A NIR light-triggered drug delivery system using core-shell gold nanostars-mesoporous silica nanoparticles based on multiphoton absorption photo-dissociation of 2-nitrobenzyl PEG

Article abstract of DOI:10.1039/c9cc04260a

Gold nanostars coated with a mesoporous silica shell and functionalized with poly(ethylene glycol) containing photolabile 2-nitrobenzyl moieties are able to release doxorubicin after NIR light irradiation at low power irradiance via a multiphoton absorpti

Full text of DOI:10.1039/c9cc04260a

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Alfonso, M. Orzáez, M. D. Marcos, R. Martinez-Manez and F. Sancenón, Chem. Commun., 2019, DOI:
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DOI: 10.1039/C9CC04260A
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NIR light-triggered drug delivery system using core-shell gold
nanostars-mesoporous silica nanoparticles by multiphoton
absorption photo-dissociation of 2-nitrobenzyl PEG
Received 00th January 20xx,
Accepted 00th January 20xx
Andy Hernández-Montoto,a,b Mónica Gorbe,a,b,c Antoni Llopis-Lorente,a,b José Manuel Terrés,a
Roberto Montes,a Roberto Cao-Milán,d Borja Díaz de Greñu,a,b María Alfonso,a,b Mar Orzaez,c,e
María Dolores Marcos,a,b,c,f Ramón Martínez-Máñez,*a,b,c,f Félix Sancenóna,b,c,f
DOI: 10.1039/x0xx00000x
Gold nanostars coated with
a mesoporous silica shell and overcome this shortcoming, multiphoton absorption of near
functionalized with poly(ethylene glycol) containing photolabile 2- infrared (NIR) radiation is an appealing alternative when using
nitrobenzyl moieties are able to release doxorubicin after NIR light photo-labile molecules.8 However, photoreactions activated by
irradiation at low power irradiance via a multiphoton absorption this process have some drawbacks such as low multiphoton
photo-dissociation process.
absorbing cross sections of most chromophores and the need
of using high laser powers.9,10 As an alternative, it has been
reported that electric field enhancement produced by
quantized oscillation of collective electrons in metal
nanoparticles allows overcoming the required high irradiances
for multiphoton absorption of organic molecules.11,12 For
instance, it has been described that excitation of localized
surface plasmons of gold nanostars (AuNSts) in NIR region
leads to strong electromagnetic field enhancement taking
place at their sharp tips13 which favour multiphoton
absorption in molecules near to the surface of the
nanoparticle. However, this concept has been barely studied
for drug delivery applications and as far as we know, photo-
delivery systems based on NIR light triggered multiphoton
molecular dissociation of photo-labile molecules using core-
shell AuNSts-MS nanoparticles have not been reported yet. In
fact, developing materials with enhanced optical and drug
delivery properties14-17 is a hot topic in nanotechnology.
The development of smart delivery systems1,2 able to release
an entrapped payload upon application of specific stimuli has
attracted much attention in recent years due to their potential
application in biomedicine, in recognition/sensing and in
communication protocols.3,4 Among drug nanocarriers,
mesoporous silica (MS) supports are especially appealing
because of their unique properties, such as chemical stability,
high loading capacity, low cost and biocompatibility.
Moreover, MS can be functionalized with (bio)chemical or
supramolecular ensembles, which allow the development of
stimuli-responsive systems able to release an entrapped cargo
in the presence of certain and well-defined physical, chemical
or biochemical stimuli.5
In this field, gated nanodevices for controlled release of
loaded drugs in response of light irradiation has attracted
great attention because cargo release can be defined spatially
and temporally by fine-tuning the area and time of the light
stimulus.5 A common approach in light-triggered gated MS is
the use of photo-labile molecules that have been used for
remote activation and release of loaded drugs.6 However,
molecular photo-dissociation involves high energy radiations
limiting their use in realistic applications.7 In order to
Based on the above-mentioned facts, we report herein the
combination of the well-known properties of MS to design
capped materials for drug delivery applications and AuNSts as
NIR light sensitizer able to induce multiphoton molecular
dissociation. Our design uses an AuNSts core coated with a
mesoporous silica shell (AuNSt@mSiO2). The pores of the
AuNSt@mSiO2 support are loaded with doxorubicin (Dox) and
then, the external surface functionalized with
a bulky
a. Instituto Interuniversitario de Investigación de Reconocimiento Molecular
y
Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de
València. E-mail: rmaez@qim.upv.es
poly(ethylene glycol) (PEG) derivative containing a photo-labile
2-nitrobenzyl linker (N2 nanoparticles in Scheme 1).18,19 NIR
irradiation of N2 induces photo-dissociation of 2-nitrobenzyl
linker at low power irradiance via a multi-photonic excitation
process, with the subsequent detachment of the bulky PEG
derivative from the surface of the nanoparticles and release of
Dox from the mesoporous shell. Studies with N2 internalized in
b. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN).
c. Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y
Nanomedicina. Universitat Politècnica de València-Centro de Investigación
Príncipe Felipe, Valencia, Spain.
d. Facultad de Química, Universidad de La Habana, 10400 La Habana, Cuba.
e. Centro de Investigación Príncipe Felipe, Laboratorio de Péptidos y Proteínas,
Carrer d'Eduardo Primo Yúfera, 3, 46012 València, Spain.
f. Departamento de Química, Universitat Politècnica de València, Camino de Vera
s/n, 46022 Valencia, Spain.
HeLa cells demonstrate that NIR irradiation induced
a
Electronic Supplementary Information (ESI) available: Synthesis, procedures,
characterization, and additional experiments. See DOI: 10.1039/x0xx00000x
remarkable reduction in cell viability due to a synergistic
combination of chemotherapy (via AuNSts-mediated light-
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induced uncapping and Dox release) and hyperthermia (due to nanoparticles exhibited a peak at 2θ = 2.21o, which could be
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the presence of the AuNSts and the transformation of light to indexed to (100) diffraction plane of aDhOeI:x1a0g.1o0n3a9/lCu9nCiCt0c4e2l6l0.2A5
heat).
This peak also suggested the presence of radial mesopore
channels and an ordered mesostructure (Figure S1a).26 In the
wide-angle PXRD pattern, four Au diffraction peaks were
clearly discerned at 2θ = 38.15, 44.36, 64.61 and 77.60o, which
can be assigned to (111), (200), (220), and (311) reflections of
the face-centred cubic gold lattice, respectively.27 Moreover,
N2 adsorption-desorption isotherms of AuNSt@mSiO2-NH2
nanoparticles showed a typical Type IV curve for mesoporous
materials.28 The average pore size was 2.5 nm, whereas the
BET surface area and total pore volume were calculated to be
252 m2/g and 0.31 cm3/g, respectively (Figure S1b).22,27,29
Scheme 1 NIR light triggered drug delivery system N2 based on
AuNSt@mSiO2 nanoparticles capped with photo-labile PEG derivative
containing a 2-nitrobenzyl linker.
OH
NO2
O
O
O
O
Br
NO2
O
O
HNO3
Ac2O
NaBH4
THF
Na2CO3 / DMF
O
O
O
O
O
O
O
O
O
OH
1
O
2
OH
PEG-NH2
EDC, HOBt
3
OH
O
Figure 1 (a,b) TEM images of AuNSt@mSiO2-NH2 and (c,d) N2
nanoparticles (Scale bars: (a,c) 100 nm; (b,d) 20 nm); (e) Optical
extinction spectra of AuNSt@mSiO2-NH2 (black line) and N2
nanoparticles (red line); (f) Hydrodynamic diameter and (g) zeta
potential distributions of AuNSt@mSiO2-NH2 (black line) and N2 (red
line) nanoparticles by DLS.
OH
NO2
O
HO
O
O
O
O
NO2
O
DMAP
O
O
O
O
PEG
O
PEG
4
N
5
N
H
H
Scheme 2. Synthesis of photolabile PEG derivative 5 bearing a 2-
nitrobenzyl linker.
Once prepared, AuNSt@mSiO2-NH2 nanoparticles were
loaded with Dox and the pores were capped by an amidation
reaction between the amino groups onto the loaded support
and the photo-labile PEG derivative 5 using EDC/NHS to
activate the carboxylic acid moiety (N2 nanoparticles). Bulky
PEG was expected to act as gatekeeper preventing drug
release from mesoporous shell.18,19 Aqueous suspensions of
N2 nanoparticles showed a strong LSPR absorption band at
875 nm (see Figure 1e). Besides, hydrodynamic diameter and
zeta potential measurements of nanoparticles by DLS (Figures
1f and 1g) showed an average hydrodynamic diameter for
AuNSt@mSiO2-NH2 of 296 nm, which increased to 301 nm for
N2 after functionalization of the external surface with the PEG
derivative. On the other hand, the zeta potential decreased
from +35.7 (for AuNSt@mSiO2-NH2) to -26.5 mV (for N2)
(Figure 1g). Besides, the organic content in N2 nanoparticles
was calculated to be 15 % by TGA (Figure S3).
For the preparation of N2, the photo-labile molecule 5,
bearing a 2-nitrobenzyl linker with a carboxylate group and a
bulky PEG moiety, was synthesized from vanillin (Scheme 2).20
On the other hand, AuNSts were obtained by the seeded
growth method using polyvinylpyrrolidone (PVP) solution in
N,N-dimethylformamide (DMF).21 This procedure is based on
-
the chemical reduction of AuCl4 complexes by DMF and the
subsequent deposition of gold atoms in the presence of PVP
on spherical gold nanoparticles (AuNPs), acting as seeds.
Nanostars with size of 120 nm were synthesized using seeds
(AuNPs) of 15 nm. AuNSt@mSiO2-NH2 nanoparticles were
obtained by a process in which AuNSts were directly coated
with a mesoporous silica shell using a surfactant-templated
synthesis
and
then
functionalized
with
(3-
aminopropyl)triethoxysilane.22,23 The process was carried out
under inert atmosphere to avoid gold oxidation and core
reshaping in presence of CTAB.24 Small angle powder X-ray
After the synthesis and characterization of the hybrid
nanocarrier, NIR light-triggered photo-release of doxorubicin
from N2 nanoparticles was studied. For this purpose, an
diffraction
(PXRD)
patterns
of
AuNSt@mSiO2-NH2
2 | J. Name., 2012, 00, 1-3
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aqueous N2 suspension was irradiated at 808 nm using a laser irradiated with a laser at 1 W cm-2. After irradiation, cells were
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at low power irradiance (1 W cm-2)30 whereas a control sample further incubated for 48 h and ceDllOIv:i1a0b.1i0li3t9y/Cw9CaCs04t2h6e0nA
was kept in the dark. At scheduled times, samples were evaluated. The obtained results are shown in Figure 2c. As
centrifuged (to remove the nanoparticles) and the emission of could be seen, the viability of HeLa cells treated with N2 and
Dox released to the solution at 595 nm was measured (λexc
=
irradiated with NIR light at low power irradiance (1 W cm-2)
490 nm). The obtained results are shown in Figure 2a. As could decreased to ca. 25%. This could be due to either, the photo-
be seen, a fast and remarkable release was observed (ca. 70% dissociation of 2-nitrobenzyl linker with subsequent PEG
of the total Dox delivered after 60 min) when N2 nanoparticles detachment and Dox delivery, or hyperthermia. In order to
were irradiated with NIR light (red curve), whereas in the evaluate the independent contribution of both effects, HeLa
absence of irradiation the Dox release was lower than 20% cells were incubated with N2empty nanoparticles (similar to N2
(black curve). The observed Dox release upon irradiation of N2 but without payload) under the same conditions as above. As
suspensions with NIR light was ascribed to the AuNSts- could be seen in Figure 2c, upon NIR light irradiation, HeLa
mediated photo-cleavage of the 2-nitrobenzyl linker located in cells viability only decreased to ca. 85%, which is ascribed to
the PEG capping ensemble. As a consequence, PEG was hyperthermia. Therefore, cells treated with N2 nanoparticles
detached from the surface with subsequent pore opening and and then irradiated with a laser at 1 W cm-2 reduced viability
payload release from the mesoporous shell.
by a synergistic combination of hyperthermia (ca. 15%) and
chemotherapy (ca. 60%).
(a)
a)
(b)
(c)
Figure 2 (a) Cumulative release of Dox from N2 in the presence (red)
and absence (black) of NIR light; (b) Cell viability of HeLa cells in the
presence of N2 nanoparticles at different concentrations; (c) Cell
viability of HeLa cells in the presence of N2 and N2empty nanoparticles
at 100 µg mL-1 upon 808 nm laser irradiation (red bars) or without any
NIR light treatment (black bars).
b)
As
a further step, the potential application of N2
nanoparticles in cells was evaluated. In a first step, the
internalization of N2 nanoparticles in HeLa cells was tested
using transmission electron microscopy (TEM) measurements.
TEM images showed an efficient nanoparticle uptake after
incubation of HeLa cells with a N2 suspension in DMEM (Figure
S4). In a second step, the viability of HeLa cells in the presence Figure 3 (a) NIR light triggered release of Dox from N2 nanoparticles in
of N2 nanoparticles at different concentrations (10, 50 and 100 HeLa cells monitored by confocal laser scanning microscopy. From left
µg mL-1, as relevant range recommended for the study of MS to right: DNA marker (Hoechst 33342), doxorubicin (Dox) and
toxicity)31 for 48 h was assessed using WST-1 assay. The combined (merge) fluorescence channels. From top to down: control
obtained results (Figure 2b) demonstrated that N2 showed no cells (control), non-irradiated cells after incubation with nanoparticles
cytotoxicity to HeLa cells up to concentrations of 100 µg mL-1, (N2), and cell irradiated with NIR light after incubation with
thus demonstrating that Dox was efficiently entrapped inside nanoparticles (N2 + Laser). Scale bars: 100 µm. (b) Quantification of
the mesoporous silica shell in the nanoparticles.
the Dox intensity delivered from N2 nanoparticles by confocal images
Once assessed the non-toxicity and the efficient uptake of analysis.
N2 nanoparticles by HeLa cells, we carried out in vitro NIR
light-triggered Dox release studies. In a typical experiment,
Moreover, NIR light-triggered release of Dox from N2
HeLa cells were incubated with N2 nanoparticles and then nanocarriers in HeLa cells was demonstrated by confocal laser
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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2
3
4
5
6
7
G. Bao, S. Mitragotri, S. Tong, Annu. Rev. Biomed. Eng. 2013,
scanning microscopy. For this purpose, HeLa cells were stained
with the DNA-marker dye Hoechst 33342 and the intracellular
delivery of Dox after laser irradiation (power density of 1 W
cm-2) was monitored. The obtained images are shown in Figure
3a. A negligible Dox fluorescence signal was observed in cells
treated with N2 nanoparticles in the absence of NIR radiation.
However, an increase of Dox fluorescence in HeLa cells was
found when irradiated with 808 nm NIR light (a marked 19-fold
enhancement was found Figure 3b). Control experiments with
N2empty were also carried out and shown in Figure S5. Besides,
it was also found that intracellular release of Dox from N2
nanoparticles could also be triggered by in situ irradiation at
633 nm using the confocal laser scanning microscope (Figure
S7). These results are consistent with the rupture of the 2-
nitrobenzyl linker located in the PEG derivative attached onto
the hybrid nanoparticle surface, as consequence of strong
electromagnetic field enhancement taking place at their sharp
tips in AuNSts that favour multiphoton absorption of the
photo-labile 2-nitrobenzyl linker32 (see additional discussion in
the SI). Thus, N2 nanoparticles can be a suitable platform for
NIR light-triggered drug delivery in therapy applications.
In this work a novel drug photo-delivery system based on
NIR light triggered photo-cleavage of a 2-nitrobenzyl linker,
located in a bulky PEG derivative, using gold nanostars coated
with a mesoporous silica shell (AuNSt@mSiO2) was developed.
The prepared nanodevice was able to release an entrapped
payload (Dox) upon irradiation with 808 nm light at low power
irradiance as a consequence of the multiphoton absorption
and dissociation, mediated by the AuNSts, of the photo-labile
PEG derivative used as capping ensemble. This is one of the
few reported MS nanoparticles able to deliver a cargo by using
multiphoton absorption and dissociation of a linker upon NIR
light irradiation. Besides, the prepared nanoparticles were
non-toxic to HeLa cells. However, a marked decrease in HeLa
cells viability (ca. 75%) was observed after N2 uptake and NIR
light irradiation due to a synergic effect of the Dox released
and hyperthermia. The methodology employed in this work
could be used to obtain other AuNSt@mSiO2 gated materials,
based in the photo-dissociation of certain linkers at low power
irradiance via a multi-photonic excitation process, for drug
delivery applications.
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The authors gratefully acknowledge financial support from
the Spanish Government (projects RTI2018-100910-B-C41 and
RTI2018-101599-B-C22 (MCUI/AEI/FEDER,UE)), the Generalitat
Valenciana (Project PROMETEO2018/024) and European Union
(Programme European Union Action 2-Erasmus Mundus
Partnerships, GRANT AGREEMENT NUMBER-2014-0870/001-
001). A. H. thanks Erasmus Mundus Programme for his PhD
scholarship at EuroInkaNet project.
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Conflicts of interest
There are no conflicts to declare.
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