning electron microscopy (SEM) as shown
in Figure 7(a). Vesicles with hollow interiors were seen as
hollow nanoparticles in the both SEM and TEM images (Sup-
porting Information Fig. S6), due to the flattening of vesicles
after the removal of the solvent. The size of vesicles is in the
range of 300–600 nm with an average size of 510 6 107 nm
1
81 28 22 2
JJ OO UU RR NN AA LL OO FF PP OO LL YY MM EE RR SS CC II EE NN C EE ,, PP AA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM I ISS TT RR YY 2 20 01 18 8, ,5 56 6, ,1 18 81 15 5– –1 18 82 24 4

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
WW WW WW .. PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
AA RR TT II CC LL EE
added into a dialysis bag against acetate buffer at pH 3.6.
The fluorescence intensity for RB in the acetate buffer was
monitored every 30 min. The release profile of RB is plotted
in Figure 8(a). It is evident that the release of RB was
much faster at a lower pH; while, at neutral conditions or
physiological pH, less than 5% of RB was released. The
release profile of RB is similar to the acid cleavage kinetics
of acetal (a first-order reaction) where 17.5% of RB was
released in the first 30 min and ꢀ35% of RB was released
in 12 h. Those results suggest that polymer vesicles of
PEO114-b-PDMBPMA67 were stable under physiological pH
in dark and the disruption of polymer vesicles led to the
results of hydrophilic payloads in vesicles. For light-
triggered release, water-soluble ibuprofen sodium was used
due to the strong photobleaching of RB under UV light. The
control release experiments were similar to that of RB,
except that the release amount of ibuprofen sodium was
examined by LC/MS. The light-controlled release profile is
shown in Figure 8(b). It can be seen that the cumulative
amount of ibuprofen sodium shows a linear correlation
with the irradiation time, similar to the profile of a zero-
order kinetics. This, again, indicates that the release profile
of payloads is highly dependent on the cleavage rate of
acetals.
CONCLUSIONS
To summarize, we demonstrated a new design of light- and
acid-cleavable acetal-containing polymers. Using acetalization
reaction of 2,3-dihydroxypropyl methacrylate with o-nitro-
benzaldehyde and 2,5-dimethoxy benzaldehyde, two new
monomers with cleavable acetal groups were synthesized.
The two monomers could be polymerized using ATRP with
excellent molecular weight and dispersity control. The cleav-
age reaction kinetics and mechanism of acetal groups in
both monomers and amphiphilic di-BCPs were studied using
FIGURE 8 The application of light/pH responsive acetal poly-
mers for delivery. (a) pH-controlled release of Rb from PEO114
-
b-PDMBPMA67 vesicle using acid as a trigger at room tempera-
ture. (b) Light-controlled release of ibuprofen sodium from
PEO114-b-PDMBPMA67 vesicle using light as a trigger. [Color
figure can be viewed at wileyonlinelibrary.com]
polymer vesicle solution. Along with the increase in irradia-
tion time, the scattering intensity of solution dropped by
1
H NMR and UV–vis spectroscopy. o-Nitrobenzaldehyde ace-
tal showed a Norrish Type II intramolecular rearrangement
to form benzoic ester instead of acetal cleavage. DMBPMA
ꢀ
36% after irradiation for 2 h. This suggests that the photo-
cleavage did not complete within 2 h for polymer vesicles.
The photolysis of acetal was slow in polymer vesicles since
the concentration and the volume of polymers were much
higher, compared to NMR and UV–vis measurements. Second,
after photocleavage reaction, the disruption of polymer
vesicles has been investigated by SEM. The disappearance of
hollow nanostructures is shown in Figure 7(b). Third, the
disruption of polymer vesicles was monitored by the release
of dimethoxybenzaldehyde. The vesicular solution showed a
weak fluorescence peak at 375 nm when excited at 350 nm
(
2,5-dimethoxy benzaldehyde acetal) was photolabile to
completely release diols. The acid-cleavage of DMBPMA is a
first-order reaction, but the cleavage kinetics became slower
for polymers, compared to that of DMBPMA monomers.
However, the photocleavage of DMBPMA is a zero-order
reaction in regardless of molecular states of acetals. The
photocleavage of DMBPMA in polymers seemed to be a two-
step reaction, including demethylation and proton-assisted
acetal cleavage. We demonstrated the potential applications
of those polymer vesicles for dual photo- and pH-triggered
release. The release profile of payloads in vesicles was highly
controllable through the triggers of pH and light. The photol-
ysis strategy of acetal-containing polymers can be easily
extended to other chromophores absorbing visible light. Our
design of photolabile acetal-containing monomers is
expected to enrich molecular building blocks to photores-
ponsive polymers for applications such as photoresists and
drug delivery.
(
see Supporting Information Fig. S8). After photocleavage
reaction, the release of dimethoxybenzaldehyde chromophore
enhanced the fluorescence intensity with a red-shift of its
maximum emission wavelength to 395 nm.
Finally, we demonstrated the potential application of those
acetal-containing polymers as dual-responsive vehicles for
drug delivery. For pH-controlled release, RB used as a model
compound was first loaded into the polymer vesicles of
PEO114-b-PDMBPMA . RB-loaded polymer vesicles were
67
J OJ OU UR RN NA AL LO OF FP PO OL LY YMM E ER RS SC CI EI ENN C CE E, ,P PAA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY 22 00 11 88 ,, 55 66 ,, 11 81 55 –– 11 88 22 44
1 18 82 23 3

JJ OO UU RR NN AA LL OO FF
PP OO LL YY MM EE RR SS CC II EE NN CC EE
AA RR TT II CC LL EE
WW WW WW . .PP OO LL YY MM EE RR CC HH EE MM II SS TT RR YY .. OO RR GG
ACKNOWLEDGMENTS
15 X. Jiang, C. A. Lavender, J. W. Woodcock, B. Zhao, Macro-
molecules 2008, 41, 2632.
JH is grateful for the financial support from the University
of Connecticut. YH acknowledges the Chinese Scholarship
Council to support his work at the University of Connecticut.
The authors thank Youjun Fu for his assistance to measure
LC/MS. The SEM/TEM studies were performed using the
facilities in the UConn/FEI Center for Advanced Microscopy
and Materials Analysis (CAMMA). This work was also par-
tially supported by the Green Emulsions Micelles and Surfac-
tants (GEMS) Center.
1
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81 28 42 4
JJ OO UU RR NN AA LL OO FF PP OO LL YY MM EE RR SS CC II EE NN C EE ,, PP AA RR TT AA :: PP OO LL YY MM EE RR CC HH EE MM I ISS TT RR YY 2 20 01 18 8, ,5 56 6, ,1 18 81 15 5– –1 18 82 24 4