Stabilized vesicles consisting of small amphiphiles for stepwise photorelease via UV light

Article abstract of DOI:10.1021/la203829d

A small amphiphile consisting of hydrophilic tetraethylene glycol monoacrylate and hydrophobic alkyl chain which were connected by an o-nitrobenzyl unit, a photolabile group, was designed and synthesized. The critical aggregate concentration of the synthesized amphiphile was determined to be about 3 × 10^-5 M by the fluorescence probe technique. Nanosized vesicles were prepared and stabilized by in-situ radical polymerization without altering the morphology. The polymeric vesicle was highly stable which retained vesicular shape under dilution or UV irradiation. Hydrophobic guests can be encapsulated within the vesicle membrane and released out of the vesicle by UV stimulus through splitting the amphiphilic structure of the amphiphile. Distinguished dose-controlled photorelease of the polymeric vesicle is achieved due to the maintenance of the vesicular shape integrity which makes the guest release depend on the cleavage amount of amphiphilic structure during UV irradiation. This study provides a promising strategy to develop stable drug delivery systems for sustained and phototriggered release.

Full text of DOI:10.1021/la203829d

Article
pubs.acs.org/Langmuir
Stabilized Vesicles Consisting of Small Amphiphiles for Stepwise
Photorelease via UV Light
Jianming Dong, Yi Zeng,* Zhiqing Xun, Yongbin Han, Jinping Chen, Ying-Ying Li, and Yi Li*
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: A small amphiphile consisting of hydrophilic tetra-
ethylene glycol monoacrylate and hydrophobic alkyl chain which were
connected by an o-nitrobenzyl unit, a photolabile group, was designed
and synthesized. The critical aggregate concentration of the synthesized
amphiphile was determined to be about 3 × 10−5 M by the fluorescence
probe technique. Nanosized vesicles were prepared and stabilized by in-
situ radical polymerization without altering the morphology. The
polymeric vesicle was highly stable which retained vesicular shape
under dilution or UV irradiation. Hydrophobic guests can be
encapsulated within the vesicle membrane and released out of the
vesicle by UV stimulus through splitting the amphiphilic structure of the
amphiphile. Distinguished dose-controlled photorelease of the polymeric vesicle is achieved due to the maintenance of the
vesicular shape integrity which makes the guest release depend on the cleavage amount of amphiphilic structure during UV
irradiation. This study provides a promising strategy to develop stable drug delivery systems for sustained and phototriggered
release.
have been being made to the development of stable surfactant
drug carriers.22−24
INTRODUCTION
■
Over the past several decades, numerous nanosized self-
assembled systems have been developed in drug delivery,1,2
such as micelles, vesicles, capsules, nanotubes, and nano-
particles which can carry drugs, prolong circulation time of
drugs, and reduce systemic toxicity. Compared to the
conventional drug carriers, the drug delivery systems capable
of targeting and triggered release have received more attention
due to their improved therapeutic activity. Thus far, various
kinds of stimuli, such as pH,3−5 temperature,6−8 redox,9−11
light,12−15 gamma ray,16 and enzyme,17,18 have been explored
for triggered release in drug delivery systems. Stimuli-
responsive assemblies commonly undergo rapid dissociation
or morphology change as long as the stimuli are applied,
resulting in almost complete release of their payload suddenly
which is called burst or rapid release.19,20 Therefore, there is a
growing challenge to the spatially and temporally controlled
release in a sustained or dosage manner.14,21
Herein, we describe a rational design of stable nanoassembly
formed by photoresponsive small-molecule amphiphiles capa-
ble of highly controlled release. The prototype molecule 1 is
composed of a hydrophobic alkyl chain and a hydrophilic
tetraethylene glycol monoacrylate segment, which are con-
nected by a photocleavable o-nitrobenzyl group (Scheme 1).
The assembly behavior of the amphiphilic molecule was studied
by the fluorescence probe technique, dynamic light scattering
(DLS), scanning electron microscopy (SEM), and transmission
electron microscopy (TEM). The molecule 1 formed vesicular
assemblies in water, and the vesicle was stabilized by
polymerizing the terminal acrylate group. The encapsulation
and phototriggered release properties of the stabilized vesicle
were investigated by using a hydrophobic dye, Nile Red (NR),
as a model drug. Experimental data demonstrated that the
highly dose-controlled release was achieved by using the
stabilized vesicle with UV irradiation.
Organic approaches toward stimuli-responsive drug carriers
usually involve the assemblies of amphiphilic molecules, such as
polymers, dendrimers, peptides, and surfactants. In particular,
small amphiphiles (surfactant-type) have attracted widespread
attention due to their easy synthesis, biocompatibility, and
functional versatility.20−22 However, a disadvantage encoun-
tered in the application of surfactant assemblies is the relatively
low thermodynamic stability which leads to premature drug
leakage. One of the practical routes to overcome this drawback
is the utilization of polymerizable surfactants, and great efforts
EXPERIMENTAL SECTION
■
Materials. All chemicals were purchased from Alfa Aesar or Aldrich
or TCI and used without further purification, unless otherwise stated.
Milli-Q water (18.2 MΩ·cm) was used in aqueous experiments.
CH2Cl2 was distilled from CaH2, and THF was purified by distillation
from sodium with benzophenone.
Received: September 30, 2011
Revised: December 13, 2011
Published: December 15, 2011
© 2011 American Chemical Society
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(ppm), 8.66 (d, 1H), 8.26 (m, 1H), 7.68 (d, 1H), 6.43 (d, 1H), 6.17
(dd, 1H), 5.83 (d, 1H), 4.84 (s, 2H), 4.52 (t, 2H), 4.29 (t, 2H), 3.85−
3.65 (m, 12H). IR (KBr pellet, cm−1): 2917.5, 2360.5, 1725.9, 1621.1,
1538.0, 1265.6. HRMS(ESI): calcd [M + Na]+ m/z 512.0532; found
512.0526.
Scheme 1. Synthetic Route and Photolysis of
Photoresponsive Amphiphile 1
Synthesis of Amphiphile 1. DBU (0.76 g, 5 mmol, dissolved in 5
mL of ethyl acetate) was added to 15 mL of ethyl acetate solution of
dodecanoic acid (1.0 g, 5 mmol) and compound 3 (2.45 g, 5 mmol)
over 10 min. The reaction mixture was stirred at 50 °C for 1 h in a
nitrogen atmosphere. The resulting solution was poured into water
and extracted with CH2Cl2. The organic layer was dried over
anhydrous magnesium sulfate. The solvent was removed in a rotary
evaporator, and the crude product was purified by silica gel column
chromatography eluting with a mixture of petroleum ether:ethyl
1
acetate (2:1 v/v) to yield 2.2 g (72%) 1 as light yellow oil. H NMR
(400 MHz, CDCl3): δ (ppm), 8.73 (d, 1H), 8.31 (m, 1H), 7.69 (d,
1H), 6.43 (d, 1H), 6.15 (dd, 1H), 5.84 (d, 1H), 5.55 (s, 2H), 4.54 (t,
2H), 4.30 (t, 2H), 3.86−3.66 (m, 12H), 2.43 (t, 2H), 1.68 (m, 2H),
1.2 (m, 16H), 0.9 (t, 3H). IR (KBr pellet, cm−1): 2924.5, 2360.6,
1728.3, 1622.7, 1538.7, 1275.6. HRMS (ESI): calcd [M + Na]+ m/z
632.3047, found 632.3048.
Determination of CAC by Fluorescent Probe. A certain
amount of stock solution of Nile Red in CH2Cl2 was added in vials,
and the solvent was removed by a N2 stream. A series of solutions of
amphiphile 1 with different concentrations were added to the vials and
sonicated for 3 h. The excess Nile Red was filtered, and then the
solution was examined with fluorescence spectrometer.
Preparation of Vesicles. 0.4 mL of amphiphile 1 chloroform
solution (10−2 M) was added to a test tube and dried in vacuum. 40
mL of water was added to the test tube and sonicated at 55 °C for 1 h.
Then vesicles were formed, and the solution was stored at room
temperature overnight for test.
Polymerization of Vesicles. An appropriate amount of stock
aqueous solution of 2,2′-azobis(2-amidinopropane hydrochloride)
(AAPH) was added to the vesicle sample giving an initiator/monomer
mole ratio of 0.02. The vesicle solution was shaken vigorously and
flushed with nitrogen for 1 h to ensure the initiator distribution
uniformly. Polymerization was carried out at 60 °C for 40 h under a
nitrogen atmosphere. The solution was cooled down to room
temperature and ready for next experiments.
Encapsulation of Nile Red in Vesicles. The excess amount of
Nile Red CH2Cl2 solution (0.6 mg/mL) was injected to the aqueous
solution of vesicles. The mixture was sonicated for 10 min at room
temperature. The organic solvent and the precipitated NR were
removed by evaporation and filtration, respectively.
Instruments. IR spectra were recorded on a Varian Excalibur 3100
spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were performed on a Bruker Avance Π-400 spectrometer. ESI mass
spectra were obtained from a Waters LCT Premier XE apparatus. UV/
vis absorption and fluorescence emission spectra were run on a
Shimadzu UV-1601PC spectrometer and a Hitachi F-4500 spec-
trometer, respectively. Dynamic light scattering measurements were
performed using a Malvern Zetasizer 3000HS. The turbidity
measurement was carried out on a Shimadzu UV-1601PC
spectrometer. The SEM images were obtained from a Hitachi S-
4300 scanning electron microscope operated at 10 kV. The TEM
images were recorded by a JEM200CX or a FEI TECNAI F20
transmission electron microscope performed at 200 kV. Photolysis and
photorelease experiments were carried out by using a mercury lamp
equipped with a long-pass filter with cutoff wavelength at 315 nm, and
the light intensity before the sample vessel was ca. 12 mW/cm2.
Synthesis of Compound 2. 3-Nitro-4-(bromomethyl)benzoic
acid was prepared according to the literature25 and obtained as light
yellow needles: mp 129 °C. 1H NMR (400 MHz, DMSO-d6): δ (ppm)
10.8 (s, 1H), 8.6 (d, 1H), 8.2 (d, 1H), 7.8 (d, 1H), 4.9 (s, 2H).
Synthesis of Compound 3. N,N′-Dicyclohexylcarbodiimide
(DCC, 4.5 g, 22 mmol, dissolved in 20 mL of distilled CH2Cl2) was
slowly added to 30 mL of CH2Cl2 solution of tetraethylene glycol (5.9
g, 30 mmol), acrylic acid (1.0 g, 13.9 mmol), and a catalytic amount of
4-(dimethylamino)pyridine (DMAP) under vigorous stirring at 0 °C.
The reaction mixture was stirred for 1 h in an ice bath and then
brought to room temperature over 24 h. After that, the reaction
mixture was filtered, and the solvent was removed in a rotary
evaporator. The crude product was purified by silica gel column
chromatography eluting with a mixture of ethyl acetate:methanol (50:1
v/v) to yield 2.1 g (51%) of colorless oil. 1H NMR (400 MHz,
CDCl3): δ (ppm) 6.44 (d, 1H), 6.18 (dd, 1H), 5.84 (d, 1H), 4.41 (t,
2H), 4.13 (t, 2H), 3.74−3.58 (m, 12H), 2.4 (s, 1H). IR (KBr pellet,
cm−1): 3438.2, 2877.3, 2360.1, 1723.9, 1636.1, 1104.0. HRMS (ESI):
calcd [M + Na]+ m/z 271.1158; found 271.1147.
Transmittance Experiment. The solution of vesicle sample was
stored in a quartz cuvette and irradiated for different times with a
medium−high mercury lamp. The optical transmittances at 500 nm
were recorded on a Shimadzu UV-1601PC spectrometer after different
UV irradiation times.
RESULTS AND DISCUSSION
■
The amphiphilic molecule 1 was synthesized through several
simple reactions, such as esterification, bromination, and
nucleophilic substitution, involving 4-methylbenzoic acid,
tetraethylene glycol, and lauric acid which are common stuff
in daily chemical industry. The o-nitrobenzyl group was chosen
as the photocleavable unit, owing to its capabilities of
controlled cleavage as a photolabile linker for solid phase
synthesis26 and caged compounds for biological applications.27
Upon UV irradiation, the intramolecular rearrangement of o-
nitrobenzyl leads to a cleavage of amphiphile 1 (Scheme 1).
The assembly behavior of amphiphile 1 was investigated in
water by using Nile Red, a hydrophobic fluorescence dye used
for probing polarity or effective dielectric constant of
microenvironments.31,32 The fluorescence emission of NR is
very low in water due to the polar environment and its poor
solubility. Once the Nile Red molecule is sequestered within a
Synthesis of Compound 4. DCC (0.82 g, 4 mmol, dissolved in 5
mL of distilled CH2Cl2) was slowly added dropwise to 20 mL of
CH2Cl2 solution of 3-nitro-4-(bromomethyl)benzoic acid (1.04 g, 4
mmol), compound 3 (1.0 g, 4 mmol), and DMAP (0.043 g, 0.35
mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C and then
reacted at room temperature over 24 h. The product was collected
after filtration. The solvent was removed in a rotary evaporator, and
the crude product was purified by silica gel column chromatography
eluting with a mixture of petroleum ether:ethyl acetate (3:2 v/v) to
1
yield 1.76 g (90%) as colorless oil. H NMR (400 MHz, CDCl3): δ
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hydrophobic environment, such as micelles or the membrane of
vesicles, its fluorescence intensity increases dramatically and
experiences a slight hypsochromic shift. The fluorescence
spectra of Nile Red (λex = 560 nm) in aqueous solution of
amphiphile 1 of different concentrations are illustrated in
Figure 1. A plot of the fluorescence intensity at 625 nm versus
was adopted to be the polymerizable unit and attached to the
end of the hydrophilic chain of amphiphile 1. The polymer-
ization of the vesicle was achieved by radical polymerization
using 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH) as
a hydrophilic thermal initiator.28 As presented in Figure 3, the
Figure 3. TEM image of the vesicles after polymerization.
TEM image shows that the aggregate of amphiphile 1 remained
vesicular structure after polymerization, and only the diameter
of the vesicle decreased slightly (ca. 236 nm by DLS, Figure
S1b), which can be attributed to the closer stacking of
polymerized bilayer. The stability of polymeric vesicles was
tested by simply diluting the vesicle solution to the
concentration below CAC or adding tetrahydrofuran (50%
THF in volume) to the aqueous solution. The unpolymerized
vesicles dissociated immediately once THF was added, while
the polymeric vesicles existed stably without significant
diameter change at the beginning (Figure S1c) and then
swelled gradually and dissolved completely in about 1 h,
suggesting that the stability of vesicles has been dramatically
improved by the polymerization.
Figure 1. Fluorescence spectra of Nile Red (λex = 560 nm) in aqueous
solutions with amphiphile 1 of different concentrations. Inset shows
the emission intensity at 625 nm versus the logarithm of concentration
of amphiphile 1.
the logarithm of concentrations of amphiphile 1 shows a
nonlinear relationship and the abrupt increase in emission at a
certain concentration indicates the formation of aggregates.
The critical aggregate concentration (CAC) was determined to
be 3 × 10−5 M from the extrapolated intersection of two linear
regions of the plot. The dynamic light scattering result further
confirmed that amphiphile 1 formed aggregates in water with
an average hydrodynamic diameter (Dh) of ca. 258 nm (Figure
S1a). SEM and TEM were also used to characterize the
morphology of the aggregates derived from amphiphile 1. As
shown in Figure 2, the microscopic images reveal that the
The photoinduced cleavage of amphiphile 1 in polymeric
vesicles exposed to UV irradiation (λ > 315 nm) was monitored
by observing the absorption changes of the vesicle solution. As
shown in Figure 4a, irradiation of the polymeric vesicle solution
Figure 2. (a) SEM and (b) TEM images of the vesicles formed by
amphiphile 1 in aqueous solution. Insets show the magnified
photographs of the vesicle.
amphiphile 1 formed spherical aggregates in water with a
diameter of about 250 nm which is consistent with the DLS
result. Moreover, the TEM image shows an obvious contrast
between the periphery and the central area of the sphere,
indicative of the formation of vesicles in aqueous solution. The
average wall thickness of vesicles obtain from the magnified
TEM image is about 6 nm, which is approximately twice length
of a single optimal molecule 1 (3.5 nm obtained by Hyperchem
molecular model), demonstrating that the vesicle membrane is
a bilayer structure.
Figure 4. (a) Absorption spectra of polymeric vesicles upon UV
irradiation. (b) Optical transmittance of different vesicle solutions as a
function of UV irradiation time. SEM images of (c) unpolymerized
vesicles and (d) polymeric vesicles after UV irradiation for 60 min.
with UV light resulted in a continuous drop of the absorption at
∼315 nm and a slight increase ∼350 nm, which originate from
the formation of 2-nitrosobenzaldehyde, a byproduct of the
As mentioned above, the instability of vesicles consisting of
small amphiphiles can be overcome by taking the advantage of
polymerization of amphiphile. In this approach, acrylate group
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cleavage reaction. This result gives the evidence that the
photocleavage of amphiphile 1 occurs effectively in the
polymeric vesicle, indicative of the application potential of
the vesicle for photocontrolled release.13,29 Furthermore, the
stability of unpolymerized/polymeric vesicles during the UV
irradiation was also examined. The optical transmittance at 500
nm of the polymerized and the unpolymerized vesicle solutions
was monitored at various irradiation times (Figure 4b). The
transmittance of the unpolymerized vesicle solution increased
rapidly within the first 30 min of irradiation and reached a
plateau when prolonging the irradiation time, suggesting the
dissociation of unpolymerized vesicles due to the photocleavage
of amphiphile 1. By contrast, the transmittance of the polymeric
vesicle solution only showed slight increase upon sufficient UV
light exposure, implying an evident stability enhancement of
vesicles due to the polymerization of acrylate. SEM images were
also obtained to reveal the different appearances of the two
kinds of vesicles after UV irradiation (Figure 4c,d). The
unpolymerized vesicles were entirely destroyed by UV
exposure, while the polymeric one retained the shape integrity
according to the TEM image (Figure S3) although the
amphiphilic structure of amphiphile 1 was broken by UV
irradiation, which were consistent with the optical trans-
mittance measurements.
light was shut down the release process was ceased with no
significant leakage of dye, showing a stepwise-release fashion as
demonstrated in Figure S5. The stair height of the curve
denoted the amount of NR expelled out of the vesicle which
was dependent on the irradiation time. This result reveals that
the polymerization makes vesicles not only shape-persistent but
also guest molecule-sequestered even when part of the
amphiphile structure has already been broken by UV
irradiation. In contrast, the absorption of NR in the
unpolymerized vesicle solution showed a steep decrease at
the first irradiation period and reached a plateau only after three
irradiation periods, and its release profile is shown in Figure S5.
This phenomenon is understandable that the vesicles under-
went the dissociation when the amphiphile was cleaved by UV
irradiation, resulting in a NR abrupt release and much fewer
stimuli-responsive cycles. Apparently, the temporal controlled-
release performance of the polymeric vesicle is much better
than the unpolymerized one according to the data above.
Therefore, a stepwise release of hydrophobic guests from the
polymeric vesicle can be easily achieved by splitting demanded
amount of amphiphilic parts through repeating the UV
exposure and the subsequent dark condition, implying the
application potential of polymeric vesicle for a dose control
carrier. A visual expression of the photocontrolled release
process of the stabilized vesicle is shown in Figure 5.
After the stabilized vesicle was obtained, the light-triggered
release properties of the polymeric vesicles were investigated by
using hydrophobic dye NR as a model payload. The
encapsulation and the release process can be explored by
monitoring the NR absorption of the vesicle solution because
NR is solubilized in vesicles and the solubility of NR in water is
negligible. After the solution of polymerized vesicles was
treated with NR, the solution showed a typical absorption of
NR with maximum at ∼550 nm, indicating the loading of NR
into the hydrophobic interior of vesicle membranes. Irradiation
of the vesicle solution with λ > 315 nm UV light led to a
gradual drop in the absorption spectra of solution as depicted in
Figure S4a, which indicated that NR was being released out of
the vesicle. During the photocleavage, the amphiphilic structure
of amphiphile 1 is split and lauric acid is possibly expelled out
of the vesicle membrane because of its higher CAC in water
(∼0.025 M),30 while the vesicular structure still retains. The
release of hydrophobic guest is rationalized to the lower
accommodative capability due to the loss of hydrocarbon
components. In addition, the release of NR in unpolymerized
vesicles and the control experiment were carried out as
comparison. The absorption change of the polymeric vesicle
solution showed a smooth style over time of irradiation, while
the release process in unpolymerized vesicle was much faster
and reached a plateau in about 10 min, and the absorption
almost kept constant for the polymeric vesicle in the absence of
UV irradiation (Figure S4b). These results clearly substantiate
that the polymeric vesicle can release hydrophobic molecules
effectively and sustainedly as a consequence of splitting the
amphiphilic structure with UV light stimulus. Because the
photolysis amount of o-nitrobenzyl group is dependent on the
UV light dosage, the release of NR can be easily tuned and
controlled by adjusting the UV irradiation within a wide time
range.
Figure 5. Visual expression of the photocontrolled release process of
the stabilized vesicle.
CONCLUSION
■
A novel amphiphile with an acrylate tail and nitrobenzyl unit in
the middle, which is capable of polymerizing and photo-
cleavage, was designed and synthesized. The nanosized vesicles
formed by the synthesized amphiphile in water can be stabilized
by in-situ polymerization of the peripheral acrylate groups. The
polymeric vesicle with high stability can encapsulate hydro-
phobic guests within its membrane and release the cargo
through splitting the amphiphilic structure of the amphiphile by
UV irradiation. The release process from the polymeric vesicle
was smoother than that form the unpolymerized one and a
stepwise controlled-release profile was presented by simply
turning on/off the UV illumination, implying that a better
sustained controlled release of guests from the polymeric
vesicle. Such a promising approach provides potential
applications in stimuli-responsive and dose-controlled release
systems for drug delivery and other biological investigations.
We are currently studying new controlled-release assemblies
containing two-photon sensitive groups, which are more
appropriate for the applications in living systems.
To further evaluate the temporal controlled release of the
polymeric vesicle, the photorelease was investigated by
periodically turning on and off the UV illumination. A series
of evident drop of absorbance were generated due to the release
of encapsulated NR by each UV irradiation, and once the UV
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ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data of amphiphile 1, DLS data, TEM image,
and photorelease data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(31) Watkins, D. M.; SayedSweet, Y.; Klimash, J. W.; Turro, N. J.;
Tomalia, D. A. Langmuir 1997, 13, 3136.
(32) Jee, A. Y.; Park, S.; Kwon, H.; Lee, M. Chem. Phys. Lett. 2009,
477, 112.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yili@mail.ipc.ac.cn (Y.L.); zengyi@mail.ipc.ac.cn
(Y.Z.).
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Grants 20733007, 21103210,
21004072, 21002109, 21073215, and 21173245) and the
National Basic Research Program (Grant 2010CB934500) is
gratefully acknowledged.
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