A novel glutathione-Triggered theranostic prodrug for anticancer and imaging in living cells

Article abstract of DOI:10.1039/c8ra00271a

A novel theranostic prodrug was designed and synthesized by conjugating a naphthalimide derivative with Vitamin D₂via a disulfide linker. The prodrug featured a highly selective detection process for glutathione (GSH) and showed a red-shifted f

Full text of DOI:10.1039/c8ra00271a

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A novel glutathione-triggered theranostic prodrug
for anticancer and imaging in living cells†
Cite this: RSC Adv., 2018, 8, 11419
Hengrui Zhang and Zhijie Fang
*
Received 10th January 2018
Accepted 7th March 2018
A novel theranostic prodrug was designed and synthesized by conjugating a naphthalimide derivative with
vitamin D via a disulfide linker. The prodrug featured a highly selective detection process for glutathione
(GSH) and showed a red-shifted fluorescence within 30 min. Notably, it also exhibited antitumor activity
similar to vitamin D and could be monitored by cellular imaging.
2
DOI: 10.1039/c8ra00271a
2
rsc.li/rsc-advances
As an important sterol, vitamin D plays a critical role in
calcium homeostasis and bone mineralization and also
Theranostics is an emerging technology, which is dened as regulates the proliferation and differentiation of various
1
Introduction
2
3–27
a combination of therapy and diagnostic imaging. Due to its types of cancer cells.
However, there has been no report
potential to be targeted in a specic manner to the site of about vitamin D-based theranostic prodrug before. Inspired
disease and reduce or eliminate the possible numerous unto- by this and as continuation of our study, herein, we report
2
ward side effects, theranostics has attracted considerable a novel theranostic prodrug, which can release vitamin D in
1,2
attention. Until now, various imaging techniques have been the presence of GSH and exhibit distinct uorescence
3
28–30
used for theranostics, such as ultrasound, computed tomog- variation.
4
5
raphy (CT), positron emission tomography (PET) and
magnetic resonance imaging (MRI). However, these methods
always suffered from some drawbacks, including poor resolu-
tion and high costs. In contrast to these conventional methods,
6
2
2
Results and discussion
.1 Design and synthesis of prodrug
7
naphthalimide-based uorescence imaging has been devel-
The theranostic prodrug was designed using three elements. (1)
A naphthalimide derivative served as uorescent reporter,
which could be synthesized conveniently from the corre-
sponding 1,8-naphthalic anhydrides by reacting with ethyl-
amine. (2) A disulde linker that could be cleaved by GSH with
high sensitivity and rapid response. (3) An anticancer drug
oping rapidly due to the advantages of low cost, convenient
8–11
preparation and high resolution.
Biological thiols including glutathione (GSH), cysteine (Cys)
and homocysteine (Hcy) always play crucial roles in biological
12–17
systems.
An abnormal level of biothiols could be an indi-
cator in many diseases. Given that cancer cells have much
higher intracellular glutathione (GSH) concentration than
normal cells and tissues, considerable efforts have been devoted
2
vitamin D , which could be used to regulate gene expression in
functions as varied as calcium and phosphate homeostasis,
cancer cell growth regulation and differentiation.
Treatment of 4-bromo-1,8-naphthalic anhydride in DMF
with sodium azide at room temperature provided the
18–20
to the development of GSH-activatable prodrugs.
Due to its
high sensitivity and rapid response to the disulde bond, GSH
has been broadly utilized as a trigger to cleave the disulde-
containing prodrug and release the active drug. For instance,
Zhou et al. designed and synthesized a prodrug for cancer
treatment by conjugating a naphthalimide derivative and
compound 2. It was then reduced with H and 10% Pd/C as
2
catalyst to afford the compound 3. Without any purication,
the obtained naphthalic anhydride was condensed with eth-
ylamine to give the key intermediate 4, which was then reacted
with triphosgene and 2,2-dithiolethanol to afford compound
21
chlorambucil (CLB) via a disulde linker. Kim et al. also
conjugated a naphthalimide derivative with camptothecin
5
. Finally, the desired theranostic prodrug was obtained by
(
CPT) using a disulde linker, which was highly desirable for in
reacting compound 5 with vitamin D (Scheme 1). The struc-
2
1
22
situ uorescence-tracking of cancer chemotherapy.
13
ture of prodrug was characterized by H NMR, C NMR and
HRMS.
School of Chemical Engineering, Nanjing University of Science & Technology, 200 Xiao 2.2 Rapid optical response of the prodrug to GSH
Ling Wei, Nanjing 210094, P. R. China. E-mail: zjfang@njust.edu.cn
As expected, the prodrug displayed both colorimetric and
†
Electronic supplementary information (ESI) available: NMR spectra and
supplementary data spectra associated with this article can be found. See DOI:
0.1039/c8ra00271a

uorescence spectral changes upon the addition of GSH. When
1
GSH (200 mM) was added to the PBS/DMSO solution containing
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2.3 The optical pH range and selectivity of the prodrug for
GSH
Similar spectroscopic changes could be observed upon the
addition of other free thiols, such as Cys and Hcy. Moreover, the
presence of other analytes including amino acids and metal
ions induced small or no uorescence change (Fig. 2a).
However, since the concentration of Cys and Hcy was lower than
that of GSH in cytoplasm, the possible interference of Cys and
Hcy could be neglected. The uorescence intensity of the pro-
drug was unaffected over a wide pH range and indicated that
the prodrug was quite stable. When GSH (200 mM) was added to
the solution, a dramatic uorescence enhancement could be
observed over a pH range of 6–10 (Fig. 2b). These results
demonstrated that the prodrug can be applied as a GSH-
triggered prodrug in theranostic system with high selectivity
over various potential interferons.
3
Scheme 1 Synthesis of prodrug (a) NaN , DMF, 89.3%; (b) 10% Pd/C,
H
2
, DMF, 36 h, 80.1%; (c) ethylamine, ethanol, 4 h, 89.1%; (d) tri-
phosgene, triethylamine, 2-hydroxyethyl disulfide, DCM, 73.2%; (e)
triphosgene, triethylamine, vitamin D , 39.1%.
2
2.4 Proposed response mechanism of the prodrug for GSH
prodrug (10 mM), the absorption peak at 374 nm decreased
sharply, and a new band centered at 437 nm could be observed
The proposed mechanism of the prodrug for GSH was displayed
by a two-step reaction: cleavage of the disulde bond and
(Fig. 1a). Meanwhile, signicant uorescence turn-on signal
31–33
intramolecular cyclization (Scheme 2).
MS and spectro-
changes at 534 nm were observed. Thus, the solution revealed
strong yellow uorescence (Fig. 1b). The uorescence intensity
at 534 nm exhibited a good linear relationship with the GSH
concentration and the detection limit was 1.98 mM (Fig. 1c). In
addition, the uorescence intensity of prodrug at 534 nm
gradually increased to a plateau within 30 min (Fig. 1d). The
time-dependent release efficiency of prodrug in the presence of
GSH was displayed in Fig. S1.†
scopic studies were used to verify the hypothesis. First, the
spectra of compound 4 were consistent with that of the prodrug
aer the treatment with GSH, suggesting that compound 4 was
the product (Fig. S2†). Furthermore, ESI-MS titration experi-
ment was carried out to prove the anticipated release of vitamin
D . The peaks at m/z of 279.07 and 435.35 were observed, which
2
+
+
were attributed to [compound 4 + K] and [vitamin D
2
+ K]
(Fig. S3†). These results were indicative of the cleavage of the
Fig. 1 (a) UV-Vis spectra changes and (b) fluorescent spectra changes of prodrug (10 mM) before and after incubation with GSH (200 mM) in PBS/
ꢀ
DMSO (40 : 60, v/v, pH ¼ 7.4, 10 mM) at 37 C for 30 min. Fluorescence of prodrug in the absence (A) and in the presence (B) of GSH are inserted. (c)
Fluorescence intensity changes of prodrug (10 mM) at 534 nm upon the addition of different concentrations of GSH in PBS. Inset: the linear rela-
tionship between fluorescent intensity and GSH concentration (d) time dependence of fluorescence intensity of prodrug in the presence of GSH.
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3+
2+
3ꢁ
42ꢁ
Fig. 2 (a) Fluorescent spectra responses of prodrug for various analytes (1–14 represent: (1) Al , (2) Cu , (3) NO , (4) SO , (5) Leu, (6) Tyr, (7)
Arg, (8) Glu, (9) Lys, (10) Thr, (11) Ser, (12) Hcy, (13) Cys, (14) GSH). (b) The pH effect of the fluorescence intensity of prodrug in the absence and in
the presence of GSH. Each spectrum was collected after 30 min of mixing each analyte with prodrug in PBS/DMSO (40 : 60, v/v, pH ¼ 7.4, 10
ꢀ
mM) at 37 C.
2
Fig. 3 Antitumor activity of compound 5, vitamin D and prodrug on
HeLa cancer cells.
the cellular uptake and intracellular localization of prodrug
were investigated using a uorescence microscope. When HeLa
cells were incubated with the prodrug for 30 min, weak uo-
rescence from prodrug was observed, indicating that the pro-
drug was sufficiently activated by the high concentration of GSH
in cancer cells. To demonstrate the role of the GSH presented in
disulde cleavage, additional 1.0 mM prodrug was added to
HeLa cells and an enhanced uorescence was observed (Fig. 4).
These results were fully consistent with the design expectations
Scheme 2 Proposed response mechanism of the prodrug for GSH.
disulde group and the production of uorophore and vitamin
2
D in the sensing reaction.
2
.5 Antitumor activity evaluation and live cell imaging
The prodrug displayed good biocompatibility to HEK 293T cells
Fig. S4†). Inspired by above results, we further investigated the
practicability of the prodrug in biological systems by carrying
(
out antitumor activity and bioimaging experiments. To deter- Fig. 4 The upside: images of HeLa cells incubated only with the
prodrug (10 mM) for 30 min; (A) fluorescence image at the blue
2
mine the antitumor activity, vitamin D , compound 5 and pro-
channel, (B) fluorescence image at the green channel, (C) bright-field
image. The downside: images of HeLa cells incubated with GSH (1.0
mM) for 30 min, then treated with the prodrug (10 mM) for 30 min. (D)
Fluorescence image at the blue channel, (E) fluorescence image at the
drug were rst incubated with HeLa cells and then evaluated by
using typical MTT assays. Prodrug and vitamin D2 showed
similar antitumor activity against HeLa cell lines, while
compound 5 showed low activity for living cells (Fig. 3). Then, green channel, (F) bright-field image.
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ꢀ
and suggested that the prodrug can be used to monitor the drug stirred for 0.5 h at 0 C, following which triethylamine (1.7 mL)
release process in cancer cells.
was added and stirred for another 60 min. Then, 2-hydroxyethyl
disulde (2.8 mL) was added and stirred at room temperature to
obtain yellow precipitate. The precipitate was ltered and dried
3
Conclusion
1
to give compound 5 (1.3 g, 73.2%). H NMR (500 MHz, DMSO):
In summary, we developed a novel theranostic prodrug by d 10.29 (1H, s), 8.64 (1H, d, J ¼ 8.5 Hz), 8.40 (2H, m, J ¼ 7.7 Hz),
conjugating the naphthalimide chromophore and vitamin D
8.13 (1H, d, J ¼ 8.2 Hz), 7.76 (1H, s), 4.49 (2H, t, J ¼ 6.4 Hz), 4.05
via a disulde bond. This prodrug can discriminate GSH from (2H, d, J ¼ 7.1 Hz), 3.69 (2H, d, J ¼ 6.4 Hz), 3.14 (2H, t, J ¼ 6.4
2
1
3
a wide array of amino acids and ions. It also can be used to Hz), 2.90 (2H, t, J ¼ 6.4 Hz), 1.22 (3H, t, J ¼ 7.0 Hz) ppm;
C
quantify GSH with a detection limit as low as 1.98 mM and rapid NMR (126 MHz, DMSO): d 162.58, 162.02, 153.25, 139.97,
detection process for GSH within 30 min. In addition, this 130.89, 130.14, 128.60, 127.58, 125.62, 123.15, 121.53, 117.52,
prodrug displayed similar antitumor activity with vitamin D
and can be used for intracellular uorescence imaging. Overall,
2
116.44, 62.48, 58.92, 40.62, 36.22, 34.08, 12.58 ppm.
this prodrug can be used as a valuable research tool for GSH- 4.4 Synthesis of prodrug
activatable drug delivery system and can be easily monitored
by cellular imaging.
Compound 5 (0.2 g, 0.5 mmol) and triphosgene (0.62 g, 2.01
mmol) were dissolved in dichloromethane (30 mL) and stirred
ꢀ
for 0.5 h at 0 C, following which triethylamine (1.69 mL) was
4
Experimental procedures
added and stirred for another 60 min. Then, vitamin D
2
(0.2 g,
0.05 mmol) was added and stirred at room temperature until
4.1 Materials and apparatus
the reaction was complete. Finally, the mixture was concen-
trated under reduced pressure and puried by column chro-
matography on silica gel to obtain the prodrug (0.15 g, 39.1%).
All chemical reagents and solvents were purchased from
commercial suppliers and used without further purication. H
1
1
3
and C NMR spectra were obtained on Bruker Avance III 500
MHz spectrometer. HRMS spectra were obtained on a Bruker
ApexII by means of the ESI technique. Absorption and uores-
cence spectra were obtained on Lambda 35 UV-Vis spectropho-
tometer and a Shimadzu RF-5301PC Fluorescence Spectrometer,
respectively. All titrations were carried out in PBS/DMSO solu-
tion (40 : 60, v/v, pH ¼ 7.4).
1
H NMR (500 MHz, CDCl ): d 8.62 (1H, m, J ¼ 13.2 Hz), 8.33 (1H,
3
m, J ¼ 8.4 Hz), 7.84 (1H, s), 7.80 (1H, m), 6.19 (1H, d, J ¼ 11.2
Hz), 5.98 (1H, d, J ¼ 11.2 Hz), 5.17 (1H, m, J ¼ 7.4 Hz), 5.04 (1H,
s), 4.89 (1H, m), 4.55 (1H, t, J ¼ 6.1 Hz), 4.51 (1H, m), 4.24 (1H, q,
J ¼ 7.1 Hz), 3.15 (2H, m), 2.81 (1H, m), 2.60 (1H, m, J ¼ 13.4 Hz),
2
1
.40 (1H, m, J ¼ 6.2 Hz), 2.21 (1H, m), 2.08 (2H, m), 1.89 (1H, m),
.75 (3H, m), 1.52 (3H, m), 1.37 (5H, m), 1.05 (2H, m), 0.96 (6H,
1
3
m), 0.52 (2H, s) ppm; C NMR (126 MHz, CDCl ): d 162.96,
3
4
.2 Synthesis of compound 4
Initially, 4-bromo-1,8-naphthalic anhydride (10 g, 36.1 mmol)
was dissolved in DMF (50 mL) and then, NaN (3.5 g, 53.8 mmol)
162.46, 153.53, 152.12, 143.01, 141.77, 138.09, 134.59, 132.49,
1
6
3
1
31.17, 130.22, 127.87, 125.54, 122.12, 116.54, 112.20, 75.17,
4.62, 62.28, 55.43, 44.81, 41.82, 40.99, 39.39, 36.55, 35.73,
3
4.51, 32.12, 30.83, 28.06, 26.80, 22.58, 21.22, 20.13, 18.84,
was added into the solution. The mixture was stirred overnight
and added to water to obtain yellow precipitate. The precipitate
was ltered and dried to obtain compound 2 (7.6 g, 89.3%).
Compound 2 (5 g, 20.8 mmol) was dissolved in DMF (50 mL),
followed by the addition of 10% Pd/C (400 mg). Then, the
+
6.62, 12.39, 11.26 ppm. HRMS [M
842.3998, found 843.4071.
+
H] : calcd for
48 62 2 7 2
C H N O S
4.5 Absorption and uorescence spectroscopy
mixture was stirred under H atmosphere at room temperature
for 36 h. Aer ltration, water was added into the solution to
2
Stock solution of prodrug, vitamin D
2
and compound 4 (2.0 ꢂ
ꢁ3
10
M) was prepared in DMSO. Individually, stock solutions (1
obtain yellow precipitate. The precipitate was ltered and dried mM) of the analytes Cys, Hcy, GSH, leucine (Leu), tyrosine (Tyr),
to give compound 3 (3.5 g, 80.1%).
arginine (Arg), glutamic acid (Glu), lysine (Lys), threonine (Thr),
Compound 3 (3 g, 14.1 mmol) was dissolved in ethanol (160 and serine (Ser) were prepared in ultrapure water. For a typical
mL), following which ethylamine (4 mL) was added dropwise. optical study, the prodrug (10 mM) solution in PBS/DMSO
The mixture was reuxed for 4 h and then added to water to (40 : 60, v/v, pH ¼ 7.4, 10 mM) was prepared. Then, 3.0 mL of
obtain precipitate. The precipitate was ltered and dried to yield
compound 4 (3.7 g, 89.1%). H NMR (500 MHz, DMSO): d 8.51
the solution was placed in a quartz cuvette at room temperature.
1
For uorescent measurements, slit width was set at dex ¼ 3 nm,
(
1H, d, J ¼ 8.1 Hz), 8.30 (1H, d, J ¼ 7.2 Hz), 8.10 (1H, d, J ¼ 8.4
d
em ¼ 3 nm.
Hz), 7.65 (1H, m), 7.33 (2H, s), 6.76 (1H, d, J ¼ 8.4 Hz), 3.97 (2H,
1
3
d, J ¼ 7.1 Hz), 1.11 (3H, t, J ¼ 7.0 Hz) ppm; C NMR (126 MHz, 4.6 Cell incubation and imaging
DMSO): d 162.58, 152.11, 133.30, 130.34, 128.89, 123.37, 121.27,
HeLa cells used in this study were purchased from Cobioer
Biosciences Co., Ltd. (Nanjing, China). HEK 293T cells used in
this study were purchased from Chinese Academy of Sciences
118.82, 107.36, 33.68, 12.78 ppm.
4.3 Synthesis of compound 5
(Shanghai, China). HeLa cells were cultured in Dulbecco's
Compound 4 (0.5 g, 1.1 mmol) and triphosgene (1.2 g, modied Eagle's medium (DMEM) supplemented with 10%
ꢀ
4
.0 mmol) were dissolved in dichloromethane (30 mL) and fetal bovine serum (FBS) at 37 C in an atmosphere of 5% CO
2
.
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ꢀ
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