Light and reductive dual stimuli-responsive PEI nanoparticles: "aND" logic response and controllable release

Article abstract of DOI:10.1039/c4tb00087k

"AND" logic responsive polyetherimide (PEI)-based polymers PENS were constituted by attaching the photoresponsive o-nitrobenzyl phototrigger and reductive responsive disulfide linker to the polymer PEI. This dual-responsive system maintained micelle-like assembly upon single photo or reductive stimuli. The disassembly only occurred when photo and reductive signals were input at the same time. This smart system was therefore applied as a carrier for the controlled release of the anti-cancer drug doxorubicin (DOX), which exhibited effective release only when UV irradiation and GSH reduction were applied simultaneously. the Partner Organisations 2014.

Full text of DOI:10.1039/c4tb00087k

Journal of
Materials Chemistry B
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PAPER
Light and reductive dual stimuli-responsive PEI
nanoparticles: “AND” logic response and
controllable release
Cite this: J. Mater. Chem. B, 2014, 2,
3333
*
Qi Huang,† Tao Liu,† Chunyan Bao, Qiuning Lin, Meixin Ma and Linyong Zhu
“AND” logic responsive polyetherimide (PEI)-based polymers PENS were constituted by attaching the
photoresponsive o-nitrobenzyl phototrigger and reductive responsive disulfide linker to the polymer PEI.
This dual-responsive system maintained micelle-like assembly upon single photo or reductive stimuli.
The disassembly only occurred when photo and reductive signals were input at the same time. This
smart system was therefore applied as a carrier for the controlled release of the anti-cancer drug
doxorubicin (DOX), which exhibited effective release only when UV irradiation and GSH reduction were
applied simultaneously.
Received 14th January 2014
Accepted 20th February 2014
DOI: 10.1039/c4tb00087k
www.rsc.org/MaterialsB
point also induced the disassembly of the micelles due to the
transformation of the pNIPAm block from hydrophobic to
Introduction
hydrophilic. Thayumanavan and co-workers reported a series of
triply stimuli responsive block copolymers which were respon-
sive to the change of temperature, pH and redox potential,
respectively, and could be used as carriers to achieve controlled
release of loaded guest molecules.28 Recently, we also prepared
dual-stimuli responsive inorganic mesoporous silica nano-
particles (SPA-MSNs) by attaching a reductively cleavable pho-
toreactive disulde–phenylazide linker (SPA) on the surface.29
Upon light irradiation, the generated phenylnitrene helped to
chemisorb biocompatible dextran polymers or proteins to
encapsulate the embedded guest molecules and the control-
lable release was achieved with treatment by reducing agents,
which enabled the SPA-MSNs to be an excellent nanocarrier for
controllable release.
Although the above multi-stimuli responsive nanoparticles
were sensitive to multiple chemical and physical inputs, the
release of their encapsulated cargo still occurred upon the
application of a single stimulus. Due to the complexity of
the targeting and release prole, it is necessary to design a more
smart trigger mechanism from which the drug can be only
released when multiple stimuli are present simultaneously,
namely “AND” logic responsive systems based on the logic gate
concept, leading to greater programmed specicity regarding
where and when release is triggered.30 However, “AND” logic
multi-stimuli responsive nanoparticles are synthetically chal-
lenging and only limited successful examples have been
reported so far.31,32
Stimuli-responsive nanoparticles that undergo structure and
property changes in response to internal or external stimuli
(including temperature,1,2 pH,3,4 redox,5,6 and light,7,8 etc.) have a
wide spectrum of practical applications in elds such as catal-
ysis,9 smart interfaces,10 tissue engineering,11 biosensors,12
diagnostics13 and drug delivery.14 Especially, stimuli-responsive
nanoparticles serving as excellent drug carriers have attracted
tremendous interest because of their suitable size to prolong
the circulation time, enhanced stability to avoid degradation in
blood, improved biocompatibility to decrease toxicity itself, and
well-modulated drug release in response to external stimuli.15,16
So far, many strategies including micelles, liposomes, micro-
gels, dendrimers and even inorganic particles have been
utilized to prepare stimuli responsive nanoparticles to achieve
controllable drug release.17–21
Compared to the single stimuli-responsive systems, multi-
stimuli responsive nanoparticles that are sensitive to two or
more stimuli allow precise tuning of the guest release kinetics
to t the therapeutic window of the drug.22–26 For example, the
group of Hennink27 has recently developed dual-stimuli sensi-
tive peptide–hybrid ABC block copolymers which self-assemble
into micelles above the cloud point of the thermosensitive
poly(N-isopropylacrylamide) (pNIPAm) block. And the peptide
linkage between the polymer blocks could be cut by a metal-
loprotease, leading to “shedding” of the corona of the micelles,
which made these systems potentially suitable for enzyme-
triggered drug delivery. While temperature lower than the cloud
In this work, we report a new polymer micelle as a drug
carrier for controllable release based on the “AND” logic
response concept with two orthogonal molecular triggers. As
shown in Scheme 1, polyetherimide (PEI) polymer was modied
with a nitrobenzyl phototrigger derivative (NBN) to obtain
Key Laboratory for Advanced Materials, Institute of Fine Chemicals, East China
University of Science and Technology, 130# Meilong Road, Shanghai, 200237, P. R.
China. E-mail: linyongzhu@ecust.edu.cn; Fax: +86-21-64253742
† These authors contributed equally to this work.
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angle of 90ꢀ was used to determine particle size distribution by
dynamic light scattering (DLS). Transmission Electron Micro-
graphs (TEM) were measured on a JEOL JEM-1400 at 120 kV.
Synthesis of compounds
1-(4,5-Dimethoxy-2-nitrophenyl)ethanone (compound 2). To
a solution of 10 mL conc. HNO3 in an ice-bath, acetic anhydride
was added and stirred for 30 min. To that solution, 1 (2.17 g, 12
mmol) dissolved in 2.5 mL acetic anhydride was slowly added.
The reaction was stirred for another 5 h and then poured in
200 mL ice-water. The residue was extracted with 30 mL CH2Cl2
3 times and the obtained organic solution was dried over
Na2SO4, and concentrated in a vacuum. Recrystallization in
ethanol gave the product (1.63 g, 61%) as a yellow solid. 1H NMR
(CDCl3, 400 MHz): d ¼ 7.62 (s, 1H), 6.77 (s, 1H), 3.99 (s, 6H), 2.51
(s, 3H); 13C NMR (CDCl3, 100 MHz): 154.0, 149.6, 138.5, 132.9,
108.6, 106.8, 56.7, 56.6, 30.4; MS (ESI): m/z: calcd for C10H11NO5
[M + H]+: 226.1; found 226.1.
Scheme 1 Schematic presentations of the generation of the dual-
responsive polymer PENS and its responsive behaviour with or without
the photo and/or reductive stimuli.
1-(4,5-Dimethoxy-2-nitrophenyl)ethanol (compound 3). To a
solution of 2 (1.5 g, 6.7 mmol) in 50 mL methanol was added
NaBH4 (0.26 g, 6.8 mmol). The reaction was stirred at room
temperature for 1 h and acidied with 1 N HCl to pH ¼ 6. Aer
concentration under reduced pressure to remove the methanol,
the residue was extracted with 30 mL CH2Cl2 3 times and the
obtained organic phase was dried over Na2SO4 and concen-
trated in a vacuum. Recrystallization in ethyl acetate–petroleum
photosensitive amphiphilic polymers PEN which were expected
to form self-assembled micelles in water due to their amphi-
philic nature. Then, dithiodipropionic acid was used as the
crosslinker to stabilize the micelles (PENS) as well as adding the
disulde reduction trigger to the photo-responsive PEN
systems. If the crosslinks were broken by disulde reductive
cleavage, the inherent amphiphilic nature of the system would
make it still preserve the micelle-like morphology; if the
hydrophobic NBN was photocleaved, the crosslinked structures
would also prevent the collapse of the micelles. Only when
photo and reduction conditions were present simultaneously,
would the hydrophobic NBN be photocleaved and the disulde
crosslinker broken, with the amphiphilic micelle concomitantly
dissociating back to hydrophilic PEI derivatives leading to the
disassembly of the micelle. Aer complexing a hydrophobic
drug doxorubicin (DOX), effective release could only be ach-
ieved using the simultaneous application of both light and a
reducing agent. This smart system is expected to possess
improved selectivity in targeting and to be appropriate for
intracellular controlled release.
1
ether gave the product (1.29 g, 86%) as a yellow solid. H NMR
(CDCl3, 400 MHz): d ¼ 7.57 (s, 1H), 7.31 (s, 1H), 5.57 (q, J ¼ 6.3
Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 1.56 (d, J ¼ 6.3 Hz, 2H); 13C
NMR (CDCl3, 100 MHz): 153.7, 147.7, 136.9, 108.5, 107.7, 65.8,
56.4, 56.3, 24.3; MS (ESI): m/z: calcd for C10H13NO5 [M + NH4]+:
245.1; found 245.1.
1-(4,5-Dimethoxy-2-nitrophenyl)ethyl (2,5-dioxopyrrolidin-1-
yl) carbonate (NBN). To a solution of 3 (1.2 g, 5.3 mmol) in
15 mL acetonitrile was added triethylamine (1.5 mL, 10.8 mmol)
and N,N0-disuccinimidyl carbonate (1.62 g, 6.3 mmol). The
reaction was stirred at room temperature overnight and
concentrated under reduced pressure to remove the solvent.
The residue was dissolved in 50 mL ethyl acetate and washed
with citric acid solution (20% wt), saturated Na2CO3 solution
and brine. Aer drying over Na2SO4 and concentrated in a
vacuum, the crude product was recrystallized in chloroform–
petroleum ether and the product was obtained as a yellowish
solid (1.56 g, 80%). 1H NMR (CDCl3, 400 MHz): d ¼ 7.62 (s, 1H),
7.08 (s, 1H), 6.51 (q, J ¼ 6.3 Hz, 1H), 4.07 (s, 3H), 3.96 (s, 3H),
2.80 (s, 4H), 1.77 (d, J ¼ 6.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
168.5, 154.3, 150.6, 148.4, 139.3, 131.2, 107.9, 107.1, 56.6, 56.4,
25.4, 21.9; MS (ESI): m/z: calcd for C15H16N2O9 [M + NH4]+:
368.1200; found 386.1184.
Experimental section
Materials
All reagents were purchased from commercially available
sources such as Aldrich or TCI and used without further puri-
cation. Dichloromethane (DCM) was distilled from CaH2
before use, and NEt3 (TEA) was redistilled from CaH2 and dried
over KOH pellets.
Characterizations
Proton and carbon nuclear magnetic resonance (1H, 13C NMR)
spectra were recorded on a Bruker Avance 500 (400 MHz)
spectrometer. Mass spectra were recorded on a Micromass
Synthesis of photo-responsive nitrobenzyl modied
polyetherimide amphiphilic polymers (PEN)
GCTTM and a Micromass LCTTM. Irradiations were carried out To a solution of polyethyleneimine (50 mg, 0.002 mmol) and
using a CHF-XM-500 W lamp with 365 nm lter. Absorption triethylamine (0.1 mL, 0.7 mmol) in dry DCM (20 mL), NBN
spectra were recorded on a Shimadzu UV-2550 UV-vis spec- (71 mg, 0.19 mmol, P/N ¼ 6; 61 mg, 0.166 mmol, P/N ¼ 7; 53 mg,
trometer. A NICOMP zetasizer measuring at a xed scattering 0.14 mmol, P/N ¼ 8, P/N ¼ the molar ratio of amine groups in
3334 | J. Mater. Chem. B, 2014, 2, 3333–3339
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PEI to NBN) which was dissolved in 5 mL DCM was added shaken at 37 ꢀC on a shaking table at 200 rpm, and at different
slowly. The reaction was stirred at room temperature overnight time intervals, 300 mL of the medium was taken out for analysis
and concentrated in a vacuum. Reprecipitation in diethyl ether by UV-vis spectroscopy with an ultra-micro cell and then
3 times gave the product as a yellowish solid.
returned to the medium.
The drug loading efficiency ¼ (the quality of loading drug/the
quality of polymer) ꢂ 100%
Synthesis of nitrobenzyl and dithiodipropionic acid modied
polyetherimide dual-responsive polymer (PENS)
In 50 mL of pH 9.0 buffer solution, 50 mg PEN was dispersed to
constitute the micelle solution. To that solution, 3,30-dithiodi-
propionic acid (47 mg, 0.22 mmol), NHS (67 mg, 0.58 mmol)
and EDC$HCl (134 mg, 0.67 mmol) were added. The reaction
was stirred at room temperature for 24 h and dialyzed (molec-
ular weight cut off 3500) in deionized water for another 48 h.
Lyophilisation of the dialysate gave the product as a yellowish
solid.
The drug release efficiency ¼ (the quality of release drug/the
quality of loading drug) ꢂ 100%
Results and discussion
As shown in Scheme 2, the o-nitrobenzyl containing NBN
compound was synthesized from 3,4-dimethoxyacetophenone
in three steps by (1) nitration by conc. HNO3 under the catalysis
Photo-responsive behaviour study of PEN
The photo-responsive behaviour of PEN was studied by irradi- of acetic anhydride; (2) the reduction reaction by NaBH4; (3) an
ating its solution (0.1 mg mLꢁ1 in DCM) in a quartz cuvette with activating reaction using N,N0-disuccinimidyl carbonate. All the
a CHF-XM-500 W lamp with a lter of 365 nm with intensity of compounds were well prepared and characterized.
15 mW cmꢁ2. Photolysis data was collected by directly
The polymer PEN was prepared by the nucleophilic substi-
measuring the UV-vis absorption spectra of the solution in the tution reaction between the photosensitive NBN compound and
cuvette between certain time intervals of irradiation.
polymer PEI and puried by reprecipitation in diethyl ether 3
times. Here, three different feed ratios of PEI to NBN with P/N
ratios (the molar ratio of the amine groups of PEI to NBN) at 6, 7
and 8 were used. Taking the feed ratio P/N ¼ 6 as an example,
the real P/N was determined to be 6.67 by the 1H NMR spectrum
recorded in CDCl3 (Fig. 1), which was calculated from the
integral ratio of peaks a and b (7.4 and 7.0 ppm, assigned to the
aromatic ring protons of NBN) to that of multi-peaks f (around
3.0 ppm, assigned to the alkyl chain protons of PEI).
The successful conjugation between NBN and PEI also could
be conrmed by FT-IR and UV-vis spectra. As shown in Fig. 2a,
the FT-IR spectrum of PEN (feed ratio P/N ¼ 7) not only
preserved the characteristic peaks of PEI, but also showed the
characteristic stretching vibration peak at 1705 cmꢁ1 of
carbonyl groups, the linking bond between NBN and PEI.
Moreover, the presence of other peaks at 1674, 1518 and 1273
cmꢁ1, belonging to benzene and nitro groups of NBN, further
suggested the successful conjugation between NBN and PEI. In
the UV-vis absorption spectra as shown in Fig. 2b, the appear-
ance of the maximum absorption at 350 nm of PEN, originating
from the NBN chromophore, also conrmed the successful
“AND” logic-responsive behaviour study of PENS
The “AND” logic-responsive behaviour of PENS was determined
by the analysis of DLS. The cross-linked micelle of PENS were
immersed in different buffer solutions with a concentration of
0.1 mg mLꢁ1. The buffer solutions used here were prepared as
follows: (1) 10 mM of phosphate buffer (pH ¼ 7.4) for the
conditions of [ꢁhn, ꢁGSH]; (2) 10 mM of phosphate buffer
(pH ¼ 7.4) and GSH (10 mM) for the conditions of [ꢁhn, +GSH];
(3) 10 mM of phosphate buffer (pH ¼ 7.4) and irradiation at 365
nm for 8 min for the conditions of [+hn, ꢁGSH]; and (4) 10 mM
of phosphate buffer (pH ¼ 7.4), GSH (10 mM) and irradiation at
365 nm for 8 min for the conditions of [+hn, +GSH]. For each
experiment, the solution was shaken at 37 ꢀC on a shaking table
at 200 rpm for 24 h and the obtained solution was measured
by DLS.
The loading and release of anti-tumour drug doxorubicin
(DOX)
The loading of DOX was undertaken by adding a DMF solution constitution of photosensitive polymer PEN.
(1 mL) of 10 mg PENS and 4 mg DOX to 9 mL deionized water,
The photocleaving of the o-nitrobenzyl phototrigger in PEN
the unloaded drug was removed by dialyzing (molecular weight was checked by the evolution of UV absorption upon light
cut-off: 3500) in deionized water for 48 h. Then, the remainder irradiation. Based on the photolysis mechanism for o-nitro-
was lyophilized to give the nal anti-tumour drug loaded PENS. benzyl phototriggers,33–35 PEN was photolyzed to yield the
The DOX release proles in different conditions were parent PEI, one molecule of carbon dioxide and corresponding
determined by the dialysis technique. The DOX loaded PENS nitroso ketone derivatives as photo byproducts (as shown in
(1 mg) was dispersed in 10 mL pH 7.4 buffer to form the drug Fig. 3a). The photolysis process of the PEN with feed ratio P/N ¼
loaded micelle solution. 4 ꢂ 2 mL of the above solution was 7 was initiated by irradiating the DCM solution of PEN (0.1 mg
placed within four dialysis tubes (molecular weight cut-off: mLꢁ1) with 365 nm UV light (15 mW cmꢁ2) and explored by UV
3500), respectively, followed by dialysis against different buffer spectroscopy. As shown in Fig. 3b, with the increase of irradi-
solutions as described above for the “AND” logic-responsive ation time, the UV absorption of PEN at 291 nm decreased
behaviour study of PENS. For each experiment, the solution was rapidly and a new peak at 380 nm appeared and increased due
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Scheme 2 Synthesis procedure for NBN, PEN and PENS: (a) HNO3–(CH3CO)2O, rt, 5 h, 61% yield; (b) NaBH4–CH3OH, rt, 1 h, 86% yield; (c) N,N0-
disuccinimidyl carbonate–TEA–CH3CN, rt, overnight, 80% yield; (d) PEI–TEA–DCM, rt, overnight; (e) 3,30-dithiodipropionic acid–EDC$HCl–
NHS, rt, 24 h.
Fig. 1 1H NMR spectrum of the photo-responsive polymer PEN with
feed ratio P/N ¼ 6.
to the formation of the nitroso ketone photo product,36,37 which
suggested the photolysis of the nitrobenzyl phototrigger pro-
ceeded effectively and gradually. Aer 8 min irradiation, there
were no more changes in the spectra, suggesting the achieve-
ment of maximum photocleavage. Thus, to ensure the complete
photoreaction of the phototrigger, all the illumination experi-
ments for the photo-responsive study of the micelles were set at
8 min.
Based on the amphiphilic character, the NBN containing
polymer PEN would self-assemble into polymeric micelles in
water which had a hydrophobic core and hydrophilic shell. To
Fig. 2 (a) FT-IR and (b) UV-vis spectra of polymer PEI and PEN (feed
ratio P/N ¼ 7).
further stabilize and introduce a reductive response into the
micelles, 3,30-dithiodipropionic acid was used to couple with
the outer amine groups of PEN in the presence of EDC and NHS
(as shown in Scheme 2). The nal formation of crosslinked
micelles of PENS with excellent water dispersion was proved by
the S wt% from XPS analysis. According to the different feed
ratios of P/N, three PENS polymers were constituted and
assigned as PENS6, PENS7 and PENS8, respectively. The details
of the content characterization are listed in Table 1.
To investigate the reductive and light responses of the
crosslinked PENS micelles, the micelles were exposed to GSH
and irradiation with UV 365 nm light respectively and simul-
taneously, because the disulde bond of the crosslinkers can be
cleaved through the thiol–disulde exchange reaction upon
3336 | J. Mater. Chem. B, 2014, 2, 3333–3339
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Table 2 The “AND” logic responsive change in diameters (nm) of PENS
with different P/N ratios
[ꢁhn, ꢁGSH]
[ꢁhn, +GSH]
[+hn, ꢁGSH]
[+hn, +GSH]
[1, 1]
[0, 0]
[0, 1]
[1, 0]
PENS6
PENS7
PENS8
194
230
680
193
227
780
308
360
903
892
2980
1763
diameter of the micelles. This should be attributed to their
amphiphilic nature, in which PEI is a hydrophilic polymer and
the higher content of hydrophobic NBN would induce more
compact aggregates, thus forming stable micelles with smaller
diameters. In the presence of GSH, namely in the [0, 1] state, the
disulde bonds were broken but the polymers were still
amphiphilic as with PEN which would help support their
micelle morphologies (as illustrated in Scheme 1). As expected,
the diameters of the micelles in the [0, 1] state were similar to
the original diameters except for PENS8 (Table 2). When
changed to the [1, 0] state, namely only upon light irradiation,
the hydrophobic nitrobenzyl phototrigger was cleaved from the
polymer but the crosslinked structure with disulde bonds
physically prevented the collapse of the micelles (Scheme 1). As
summarized in Table 2, the diameters of the micelles increased
about 110–130 nm compared with their original state, which
was still the OFF state for the micelles. When light and GSH
were input simultaneously, namely the [1, 1] state, both the
hydrophobic nitrobenzyl phototrigger and disulde were
Fig. 3 Illustration of the photolysis of polymer PEN with feed ratio P/N
¼ 7: (a) the proposed photolysis mechanism; (b) evolution of the UV-
vis absorption spectra as a function of irradiation time. Light source is a
CHF-XM-500 W lamp at wavelength of 365 nm with intensity of 15 mW
cmꢁ2
.
Table 1 The P/N ratios of the different corresponding PEN and S wt% cleaved, which induced the disassembly of the polymers as
of different PENS
illustrated in Scheme 1. The DLS analysis showed a signicant
increase in the diameters, especially for PENS7, it increased 13
P/Na (mol)
P/Nb (mol)
S%c (wt)
S%d (mol)
times that of the ones with no stimulus. Meanwhile, trans-
mission electron microscopy (TEM) measurements of PENS7 in
different conditions also exhibited similar results. As shown in
Fig. 4, the morphology of the micelles was retained with the
single photo or GSH stimulus, and only degraded when treated
with both the two stimuli. This huge variation for micelles made
PENS7 promising as a carrier for constructing an “AND” logic
responsive drug release system.
PENS6
PENS7
PENS8
6
7
8
6.67
7.14
8.06
5.11
7.03
7.82
7.37
10.26
11.35
Feed ratio. b Determined by 1H NMR spectroscopy. c Measured by XPS.
Calculated by XPS.
a
d
addition of GSH and the hydrophobic nitrobenzyl chromophore
An anti-cancer drug DOX was selected as the drug model to
can be cleaved upon 365 nm irradiation. Firstly, the PENS explore the controlled drug release behaviour of our PENS7
micelles were added into buffer solution containing 10 mM of micelles. The loading of DOX was prepared by mixing PENS7
GSH. In these conditions, the stimuli was just the reductive and DOX in DMF directly, and then slowly adding to deionized
signal [ꢁhn, +GSH], the input signal of the logic gate system was water to form drug-loaded micelles. Aer dialysis and lyophili-
set as 0 and 1 when GSH concentrations were 0 and 10 mM, sation, drug loaded PENS7 micelles were obtained and the drug
respectively. Then, UV 365 nm light with intensity of 15 mW loading efficiency was determined to be 39% calculated from
cmꢁ2 was employed as the other input signal and also dened the UV absorption standard curve of DOX. Fig. 5 illustrated the
as
0 and 1 without and upon irradiation, respectively. drug release proles of DOX loaded PENS7 micelles in different
Controlled by these two input signal, the stimuli-responsive conditions. In the [0, 0] state, without light and GSH stimuli, the
behaviour of the micelles was characterized by dynamic light leaking of DOX was less than 20% within 50 h. With only GSH
scattering (DLS). As shown in Table 2, in the [0, 0] ([ꢁhn, ꢁGSH]) stimulus in the [0, 1] state, the release of DOX was similar to
state, the average hydrodynamic diameters were about 194 nm that in the [0, 0] state, suggesting no more drug was released in
for PENS6, 230 nm for PENS7 and 680 nm for PENS8, respec- the presence of GSH. When changed to the [1, 0] state with light
tively. Obviously, the different P/N ratios greatly affected the irradiation, the DOX release amount was about 35% within 50
diameters of the PENS micelles, and the higher the graed h. It should be attributed to the slightly increased diameters of
content of nitrobenzyl phototriggers on PEI, the smaller the the micelles in this state that induced greater release of the
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containing linkers to constitute an “AND” logic responsive
polymer PENS. With a single photo or reductive stimulus, the
diameters of the PENS micelles changed a little; while the
micelles disassembled when both photo and reductive stimuli
were applied simultaneously. Aer physiologically encapsu-
lating the hydrophobic drug DOX, the drug release of the PENS
micelles also exhibited “AND” logic responsive properties; the
optimal drug release efficiency was achieved only when the
input signal was the [1, 1] state, which showed potential
applications in targeted delivery.
Acknowledgements
This work was supported by NSFC (51273064, 21373084), The
State Key Development Program for Basic Research of China
(2013CB733700), The Program for Professor of Special
Appointment (Eastern Scholar), Innovation Program of
Shanghai Municipal Education Commission and Fundamental
Research Funds for the Central University.
Fig. 4 TEM images of PENS7 with different stimuli.
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drug. Only when the input signal turned to [1, 1] did the DOX
release achieve the highest value and the release amount
increased to 86% within 50 h. Although the drug release cannot
be controlled in perfect ON and OFF states, this “AND” logic
responsive release exhibited 4 times the release efficiency than
the ones without any stimulus. We can speculate that this
controlled release system would work effectively in tumour
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