Imaging and therapeutic applications of Zn(ii)-cryptolepine-curcumin molecular probes in cell apoptosis detection and photodynamic therapy

Article abstract of DOI:10.1039/d0cc00524j

Novel red Zn(ii) complex-based fluorescent probes featuring cryptolepine-curcumin derivatives, namely, [Zn(BQ)Cl₂] (BQ-Zn) and [Zn(BQ)(Cur)]Cl (BQCur-Zn), were developed for the simple and fluorescent label-free detection of apoptosis, an important biological process. The probes could synergistically promote mitochondrion-mediated apoptosis and enhance tumor therapeutic effects in vitro and vivo.

Full text of DOI:10.1039/d0cc00524j

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DOI: 10.1039/D0CC00524J
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Imaging and therapeutic applications of Zn(II)-cryptolepine-curcumin molecular
probes in cell apoptosis detection and photodynamic therapy
Qi-Pin Qin,*a,b,† Zu-Zhuang Wei,c,† Zhen-Feng Wang,a Xiao-Ling Huang, a Ming-Xiong Tan,a Hua-
Hong Zou*b, and Hong Liang*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Novel red Zn(II) complex-based fluorescent probes featuring anticancer agents has yielded limited success.9 Cryptolepine is
cryptolepine-curcumin derivatives, namely, [Zn(BQ)Cl2] (BQ-Zn) a naturally occurring quindoline alkaloid10 that is extensively
and [Zn(BQ)(Cur)]Cl (BQCur-Zn), were developed for the simple used in antimalarial therapy.10 The synthesis of Zn(II)
and fluorescent label-free detection of apoptosis, an important complexes with mixed ligands could enhance their cytotoxicity;
biological process. The probes could synergistically promote to date, however, the design of Zn(II) complexes with
mitochondrion-mediated apoptosis and enhance tumor cryptolepine derivatives (BQ) or mixed H-Cur and BQ chelating
therapeutic effects in vitro and vivo.
ligands has not been reported.
Herein, we report the first examples of cryptolepine–H-cur
Zn(II) complex-based fluorescent probes featuring H-Cur and
BQ chelating ligands, namely, [Zn(BQ)Cl2] (BQ-Zn) and
Pt-based medication has been successful in combating
different types of malignancies.1 However, the development of
anticancer drugs, particularly cisplatin and its derivatives, is
hindered by several drawbacks.1 Thus, non-Pt-based
derivatives, such as Zn(II) complexes,2,3 have attracted
increased research attention.2,3 Zn is an essential element
responsible for the activity of numerous biological systems.2,3
A new family of Zn(II) complexes has been widely explored for
application to photodynamic therapy (PDT),3,4 cell bioimaging,
and biosensing.2−4 These complexes include quinolone-
phthalocyanine Zn(II) derivatives, polyethylene glycol Zn(II)
phthalocyanine complexes, and Zn(II)−thiosemicarbazone
complexes.2−4
[Zn(BQ)(Cur)]Cl
(BQCur-Zn)
and
investigate
their
antiproliferative activity against human bladder (T-24) tumor
cells in vitro and vivo.
The modes of function of traditional Chinese medicines
(TCMs) and their metal compounds in activating and/or
inhibiting DNA repair, G4 DNA, caspase-3/9, telomerase, and
DNA topoisomerase have recently been verified.5−8 Curcumin
(H-Cur), a natural product isolated from turmeric,9 has
emerged as an anticancer drug and antiangiogenic agent.9
However, the clinical use of H-cur and its metal compounds as
a. Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College
of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road,
Yulin 537000, PR China. qpqin2018@126.com (Q.-P. Qin). Tel./Fax.: +86-775-
2623650.
Scheme 1. Chemical structure and synthesis routes of BQ-Zn and BQCur-Zn
.
The cryptolepine ligand ([5-(benzo[4,5]furo[3,2-b]quinolin-
b. State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal
Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 11-yloxy)-pentyl]-bis-pyridin-2-ylmethyl-amine, BQ) was first
Yucai Road, Guilin 541004, PR China. qpqin2018@126.com (Q.-P. Qin);
designed and synthesized from 2-nitrobenzoic acid via the
gxnuchem@foxmail.com (H.-H. Zou); hliang@mailbox.gxnu.edu.cn (H. Liang).
c. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.
R. China.
synthetic route shown in Scheme 1. [Zn(BQ)Cl2] (BQ-Zn) was
prepared by treating ZnCl2 with BQ in 5.0 mL of CH3OH at 50 °C
(yield: 71.9%). The reactions between BQ-Zn and H-Cur were
carried out by dissolution in 0.1 mL of KOH solution (0.1 M)
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: Experimental details and
figures referenced throughout the text. See DOI: 10.1039/x0xx00000x.
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and 5.0 mL of CH3OH at a 1:1 molar ratio to obtain
Journal Name
The UV−vis spectroscopy and fluorescence titration analysis
View Article Online
[Zn(BQ)(Cur)]Cl (BQCur-Zn) (yield: 88.3%). Characterizations showed that BQCur-Zn displayed appreDcOiaIb: 1le0.1f0lu39o/rDe0sCcCen00c5e24inJ
and stability of BQ and its complexes BQ-Zn and BQCur-Zn are the red region (ca. 600±10 nm) of the visible spectrum under
presented in Figs. S1–S18. The Zn(II) centers of BQ-Zn and ambient conditions upon excitation at 470 and 535 nm (Figs.
BQCur-Zn exhibited a distorted five-coordinate tetragonal- S18 and S19). Next, the cellular localization behaviors of
pyramidal geometry (Scheme 1). To the best of our knowledge, BQCur-Zn (1.55 μM) and BQ-Zn (5.92 μM) were investigated
this work is the first to synthesize Zn(II)-cryptolepine-H-cur by confocal microscopy (Zeiss 710).1 Clear confocal
molecular probes that can function as mitochondrion-targeting microscopic images of T-24 cells treated with BQCur-Zn (1.55
anti-cancer drugs.
μM) were obtained at λex 535 nm (λem= 610−620nm); thus, the
red probe may be used specifically for mitochondrial imaging
Table 1. IC50 (μM) of BQ-Zn and BQCur-Zn toward human cells (Fig. 1). Moreover, substantial accumulation of BQCur-Zn
after 24.0 h of incubation
T-24
occurred within 24.0 h after treatment (Fig. 1), thus indicating
a loss in mitochondrial membrane potential (MMP)11 and
accretion of the probe within the mitochondrial membrane
(Fig. 1). In addition, BQCur-Zn could synergistically strengthen
MMP loss and MMP was almost completely destroyed during
PDT (Fig. 1). By contrast, BQ-Zn (5.92 μM) did not show such
obvious effects. Thus, the results suggest that the toxicity
mechanism of BQCur-Zn (1.55 μM) is distinct from that of BQ-
Zn (5.92 μM) and other previously reported TCM metal
complexes.5−10
SKDDP
MCF-7
HL-7702
>100
>100
>100
>50
BQ
BQ-Zn
25.23±1.15 62.09±1.09 20.13±1.93
5.92±0.35
1.55±0.04
6.08±0.39
1.93±0.46
5.25±0.53
1.80±0.10
BQCur-Zn
H-Cur
20.52±1.11 28.01±1.96 19.02±1.04
>100 >100 >100
ZnCl2
>100
cisplatin
12.56±1.00 79.49±0.13 11.24±0.47 17.02±0.76
The toxicity of BQ-Zn and BQCur-Zn to human T-24, MCF-7,
SK-OV-3/DDP (SKDDP), and HL-7702 cells (Table 1) was tested.
MTT assay revealed that BQ-Zn and BQCur-Zn possess
significant cytotoxicity due to the chelation of H-Cur and BQ
ligands with Zn(II). As expected, BQCur-Zn exhibited higher
cytotoxicity toward the four cancer cells, particularly T-24 cells,
compared with BQ-Zn or cisplatin after 24.0 h and 48 h of
treatment. The cytotoxicity of BQCur-Zn was 3.8- and 8.1-fold
those of BQ-Zn and cisplatin, respectively. However, BQ-Zn and
BQCur-Zn did not display such obvious increase in the MTT
assay form 24 to 48 h (Table S1), suggesting that 24 h was
chosen as incubation. In addition, BQ-Zn and BQCur-Zn
showed weak cytotoxicity (IC50>100 μM) to HL-7702 cells.
Fig. 2. BQCur-Zn induced T-24 cell apoptosis. (A) T-24 cells were treated
with BQCur-Zn (1.55 μM) for 4.0 h, (B) kept in the dark or (C) irradiated for
30.0 min with 470 nm LED light (22.5 mW/cm2), incubated for 20.0 h in the
dark, and then stained with Annexin-V APC and SYTO X. Changes in (D)
tumors and (E) images after treatment with vehicle controland BQCur-Zn
(2.0 mg/kg) via percutaneous injection every 2 days (q2d). The tumor
fractions were kept in the dark or irradiated for 30.0 min with 470 nm LED
light (22.5 mW/cm2) and incubated for the next injection in the dark.
After 4.0 h of incubation with different concentrations of
BQCur-Zn, PDT was performed for 30.0 min using a LED light
source (λex= 470 nm, λem= 610–650 nm).11i After another 20.0
h, cell viability was measured by MTT assay. The cytotoxicity of
BQCur-Zn to light-irradiated cells was significantly enhanced
(IC50= 0.03±0.01 μM) relative to that to dark-treated cells (Fig.
S20). Apoptosis of T-24 cells stained with Annexin-V APC and
SYTO X (Fig. 2A-C), treated with BQCur-Zn (1.55 μM) in the
dark, and irradiated with light was visualized immediately by
flow cytometry. As shown in Fig. S21 (ESI†), only light
irradiation (without BQCur-Zn addition) showed negligible
effects on the apoptosis of T-24 cells. This result is in good
agreement with the low cytotoxicity of light. The population of
Fig. 1. Imaging of T-24 cells incubated with BQCur-Zn (0.26 μM, λex= 535
nm, λem= 610−620nm) for 24.0 h and added with MitoTracker Green (100
nM, λex= 470 nm, λem = 510–530 nm). T-24 cells were treated with BQCur-
Zn (1.55 μM) for 4.0 h, kept in the dark or irradiated for 30.0 min with 470
nm LED light (22.5 mW/cm2), incubated for 20.0 h in the dark.
2 | J. Name., 2020, 00, 1-4
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1883; (c) E. Meggers, Curr. Opin. Chem. Biol., 2007, 11,
T-24 cell apoptosis was 88.84% in the light-irradiated group
was higher than that in the dark-treated group (36.23%).
Finally, we tested the efficacy of BQCur-Zn (2.0 mg/kg) in
inhibiting tumor growth in the dark and under light irradiation
using an in vivo animal model. BQCur-Zn showed greater
delays in tumor growth (tumor inhibition rate, IR=66.0%) in the
light-irradiated group than in the dark-treated group
(IR=43.0%) and in groups treated with cisplatin (IR=37.1%) and
previously reported TCM metal complexes.5−10 We also found
that model mice injected with BQCur-Zn do not exhibit
significant body weight loss (Tables S2−S4 and Fig. 2C and D,
ESI†), which suggests that BQCur-Zn has low systematic
toxicity.
The ability of BQCur-Zn (1.55 μM) to confer mitochondrial
dysfunction was studied by using Western blot. Upon
irradiation by a LED source (λex = 470 nm, λem = 610–650 nm)11i
for 30 min, clear changes in apoptosis-associated proteins
(e.g., bcl-2, bax, cytochrome c, apaf-1, and caspase-9/-3)
relative to those in dark-treated groups were observed. This
result confirms that BQCur-Zn (1.55 μM) can damage
mitochondria more extensively under light irradiation than
under dark treatment (Fig. 3).
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Fig. 3. Apoptosis-related protein levels in T-24 cells incubated with BQCur-
Zn. T-24 cells were treated with BQCur-Zn (1.55 μM) for 4.0 h, kept in the
dark or irradiated for 30.0 min with 470 nm LED light (22.5 mW/cm2), and
incubated for 20.0 h in the dark.
In summary, two new red fluorescent probes based on Zn(II)
complexes with cryptolepine-H-cur derivatives and featuring
mitochondrial membrane-targeting abilities were designed.
Upon visible light irradiation, BQCur-Zn could synergistically
strengthen mitochondrion-mediated apoptosis and enhance
tumor therapeutic effects in vitro and in vivo during PDT. We
believe that BQCur-Zn molecular probes have potential
applications in cell apoptosis detection and PDT.
This work was supported by the National Natural Science
Foundation of China (Nos. 21867017 and 21761033) and the
Natural
Science
Foundation
of
Guangxi
(Nos.
2018GXNSFBA138021 and 2018GXNSFBA281188).
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