Self-immolative polymersomes for high-efficiency triggered release and programmed enzymatic reactions

Article abstract of DOI:10.1021/ja5030832

Stimuli-triggered disassembly of block copolymer vesicles or polymersomes has been conventionally achieved via solubility switching of the bilayer-forming block, requiring cooperative changes of most of the repeating units. Herein we report an alternative

Full text of DOI:10.1021/ja5030832

Article
pubs.acs.org/JACS
Self-Immolative Polymersomes for High-Efficiency Triggered Release
and Programmed Enzymatic Reactions
Guhuan Liu, Xiaorui Wang, Jinming Hu, Guoying Zhang, and Shiyong Liu*
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, Department of
Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
S
* Supporting Information
ABSTRACT: Stimuli-triggered disassembly of block copolymer
vesicles or polymersomes has been conventionally achieved via
solubility switching of the bilayer-forming block, requiring cooperative
changes of most of the repeating units. Herein we report an
alternative approach by incorporating hydrophobic blocks exhibiting
stimuli-triggered head-to-tail cascade depolymerization features.
Amphiphilic block copolymers bearing this motif self-assemble into
self-immolative polymersomes (SIPsomes). By modular design of
terminal capping moieties, visible light, UV light, and reductive milieu
can be utilized to actuate SIPsomes disintegration into water-soluble
small molecules and hydrophilic blocks. The design of SIPsomes
allows for triggered drug co-release and controllable access toward
protons, oxygen, and enzymatic substrates. We also demonstrate
programmed (OR-, AND-, and XOR-type logic) enzymatic reactions
by integrating SIPsome encapsulation and trigger/capping moiety-selective cascade depolymerization events.
chain depolymerization and release of small molecule building
blocks upon removal of a single capping moiety at the focal
point or chain terminal. Shabat et al.16a originally reported the
synthesis of poly(benzyl carbamate) (PBC) self-immolative
polymers terminally caged with cleavable moieties (e.g., 4-
hydroxy-2-butanone); bovine serum albumin (BSA) can actuate
trigger cleavage and release either fluorescent or colorimetric
reporters. The nonlinear amplification nature renders them
ideal candidates for drug delivery17 and diagnostic18 functions.
For instance, microcapsules with triggered release character-
istics have been fabricated from self-immolative homopolymers
via either emulsification or microfluidic techniques.17c,d
However, the controlled modular synthesis and hierarchical
self-assembly of block copolymers bearing self-immolative
motifs have been far less explored.16c We envisage that
supramolecular aggregates of self-immolative block copolymers
can impart advanced properties such as minimum cleavage
events required for disintegration and robust aggregate
morphology with rich responsive modes.
INTRODUCTION
■
Lipid vesicles (liposomes) and polymeric vesicles (polymer-
somes) are artificial self-assemblies inspired by complex
biological systems such as cells and viral capsids.1 Both of
them consist of an aqueous interior entrapped by a hydro-
phobic bilayer membrane. Since discovery, they have been
frequently utilized to construct drug delivery nanocarriers,2
nanoreactors,3 and artificial organelles.4 Note that all of these
functions are related to the exchange of substances between the
outside and inside milieu. Although polymersomes are more
robust and stable than liposomes, they suffer from severe
membrane permeability concerns and are almost nonpermeable
to small substances, ions, and even water molecules.5
To address this issue, block copolymers with the core-
forming block being responsive to external milieu (e.g., pH,6
temperature,7 light,8 redox,9 sugar,10 and CO211) have been
employed to construct stimuli-responsive polymersomes.
However, solubility switching of the responsive block typically
relies on physicochemical changes of most repeating units and
requires considerable input of external stimuli (energy and
concentration),12 just as those occurred in pH titration
experiments.12b Although polymersomes containing biodegrad-
able polyester block13 or labile linkages14 can be disrupted via
spontaneous or random hydrolysis, multiple cleavage events are
needed, and the process is less controlled; in addition, irregular
aggregates might form due to the insolubility of degradation
intermediates.14b
Herein we report on the fabrication of self-immolative
polymersomes (SIPsomes) via self-assembly from amphiphilic
block copolymers consisting of a triggered degradable PBC
block and a hydrophilic poly(N,N-dimethylacrylamide)
(PDMA) block (Scheme 1). The self-immolative block was
caged with perylen-3-yl, 2-nitrobenzyl, or disulfide moieties,
which are responsive to visible light (420 nm),19 UV light (365
Since 2003, self-immolative dendrimers15 and polymers16
have emerged as a new design paradigm, featuring cascade
Received: March 27, 2014
Published: April 30, 2014
© 2014 American Chemical Society
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Scheme 1. Schematic Illustration of SIPsomes Self-
Assembled from Poly(benzyl carbamate)-b-poly(N,N-
dimethylacrylamide), PBC-b-PDMA, Amphiphilic Block
Copolymers Containing Hydrophobic PBC Blocks, Which
Are Subjected to Self-Immolative Depolymerization into
Small Molecules upon Cleavage of “Capping” Moieties (i.e.,
Perylen-3-yl, 2-nitrobenzyl or Disulfide for Stimuli of Visible
a
Light, UV Light, And Reductive Milieu, Respectively)
a
Various encapsulated bioactive agents are released from polymer-
somes upon stimuli-triggered disintegration.
Figure 1. (a) Schematics employed for the synthesis of PBC−PDMA
amphiphilic block copolymers containing hydrophobic self-immolative
blocks. Abbreviations: DBTL, di-n-butyltin dilaurate; DCC, dicyclo-
hexyl carbodiimide; DMAP, 4-dimethylaminopyridine. (b) Typical
TEM (scale bar: 200 nm), (c) SEM image (scale bar: 2 μm), and
CLSM images (scale bar: 5 μm; blue channel: perylene emission, 405
nm excitation; green channel: calcein, 488 nm excitation) recorded for
PB1 SIPsomes. Polymersomes encapsulating calcein were used for
CLSM imaging, and inset in (d) shows blue and green channel
emission intensity profiles.
nm)20 or reductive milieu,21 respectively. Upon removal of
caging moiety triggered by appropriate stimulus, the block
copolymer depolymerized into water-soluble 4-aminobenzyl
alcohol (ABA), carbon dioxide, and PDMA. Triggered drug co-
release and controllable access toward protons, oxygen, and
enzymatic substrates can be achieved for guest-loaded
SIPsomes, and further applications in programmed (OR,
AND and XOR-type logic) enzymatic catalysis are also
demonstrated.
Table 1. Molecular Parameters of Polymer Precursors and
Self-Immolative Diblock Copolymers
RESULTS AND DISCUSSION
■
Amphiphilic block copolymers containing self-immolative
hydrophobic blocks were synthesized by combining condensa-
tion polymerization and reversible addition−fragmentation
chain transfer (RAFT) polymerization (Figure 1a and Scheme
S1). First, the self-immolative PBC block (P1−P5) was
synthesized through the polymerization of caged isocyanate 1
at 110 °C,16a followed by chain terminal functionalization with
a variety of capping moieties, e.g., perylen-3-yl methanol, 2-
nitrobenzyl alcohol, diethanol disulfide, or noncleavable benzyl
alcohol. Next, PBC was transformed into a macroRAFT agent
via hydroxyl esterification reaction with RAFT agent 2 (Figure
S1). Finally, AB-type diblock (PB1−PB3 and PB5) and BAB-
type triblock (PB4) copolymers were prepared by RAFT
polymerization. The molecular parameters of all polymer
precursors and self-immolative block copolymers are summar-
ized in Table 1.
M
Mn, GPC
b
M /
wb
n, NMaR
entry
sample
(kDa)
(kDa)
Mn
P1
P2
per-PBC13
per-PBC20
2.1
3.2
2.0
2.2
2.5
6.3
7.6
7.3
7.8
4.8
6.2
1.45
1.48
1.38
1.39
1.44
1.22
1.24
1.23
1.21
P3
NB-PBC13
4.5
P4
HO-SS-PBC14
4.8
P5
Ph-PBC16
5.4
PB1
PB2
PB3
PB4
per-PBC13-b-PDMA40
per-PBC20-b-PDMA44
NB-PBC13-b-PDMA53
10.9
12.9
12.1
12.7
PDMA28-SS-PBC14-b-
PDMA28
PB5
Ph-PBC16-b-PDMA40
6.8
11.5
1.25
a
b
1
Calculated from H NMR results. Determined by GPC using DMF
as the eluent (1.0 mL/min).
The self-assembly of self-immolative diblock copolymer PB1
in aqueous media was then investigated. TEM and SEM
observations revealed the formation of robust polymersomes or
SIPsomes (Figure 1b,c); dynamic light scattering (DLS)
measurement revealed an intensity-average hydrodynamic
diameter, ⟨Dh⟩, of ∼250 nm and a polydispersity of 0.13
(Figure S2). The vesicular nanostructure of SIPsomes was also
verified using confocal laser scanning microscope (CLSM) by
encapsulating green-emitting calcein in the aqueous interior
(Figure 1d).
The driving force for SIPsome formation from PB1 with a
high hydrophilic fraction f (67 wt %), which is much higher
than the typical value (<35 wt % 10 wt %)5b required for
generating block copolymer vesicles, should be ascribed to
strong hydrogen-bonding interactions between carbamate
moieties.8 Possessing similar hydrophilic fractions, PB3 and
PB4 also self-assemble into polymersomes, as confirmed by
TEM (Figure 2g,i) and CLSM images (Figure S3). The average
diameter of PB4 SIPsomes (∼580 nm) are much larger than
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which finally disappeared after 12 h incubation (Figures 2f and
S9b). The above process was also confirmed by time-dependent
DLS measurements (Figure S10). The UV irradiation or
reductive milieu triggered disintegration of PB3 and PB4
SIPsomes was also explored. Quite comparable spontaneous
self-immolative depolymerization processes for the hydro-
phobic PBC block occurred after being subjected to 30 min
UV irradiation (Figures 2g,h and S11) or by treating with 10
mM DTT (Figures 2i,j, S3, and S12), respectively.
Polymersomes are excellent drug nanocarriers that can
encapsulate both hydrophobic and hydrophilic drugs for
combinational therapy.1,22 PB4 SIPsomes respond to intra-
cellular reductive milieu, which are ideally biological relevant,21
and thus can serve as combinational therapeutic delivery
nanovehicles upon co-encapsulating hydrophobic camptothecin
(CPT) and hydrophilic doxorubicin (DOX·HCl). In the
absence of glutathione (GSH), only ∼4% DOX and ∼19%
CPT were released in 20 h; whereas upon addition of 10 mM
GSH, the release rates considerably increased, and ∼86% DOX
and ∼82% CPT were released in the same time scale (Figure
3). This was obviously caused by GSH-triggered SIPsome
Figure 2. (a) Time-dependent depolymerization profiles recorded for
PB1 and PB5 SIPsomes without or with 420 nm irradiation (25 °C);
following 30 min blue light irradiation (blue region), the extent of
spontaneous release of ABA was monitored by HPLC. (b) DMF GPC
traces recorded for P1 (red line), PB1 (black line), and PB1 subjected
to complete self-immolative depolymerization for the hydrophobic
block (blue line). (c−f) Typical TEM images recorded for PB1
SIPsomes without irradiation (c) and upon incubating for 0 h (d), 1 h
(e), and 12 h (f) after being irradiated for 30 min (420 nm light);
yellow arrows indicate pore formation. (g,h) TEM images recorded for
PB3 SIPsomes without UV irradiation (g) and upon incubating for 12
h (h) after 30 min UV 365 nm irradiation. (i,j) TEM images recorded
for PB4 SIPsomes without DTT coincubation (i) and after being
treated with 10 mM DTT for 24 h (j). Scale bars: 1 μm.
Figure 3. In vitro co-release profiles of hydrophobic CPT and
hydrophilic Dox·HCl at 37 °C from CPT/DOX co-loaded PB4
SIPsomes (0.1 g/L; 0.1 M PBS buffer, pH 7.4) in the absence or
presence of GSH (10 mM).
SIPsomes of PB1 (∼250 nm) and PB3 (∼205 nm), which
should be ascribed to BAB triblock-type topology (Figure S2).
Possessing longer hydrophobic PBC block compared to PB1,
PB2 self-assembles into large compound vesicles (LCVs)
(Figure S4).
disruption (Scheme 1). Considering the potential applications
of SIPsomes in the field of drug delivery, we further conducted
cell viability assays to check the cytotoxicity of SIPsomes. It was
found that both irradiated and nonirradiated (420 nm, 30 min)
PB1 SIPsome dispersions exhibited negligible cytotoxicity up to
a concentration of 1.0 g/L (Figure S13).
Next, we examined visible light responsiveness of PB1
SIPsomes. After 30 min of light irradiation at 420 nm to fully
decage the perylen-3-yl capping moiety (Figures S5 and S6),
the self-immolative depolymerization process was traced by
GPC and HPLC via monitoring the concentration of released
ABA (Figure S7). Without irradiation, PB1 SIPsomes are
highly stable (inset in Figure 2a). For the irradiated dispersion,
∼6 h is required for the PBC block of SIPsomes to almost
completely depolymerize (>95% ABA release, Figure 2a). In
addition, for the control sample (PB5 SIPsomes), negligible
ABA release can be discerned over the same time period due to
that 420 nm irradiation cannot cleave the terminal benzyl
moiety of PB5. The molecular weight of resultant residual
polymer fragments was consistent with that of PDMA block in
the original PB1 block copolymer (Mn ∼ 6500 Da) (Figure
2b), confirming the full spontaneous decomposition of PBC
block. In addition, the self-immolative degradation of PBC
PB1 SIPsomes can also serve as drug delivery vehicle for
photodynamic therapy agents (eosin Y), and the 1O2
generation rate is directly linked to SIPsome integrity (Figure
4). For intact eosin-loaded PB1 SIPsomes before triggered
disassembly, the release of photosensitizer (eosin) is slow
(Figure 4a), and diffusion rate of oxygen and 1,9-
di(aminoethyloxyl)anthracene dihydrochloride (An-2NH2)
across hydrophobic SIPsome bilayers is also restricted, thus,
1O2 generation rate is retarded (Figure 4b). However, upon
SIPsome disintegration, the 1O2 generation rate is considerably
enhanced, as evidenced by the fast decay of An-2NH2 emission.
Besides, the catalytic activities of alkaline phosphatase (ALP)-
loaded PB1 and PB4 SIPsomes can be modulated via visible
light irradiation or GSH addition, respectively, due to altered
rates of substrate access (Figures S14 and S15).
1
block was also verified by H NMR studies (Figure S8).
After 30 min visible light irradiation, the spontaneous
SIPsome disintegration process was then monitored by TEM
and CLSM experiments. The shells of PB1 SIPsomes changed
from thick continuous bilayer membranes (Figures 2c and S9a)
to pore-embedded thinner ones (Figure 2d). Upon further
extending incubation duration, vesicular nanostructures were
disrupted and rearranged into irregular aggregates (Figure 2e),
Can protons diffuse freely across the SIPsome bilayers? To
answer this question, we measured the change of pH
discrepancy, ΔpH, across the bilayer membrane of PB1
SIPsomes using a ratiometric fluorescent internal pH probe
(NTEA, see Figure S16 for chemical structure). By comparison,
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Figure 4. (a) In vitro release profiles of encapsulated eosin from PB1
SIPsomes (0.1 g/L; phosphate buffer, pH 7.4) without and after being
subjected to 420 nm blue light irradiation for 30 min. (b) Time-
dependent decomposition of An-2NH2 (i.e., 1O2 generation rate)
upon 525 nm excitation recorded for eosin@PB1 SIPsomes (0.1 g/L,
phosphate buffer 0.1 M, pH 7.4) before and after blue light (420 nm)-
triggered complete SIPsome disruption.
ΔpH of NTEA-loaded PEO15-b-PS60 vesicles was also
examined, where PS is polystyrene. Due to the existence of
polar carbamate moieties in the bilayer membrane, protons can
diffuse across PB1 SIPsome membranes at a faster rate than
PEO15-b-PS60 polymersomes,5a therefore the ΔpH of PB1
SIPsome was always smaller than that the latter (Figure 5a−c).
Figure 6. Construction of AND- (a,b) and XOR-type (c,d) logic gates
based on a mixture of SIPsomes responsive to visible light irradiation
(30 min) and reductive milieu, respectively. (b) Images taken under
UV lamp for the aqueous dispersion containing 0.2 g/L ALP@PB1
SIPsomes and 0.2 g/L FDP@PB4 SIPsomes (0.04 M Tris-HCl buffer,
pH 8.0) exhibiting AND logic gate output with dual inputs of visible
light irradiation and GSH addition. (d) Images taken under UV lamp
for the aqueous dispersion containing 0.2 g/L (Lipase&EDTA)@PB1
SIPsomes and 0.2 g/L (ALP&Paraoxon)@PB4 SIPsomes exhibiting
XOR-type logic gate output (0.04 M Tris-HCl buffer, pH 8.0). (a) and
(c) show design principles. In all cases, [FDP] = [FDA] = 30 μM.
AND logic gate is composed of ALP-loaded PB1 (ALP@PB1)
SIPsomes and fluorescein diphosphate (FDP)-loaded PB4
(FDP@ PB4) SIPsomes. After being subjected to both visible
light irradiation and GSH treatment, ALP catalyzes the
hydrolysis of FDP substrate to produce intense fluorescein
emission (i.e., “1” output signal) (Figure 6a,b).
As for the XOR logic gate, the two events triggered by two
inputs respectively must be mutually exclusive, thus, we loaded
two enzymes and their corresponding inhibitors into different
types of responsive SIPsomes: lipase/EDTA (ethylene diamine
tetraacetic acid, inhibitor of ALP)@PB1 SIPsome and ALP/
paraoxon (inhibitor of lipase)@PB4 SIPsome. FDP and
fluorescein diacetate (FDA) were chosen as externally added
substrates of ALP and lipase, respectively (Figure 6c). When
subjected to (1, 0) or (0, 1) input, only one kind of enzyme can
be released from SIPsomes, while its inhibitor was still trapped
within another type of SIPsomes, so the released enzyme can
act on its corresponding substrate to generate strong emission
(“1” output). However, with (1, 1) input, both enzymes as well
as their inhibitors were released, thus generating much weaker
fluorescein emission (“0” output) (Figures 6d and S18). OR
logic gate was also fabricated by encapsulating ALP within two
types of SIPsomes responsive to two different stimuli, all
exhibiting “1” output with (1, 0), (0, 1), or (1, 1) input (Figure
S19).
Figure 5. (a−c) The measured local pH within the interior of NTEA-
loaded PEO15-b-PS60 polymersomes and PB1 SIPsomes upon
adjusting the external buffer pH in the range of pH 4.8−8.2 and
incubating for 5 min (a), 1 h (b), and 10 h (c) (25 °C; the original
inside and outside pH is 7.0). The error bars indicate standard
deviations from three parallel experiments. (d) Time-dependent
variation of pH discrepancy, ΔpH, between the inside and outside
of NTEA-loaded PB1 SIPsomes in aqueous media without or upon
blue light irradiation (420 nm); the original pH inside SIPsomes was
7.0, whereas the outside pH was adjusted to pH 5.0 using 0.1 M buffer
just prior to light irradiation.
When subjected to blue light irradiation, the ΔpH of PB1
SIPsomes decreased from ∼2 to ∼0 (Figure 5d) due to
SIPsome disintegration, whereas the ΔpH of PEO16-b-PS60
polymersomes was almost insensitive to light irradiation
(Figure S17).
The modular design of block copolymers containing self-
immolative blocks has allowed for the construction of three
types of SIPsomes responsive to different triggering stimuli
(visible light, UV light, and reductive milieu). Based on a
mixture of different types of SIPsomes selectively encapsulating
enzymes/substrates/inhibitors, we further designed OR, AND,
and XOR logic gate-type enzymatic reactions (Figure 6). The
CONCLUSIONS
■
In summary, we have developed the concept of SIPsomes based
on amphiphilic block copolymers containing hydrophobic self-
immolative blocks, which were terminally modified with three
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AUTHOR INFORMATION
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Corresponding Author
sliu@ustc.edu.cn
Notes
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ACKNOWLEDGMENTS
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The financial support from the National Natural Scientific
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