Tumor targeted gold nanoparticles for FRET-based tumor imaging and light responsive on-demand drug release

Article abstract of DOI:10.1039/c5tb01659b

In this work, a new type of gold nanoparticles (AuNPs) is designed to achieve the programmed tumor imaging and light manipulated controlled drug release. In vitro results demonstrate that these AuNPs undergo matrix metalloproteinase-2 (MMP-2) responsive fluorescence recovery of photosensitizers, protoporphyrin IX (PpIX), in the tumor region, which can differentiate tumor cells from healthy ones. Subsequently, light irradiation activates PpIX, which cleaves the reactive oxygen species (ROS) sensitive thioketal linker, leading to on-demand drug release as well as free drug diffusion into nuclei. More importantly, in vitro studies indicate the good performance of AuNPs in combined photodynamic therapy and chemotherapy with limited side effects. This AuNP based nanoplatform provides great potential for tumor targeted on-demand combination therapy.

Full text of DOI:10.1039/c5tb01659b

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Tumor targeted gold nanoparticles for FRET-based tumor imaging
and light responsive on-demand drug release
Received 00th January 20xx,
Accepted 00th January 20xx
Kai Han,a,b Jing-Yi Zhu,a Shi-Bo Wang,a Zi-Hao Li,a Si-Xue Chenga and Xian-Zheng Zhanga,
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
In this work, a new type of gold nanoparticles (AuNPs) is designed well designed nanovehicles to realize on-demand drug release
to achieve the programmed tumor imaging and light manipulated in tumor region.
controlled drug release. In vitro results demonstrate that these
Recently, imaging guided antitumor therapy provides a new
AuNPs undergo matrix metalloproteinase-2 (MMP-2) responsive strategy for on-demand therapy.14-17 For example, Wan et al.
fluorescence recovery of photosensitizer, protoporphyrin IX (PpIX), developed single-walled carbon nanohorns based theranostic
in tumor region, which can differentiate tumor cells from healthy agents for photoacoustic imaging guided near-infrared
ones. Subsequently, the light irradiation activates PpIX, which photothermal therapy.18 Shi et al. fabricated organic/inorganic
cleaves the reactive oxygen species (ROS) sensitive thioketal linker, hybrid vesicles for dual-modality imaging-guided high-intensity
leading to on-demand drug release as well as free drug diffusion focused ultrasound ablation.19 Generally, such a strategy aims
into nuclei. More importantly, in vitro study indicates the good at imaging the tumor tissue followed by providing the stimuli
performance of AuNPs in combined photodynamic therapy and to initiate a given therapy. However, these imaging techniques
chemotherapy with limited side effects. This AuNPs based are strongly dependent on fluorescence, thermal,
nanoplatform provides great potential for tumor targeted on- photoacoustic or magnetic resonance imaging (MRI) signals,20
demand combination therapy.
which are always “on” and constant, regardless of their
proximity or interaction with tumor tissues and cells.
Consequently, the limited target-to-background signal ratio
causes the difficulty in discernment of tumor tissue from the
healthy ones. On the other hand, in order to restrict side
effects furthest, the therapy modalities are usually limited to
local therapies, such as photothermal and ultrasound therapy.
Generally, inorganic materials, such as gold nanorods and
graphene, but not the chemical drugs were involved in the
therapy procedure. However, these local therapies are still far
away from practical applications. To our knowledge,
chemotherapy dominates antitumor therapy in clinical trials
currently. From the standpoint of medicine translation
potential, the ideal imaging guided therapy systems should
have properties with high resolution of tumor imaging as well
as tunable drug release in tumor tissue.
Satisfactory tumor therapy requires enhanced therapeutic
efficacy of drugs with minimized side effects.1,2 For this
purpose, fabrication of intelligent drug delivery vehicles that
can release drug on-demand in tumor tissue has attracted
great attention during the last decade.3-5 However, a great
many of the existing vehicles encapsulate drugs via
noncovalent forces, such as hydrogen bonding, hydrophobic or
π-π stacking interactions.6-9 These vehicles always suffer from
nonspecific drug leakage owing to the poor stability during
their circulation in biological systems,10 which leads to
disappointing targeted-therapy with severe systemic toxicity.
As an alternative, tumor microenvironmental activatable drug
delivery vehicles have been proposed to aim at “zero release”
of drugs in normal tissues 11,12
However, microenvironmental
,
difference between tumor tissues and normal tissues may not
be significant enough to differentiate the drug release
behavior. For instance, inflammation region was also slightly
acid.13 All these issues highlight the urgency of construction of
Benefited from the fluorescence “ON/OFF” transformation,
fluorescence resonance energy transfer (FRET) technique has
been widely used in biomarker detection and imaging with
high signal/noise ratio.21 In particular, FRET-based matrix
metalloproteinase-2 (MMP-2) detection and imaging have
attracted extensive research interest, since MMP-2 plays key
roles in tumor growth, progression, metastasis, as well as
dysregulated angiogenesis.22
In this study, we designed and fabricated multifunctional
AuNPs with MMP-2 responsibility for programmed FRET-based
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Fig. 1 TEM images of (A) Au-β-CD NPs and (B) Au/PpIX/DOX NPs.
would be beneficial to achieve enhanced sensitivity for tumor
biomarkers detection.
To determine the appropriate quencher/fluorophore ratio,
the fluorescence quenching and recovery behaviors of Au/PpIX
NPs and Au/DOX NPs were studied. Unlike the traditionally
fluorescence quenchers which could only quenched limited
fluorescent molecules owing to the spectral overlapping
Scheme 1 (A) Surface functionalization of Au-β-CD NPs via host-guest interaction, and
both the fluorescence of PpIX and DOX were quenched by Au-β-CD NPs via FRET; (B)
MMP-2 responsive PpIX detachment and imaging in tumor region; (C) cellular
internalization of freed PpIX and Au/DOX NPs by tumor cells; (D) light irradiation
triggered TK cleavage and on-demand DOX release; (E) apoptosis of tumor cells efficiency, Au as the quencher has great capability in
quenching various fluorophores.24 As shown in Fig. 2A, the
mediated by chemotherapy and photodynamic therapy.
fluorescence of PpIX could be efficiently quenched via FRET
tumor imaging and light responsive on-demand drug release. when the concentration of AuNPs was increased to 7.44 mg/L.
As shown in Scheme 1, PEGylated PpIX was conjugated to Meanwhile, the quenched fluorescence did not increase with
AuNPs using Pro-Leu-Gly-Val-Arg (PLGVR) peptide sequence as prolonging time (Fig. 2C). Once MMP-2 was added, the
a MMP-2 responsive linker, while doxorubicin (DOX) was fluorescence of PpIX increased dramatically (Fig. 2B), indicating
anchored on AuNPs through a reactive oxygen species (ROS) the rapidly hydrolysis of PLGVR sequence and detachment of
sensitive linker, thioketal (TK). Nonfluorescence nanoparticles PpIX.25 These rapid MMP-2 responsiveness was due to the
(denoted as Au/PpIX/DOX NPs) were obtained via host-guest small size of Au/PpIX NPs as mentioned above. Note that F0/Ft
interaction. Au/PpIX/DOX NPs that arrived at MMP-2 ratio was nearly 40 when Au/PpIX NPs were incubated with
overexpressed tumor region could liberate quenched PpIX, MMP-2 for 4 h (Fig. 2D), suggesting the high PpIX quenching
realizing the tumor tissue imaging. After cellular capability and sensitive response to MMP-2. In addition,
internalization, light irradiation was performed to break TK similar results were found when Au/DOX NPs were incubated
linker, which released DOX and ensured the free diffusion to with H2O2, which was chosen to simulate the ROS environment.
nuclei. This programmed imaging-guided on-demand drug Clearly, high sensitive fluorescence OFF/ON phenomenon was
release strategy may allow a combined photodynamic therapy observed in Fig. 2E-H, suggesting DOX could be quenched by
and chemotherapy with improved selectivity and efficiency.
β-cyclodextrin-SS (β-CD-SS) modified Au nanoparticles were presence of ROS, resulting in the release of DOX.26
synthesized (designated as Au-β-CD NPs) via NaBH4
Subsequently, in order to investigate the feasibility of
AuNPs and the thioketal link could be breakdown in the
reduction.23 The structure of β-CD-SS was characterized by Au/PpIX/DOX NPs in MMP-2 responsive imaging and light
electrospray ionization mass spectrometry (ESI-MS, Fig. S1A). initiated on-demand drug release, the programmed
Thermal gravimetric analysis (TGA) indicated that the weight fluorescence recovery of Au/PpIX/DOX NPs under MMP-2 and
loss value of Au-β-CD was around 20.0% at 443 ºC (Fig. S1B). light irradiation was measured. Au/PpIX/DOX NPs were
Transmission electron microscopy (TEM) image revealed that incubated with MMP-2 for 4 h and subsequently treated by
Au-β-CD NPs exhibited uniform size around of 7 nm (Fig. 1A). 630 nm light irradiation. It was found that the fluorescence of
Subsequently, Ac-PEG8-K(PpIX)DPLGVRD3K(Ad)-CONH2 and Ad- both PpIX and DOX were quenched well by Au-β-CD NPs (6.52
PEG-TK-DOX were synthesized (Scheme S1, ESI-MS in Fig. S2 mg/L) (Fig. 2J). Once MMP-2 was added, fluorescence of PpIX
and Fig. S3) and mixed with Au-β-CD NPs by vigorous stirring. increased quickly with time prolonging, while the fluorescence
Au/PpIX/DOX NPs with a typical core-shell structure formed of DOX was unchanged. 4 h later, the solution received 630 nm
via host-guest interaction between adamantine (Ad) and β-CD. laser irradiation. As expected, the fluorescence of DOX also
TEM observation indicated that surface functionalization did increased rapidly (Fig. 2K). It should be pointed out that the
not induce observable change in morphology (Fig. 1B). In the fluorescence recovery capability of DOX was lower than that of
current study, the small size of Au-β-CD NPs could facilitate the PpIX to some extent, since the sulfhydrylation of DOX occurred
fabrication of Au/PpIX/DOX NPs with good stability via the during the breakage of thioketal linker, and the steric
host-guest interaction. In addition, these AuNPs with small size hindrance caused by β-CD modification could not prevent the
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Fig. 2 Fluorescence quenching behaviors of (A) PpIX and (E) DOX by adding various amounts of Au-β-CD NPs. Fluorescence recovery of Au/PpIX NPs (B) in the presence of MMP-2
or (C) absence of MMP-2. Fluorescence recovery of Au/DOX NPs (F) in the presence of H2O2 or (G) absence of H2O2. F0/Ft ratios of (D) Au/PpIX NPs and (H) Au/DOX NPs
with/without corresponding stimulation at preset times. (I) Scheme of the programmed fluorescence recovery. Fluorescence recovery of Au/PpIX/DOX NPs (J) in the presence of
MMP-2 and (K) subsequently treated with light irradiation.
a striking biomarker is upregulated in many types of tumor
tissues. The fluorescence recovery of PpIX in cellular level was
determined by confocal laser scanning microscope (CLSM). As
shown in Fig. 3B1, only extremely low red signal of PpIX was
observed in normal COS7 (African green monkey SV40-
transfected kidney fibroblast cell line). In contrast, significant
PpIX fluorescence was found in SCC-7 (squamous cell
carcinoma cell line) (Fig. 3A1). Furthermore, quantitative result
of released PpIX was also determined via fluorescence
spectrum. The contents of released PpIX were 0.22 ± 0.02
mg/L and 0.08 ± 0.02 mg/L in SCC-7 cells and COS7 cells,
respectively. SCC-7 cells were known for their high MMP-2
expression. Clearly, the elevated fluorescence intensity and
content of PpIX in SCC-7 cells was owing to the hydrolysis of
Fig. 3 MMP-2 responsive fluorescence recovery of Au/PpIX/DOX NPs in (A1-A3) SCC-7
PLGVR peptide sequence by the overexpressed MMP-2, which
cells and (B1-B3) COS7 cells. Red signal: PpIX; A2 and B2: bright field; A3 and B3:
led to exfoliation of PpIX from Au core as well as the
merged field. The scale bar was 10 μm while the micrographs were obtained at a
fluorescence recovery. In other words, this fluorescence
magnification of 600 ×.
recovery was realized by recognition of MMP-2 overexpressed
tumor cells. More importantly, the recognition of tumor cells
interaction between Au and sulfhydrylation DOX completely.
could minimize the side effects of photodynamic therapy since
Taken together, the Au/PpIX/DOX NPs could achieve
ROS and the PDT effect was initiated via light irradiation in the
programmed fluorescence recovery with the stimulation of
tumor region.
MMP-2 and light irradiation.
To demonstrate that Au/PpIX/DOX NPs possessed capability
Encouraged by the good MMP-2 responsive fluorescence
of on-demand drug release, the fluorescence recovery and
quenching/recovery ability of Au/PpIX/DOX NPs, we expected
cellular localization of DOX were observed via CLSM.
that Au/PpIX/DOX NPs could differentiate MMP-2
Au/PpIX/DOX NPs were incubated with SCC-7 cells for 5 h and
overexpressed tumor cells from healthy ones, since MMP-2 as
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Fig. 5 (A) Cell viability of Au/PpIX/DOX NPs in COS7 and SCC-7 cells under 30-min light
irradiation.(B) Cell viability of Au/PpIX NPs in SCC-7 cells under 30-min light irradiation.
(C) Cell viability of Au/DOX NPs in SCC-7 cells. *p < 0.05, when the group was compared
with COS7 cells treated with Au/PpIX/DOX NPs with 30-min light irradiation as
determined by a Student’s t-test.
different MMP-2 expression levels of SCC-7 and COS7 cell-lines
(3.44 ± 0.18 ng/mL and 0.87 ± 0.17 ng/mL in culture medium
respectively, which was determined via enzyme-linked
immuno sorbent assay). As mentioned above, the
overexpressed MMP-2 enzyme in culture medium of SCC-7
cells hydrolyzed the PLGVR peptide sequence and released
PpIX. After cellular internalizaiton, the following light
irradiation not noly activated the photodynamic therapeutic
efficacy of freed PpIX but also broke down the TK linker, which
liberated the quenched DOX and ensured the free access to
nuclei.
Fig. 4 Light irradiation mediated fluorescence recovery of DOX when Au/PpIX/DOX NPs
were incubated with SCC-7 cells. (A1-A3) SCC-7 cells with 30 min light irradiation; (B1-
B3) SCC-7 cells without light irradiation. Red signal: DOX; blue signal: Hochest 33342;
A3 and B3: merged field. The scale bar was 10 μm while the micrographs were
obtained at a magnification of 600 ×. Fluorescence intensity profile analysis of DOX (red
line) and Hoechst 33342 (blue line) according to (C) A3 and (D) B3, respectively, across
the arrowed white line.
then replaced with 10% FBS. Thereafter, SCC-7 cells were
treated by 30-min light irradiation and further incubated for 7
h to allow the free diffusion of DOX. As shown in Fig. 4B1, the
red signal in SCC-7 cells without light irradiation was very weak,
suggesting the DOX could be efficiently quenched by Au-β-CD
NPs, and the leakage of DOX during endocytosis was negligible.
However, when SCC-7 cells were treated by light irradiation,
the red signal increased dramatically (Fig. 4A1). It was due to
the fact that cleavage of TK linker occurred under light
irradiation, leading to the emission of red fluorescence from
free DOX. Besides, it was found that part of red fluorescence
was overlapped with the Hoechst-stained cell nuclei (Fig. 4A3),
indicating free DOX entered cell nuclei. The fluorescence-
intensity-profile analysis also confirmed this result in Fig. 4C. In
contrast, across the arrowed line in Fig. 4B3, DOX (red line)
and cell nuclei (blue line) were basically sperated while red
signal of DOX was very weak (Fig. 4D). Considering that the
nucleus pore was very small, Au/PpIX/DOX NPs could not enter
the nuclei with ease. The noninvasive light irradiation
manipulation realized on-demand drug release in tumor cells,
which would show great advantages in reducing side effects.
Furthermore, MTT assay was determined to evaluate the
antitumor therapeutical efficacy of Au/PpIX/DOX NPs. As
shown in Fig. 5A, Au/PpIX/DOX NPs exhibited great cytotoxicity
in SCC-7 cells when 30-min light irradiation was performed. For
comparision, toxicity of Au/PpIX/DOX NPs in COS7 cells was
observably decreased. This result was attributed to the
Since both PpIX and DOX were widely used antitumor drugs,
the combination therapy of PpIX and DOX in SCC-7 cells was
also evaluated. Au/PpIX NPs and Au/DOX NPs were empolyed
as the controls. As mentioned above, Au/PpIX/DOX NPs
exhibited great cytotoxicity. In contrast, although the toxicity
of Au/PpIX NPs was dose-dependent (Fig. 5B), the toxicity of
Au/PpIX NPs was significantly lower than Au/PpIX/DOX NPs.
Meanwhile, Au/DOX NPs had very limited toxicity (Fig. 5C),
since the nuclear pore was less than 9 nm,27 the capability of
entering nuclei of Au/DOX NPs was weaker as compared with
free DOX, leading to the low toxicity. All these results
substantially demonstrated the well tumor targeted
combination therapeutic efficacy.
Conclusions
In summary, we designed and fabricated functional
Au/PpIX/DOX NPs for tumor triggered imaging and light
manipulated on-demand drug release in tumor cells. These
Au/PpIX/DOX NPs realized tumor recongnition by MMP-2
responsive PpIX fluorescence recovery. Subsequently, light
irradiation liberated of DOX, guaranteeing the free diffusion to
nuclei. In vitro results indicated that Au/PpIX/DOX NPs
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24 S. Lee, E. J. Cha, K. Park, S. Y. Lee, J. K. Hong, I. C. Sun, S. Y.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (51125014, 51233003 and 51273165), the
Ministry of Science and Technology of China (2011CB606202),
the Natural Science Foundation of Hubei Province of China
(2013CFA003).
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Graphical abstract
Multifunctional AuNPs with MMP-2 responsive tumor imaging and on-demand drug release were designed. Well combined
chemotherapy and photodynamic therapy with minimized side effects was realized.

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