The first silicon(iv) phthalocyanine-nucleoside conjugates with high photodynamic activity

Article abstract of DOI:10.1039/c3dt50910a

A series of novel silicon(iv) phthalocyanines conjugated axially with different nucleoside moieties (uridine, 5-methyluridine, cytidine, and 5-N-cytidine derivatives) have been synthesized and evaluated for their photodynamic activities. The uridine-containing compound 1 exhibits the highest photocytotoxicity against HepG2 human hepatocarcinoma cells with an IC ₅₀ value as low as 6 nM, which can be attributed to its high cellular uptake and non-aggregated nature in the biological media. This compound shows high affinity toward the mitochondria of HepG2 cells and causes cell death mainly through apoptosis upon illumination. The result indicates that 1 is a highly promising photosensitizer for photodynamic therapy.

Full text of DOI:10.1039/c3dt50910a

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The first silicon(IV) phthalocyanine–nucleoside
conjugates with high photodynamic activity†
Cite this: Dalton Trans., 2013, 42, 10398
Received 6th April 2013,
Accepted 26th May 2013
Xiao-Min Shen,‡ Bi-Yuan Zheng,‡ Xiu-Rong Huang, Lei Wang and
Jian-Dong Huang*
DOI: 10.1039/c3dt50910a
www.rsc.org/dalton
A series of novel silicon(IV) phthalocyanines conjugated axially have received considerable attention in recent years, because
with different nucleoside moieties (uridine, 5-methyluridine, of their enhanced biocompatibility and cellular uptake.
cytidine, and 5-N-cytidine derivatives) have been synthesized and
As part of our ongoing interest in the development of
evaluated for their photodynamic activities. The uridine-contain- Pc-based photosensitizers,10 we report herein a new series of
ing compound 1 exhibits the highest photocytotoxicity against silicon(IV) phthalocyanines (SiPcs) covalently linked with two
HepG2 human hepatocarcinoma cells with an IC50 value as low as nucleoside moieties at the axial positions, including their syn-
6 nM, which can be attributed to its high cellular uptake and non- thesis, spectroscopic properties, and in vitro photodynamic
aggregated nature in the biological media. This compound shows activities against HepG2 human hepatocarcinoma cells. The
high affinity toward the mitochondria of HepG2 cells and causes hydrophobic and π-conjugated characterizations of the
cell death mainly through apoptosis upon illumination. The result phthalocyanine skeleton favor the formation of aggregates,
indicates that 1 is a highly promising photosensitizer for photo- resulting in inefficient ROS generation and poor solubility in
dynamic therapy.
aqueous media.3 By introducing two nucleoside-containing
substituents at the axial positions, we aimed to improve the
hydrophilicity and inhibit the self-aggregation of these com-
pounds. More importantly, considering that nucleoside-based
compounds have been widely studied for their pharmacologi-
cal properties, for example, using as antiviral11 and anticancer
drugs,12 we hope to evaluate whether this functionality
has unusual effects on the photodynamic process. Indeed,
the results are very interesting. One of the conjugates
axially substituted with uridine moieties (compound 1,
Scheme 1) exhibits an extremely high in vitro photodynamic
activity.
The photobiological properties of phthalocyanines functio-
nalized with nucleoside moieties remain unexplored, although
the synthesis and characterization of a few phthalocyanine–
nucleoside conjugates have been reported.13 Ng and co-work-
ers13a firstly prepared adenine-containing zinc(II) phthalo-
cyanines (ZnPcs) and examined their spectroscopic properties.
Afterwards, Sessler and Torres et al.13b,c synthesized a novel
zinc(II) phthalocyanine peripherally linked with cytidine
derivative and investigated their interaction with guanosine
and fullerene. Reddy et al.13d also reported the synthesis
and spectroscopic properties of a trifuoromethylated zinc(II)
phthalocyanine conjugated with deoxyribonucleosides. None-
theless, all of them did not report the photodynamic activity of
these ZnPc–nucleoside conjugates. Moreover, to the best of
our knowledge, no silicon(IV) phthalocyanine containing
nucleoside moieties has been reported in the literature.
Photodynamic therapy (PDT) is an attractive minimal-invasive
modality for cancer treatment.1 It typically involves the
systemic administration of a non-toxic photosensitizer and the
tumor-oriented illumination with light of a specific wave-
length. Upon excitation by light, the tumor-localized photosen-
sitizer generates intracellular reactive oxygen species (ROS),
particularly singlet oxygen, to cause cells and tissues damage.
The overall efficacy of the treatment depends greatly on the be-
havior of the photosensitizer.2 Due to intense absorption in
the phototherapeutic window (600–800 nm), low dark toxicity,
and ease of chemical modification, phthalocyanines (Pcs) have
been found to be highly promising as photosensitizers
for PDT.2,3 A substantial number of phthalocyanines with
different functionalities have been prepared and examined for
their photodynamic activities. Among these phthalocyanines,
the analogues conjugated with biological molecules,4 such as
sugar,5 amino acids,6 antibodies,7 vitamins,8 and peptides,9
College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou 350108,
China. E-mail: jdhuang@fzu.edu.cn; Fax: +86 591 22866227;
Tel: +86 591 22866235
†Electronic supplementary information (ESI) available: Experimental details and
characterization data, HPLC profiles, additional electronic absorption spectra,
fluorescence spectra, and subcellular localization microscopies. See DOI:
10.1039/c3dt50910a
‡Xiao-Min Shen and Bi-Yuan Zheng made equal contribution as co-first author.
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Scheme 1 Preparation of compounds 1–4.
The preparation of the nucleoside–conjugated phthalocya- SiPcs are essentially free from aggregation in DMF (see Fig. S2
nines (compounds 1–4) is shown in Scheme 1. Treatment of in the ESI†). The almost identical absorption positions for all
uridine (5), 5-methyl-uridine (6), cytidine (7) or 5-N-cytidine (8) these compounds indicate that the π system of the phthalo-
with p-toluenesulfonic acid (PTSA) and dry acetone gave the cyanine ring is not perturbed by the axial substituents.
corresponding isopropylidene-protected products 9–12 in good Upon excitation at 610 nm, these compounds show a strong
yields (85–95%), respectively. These nucleoside derivatives fluorescence emission at 683–687 nm with a fluorescence
were then treated with silicon(IV) phthalocyanine dichloride in quantum yield (ΦF) of 0.29–0.37 relative to unsubstituted zinc(II)
the presence of NaH and led to axial substitution, giving com- phthalocyanine (ZnPc) (ΦF = 0.28). The fluorescence spectra
pounds 1–4 in moderate yield (40–65%). Four final products of these compounds are essentially a mirror image of
are highly soluble in common organic solvents and could be the absorption spectra in Q-band with a small Stokes shift
readily purified by column chromatography. The purity of (ca. 8 nm).
these new phthalocyanines was determined by high perform-
To evaluate the photosensitizing activities of these SiPcs
ance liquid chromatography (HPLC) and was found to be 1–4, their singlet oxygen quantum yields (ΦΔ) were also deter-
≥98% (see Fig. S1, in the ESI†). All the prepared phthalocya- mined in DMF by a steady-state method using 1,3-diphenyliso-
nines were characterized with various spectroscopic methods benzofuran (DPBF) as the chemical quencher.15 In this
including high resolution mass spectrometry (HRMS), proton method, the concentration of DPBF was monitored spectrosco-
nuclear magnetic resonance (1H NMR), Fourier transform pically at 413 nm with irradiation time and the singlet oxygen
infrared (FT-IR), and elemental analyses.
generation efficiency can be determined by comparing the rate
The spectroscopic properties of 1–4 were measured in N,N- of photodegradation of DPBF induced by the photosensitizers
dimethylformamide (DMF), and the data are summarized in with that of unsubstituted ZnPc (ΦΔ = 0.56). As shown in
Table 1. The electronic absorption spectra of all compounds in Table 1, all the prepared SiPcs are efficient single oxygen gene-
DMF are typical of non-aggregated phthalocyanines, exhibiting rators with the ΦΔ value of 0.42–0.67. It seems that the photo-
an intense and sharp Q-band at 676–678 nm. Their Q bands sensitizing activities of these compounds follow the trend
strictly follow the Lambert–Beer law, suggesting that these 4 > 3 ≈ 2 ≈ 1, and the 5-N-cytidine-containing compound 4 has
a higher ΦΔ than the other compounds, which may be due to
the introduction of N atom into the pyrimidine ring of the
nucleoside leading to the change of electronic distribution of
the nucleoside moiety.
Table 1 Photophysical and photochemical data for 1–4 in DMF
a
λmax
λem
Stokes
ε × 105
Since the in vitro photodynamic assay was determined in
RPMI 1640 cell culture medium, the absorption spectra of
compounds 1–4 (formulated with Cremophor EL16) were also
recorded in this culture medium. As shown in Fig. 1, these
compounds exhibit very similar absorption spectra with a
sharp and intense Q-band peaking at 681 nm, which also
obeys the Lambert–Beer law (see the inset of Fig. 1, using 1 as
an example). Moreover, these compounds in the culture
medium show a strong fluorescence emission peaking at
Compound (nm) (nm) shift (nm) (M−1 cm−1
)
ΦF
ΦΔ
b
c
1
2
3
4
678
676
677
676
687
684
685
683
9
8
8
7
2.00
1.76
2.13
1.80
0.37 0.44
0.29 0.46
0.36 0.42
0.30 0.67
a Excited at 610 nm. b Using unsubstituted zinc(II) phthalocyanine
(ZnPc) in DMF as the reference (ΦF = 0.28).14 c Determined using 1,3-
diphenylisobenzofuran (DPBF) as the chemical quencher, and using
ZnPc in DMF as the reference (ΦΔ = 0.56).15
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Table 2 Comparison of the IC50 values of SiPcs 1–4 against HepG2 cells
Compd
IC50 a (μM)
1
2
3
4
0.006
0.051
0.400
0.080
a Defined as the photosensitizer concentration required to kill 50% of
the cells.
in the presence of light. These data are summarized in
Table 2. It can be seen that the photodynamic activity of these
compounds greatly depends on the axial substituents. The
photocytotoxicity towards HepG2 cells follows the trend 1 > 2
≈ 4 > 3 (P < 0.01 for 1 vs. 2 or 3 or 4; P > 0.05 for 2 vs.4; and
P < 0.05 for 3 vs. 2 or 4). The compound 1 conjugated with uri-
dines exhibits the highest photoactivity with an IC50 value as
low as 6 nM, while the analogue 3 conjugated with cytidines
shows the lowest photoactivity with an IC50 value of 400 nM.
Compounds 2 and 4 present a comparable photocytotoxicity
against HepG2 cells (IC50 = 51 and 80 nM, respectively).
Fig. 1 Electronic absorption spectra of 1–4 (4 μM), formulated with Cremo-
phor EL, in cellular culture medium. The inset plots the Q-band absorbance at
681 nm versus the concentration of 1.
It is worth noting that compound 1 is highly promising as
an efficient photosensitizer. Recently, Ng’s group has made
significant progress in the rational modification of SiPc-based
photosensitizers.5b,18 They obtained a highly photocytotoxic
glucosylated SiPc with an IC50 down to 6 nM toward HepG2
cells.5b The result was found to be much higher than that of
the classical photosensitizers such as porfimer sodium and
pheophorbide a. The photoactivity of compound 1 against
HepG2 cancer cells is comparable with that of the glucoconju-
gated SiPc as well as other highly potent Pc-based
Fig. 2 Cytotoxic effects of SiPcs 1–4 on HepG2 cells in the absence (closed
symbols) and presence (open symbols, +L) of light. For the latter, the cells were photosensitizers.19
irradiated with red light (λ > 610 nm, 15 mW cm−2, 27 J cm−2). Values represent
To further account for the photocytotoxicity results, the cel-
mean standard deviation of three separate experiments, each performed in
quadruplicate.
lular uptake of these compounds was examined by fluo-
rescence microscopy. Fig. shows the bright-field and
fluorescence microscopic images of HepG2 cells after incu-
3
692–694 nm when excited at 610 nm (see Fig. S3 in the ESI†). bation with 1–4 (2 μM) for 2 h. The average relative fluo-
These observations indicate that 1–4 mainly exist as a mono- rescence intensity per cell of these compounds was also
meric form in the RPMI 1640 medium with 1% Cremophor measured and described in Fig. 4. It can be seen that the intra-
EL. Therefore, these axial nucleoside moieties are effective cellular fluorescence intensity follows the trend 1 > 2 > 4 > 3.
in decreasing aggregation of the phthalocyanine ring as we As discussed above, these compounds are essentially free from
expected due to their steric effect and hydrophilicity. The non- aggregation in biological environment and show similar fluo-
aggregated characterization of these compounds is extremely rescence emission properties. Hence, the trend in intracellular
important for PDT application, since aggregation provides an fluorescence intensity of these compounds can reflect their
efficient non-radiative energy relaxation pathway, thereby trend in cellular uptake.
greatly shortening the triplet lifetime of the phthalocyanine
molecule and then drastically reducing the overall photosensi- cells, 1 > 2 ≈ 4 > 3, may be a result of two effects of cellular
tizing efficiency.17
uptake (1 > 2 > 4 > 3) and singlet oxygen yield (4 > 3 ≈ 2 ≈ 1).
The observed trend of photocytotoxicity toward HepG2
The photodynamic activities of 1–4 in Cremophor EL emul- Compound 1 shows much stronger intracellular fluorescence
sions were evaluated against HepG2 human hepatocarcinoma in HepG2 cells than the other compounds, suggesting 1
cells. As shown in Fig. 2, all these compounds are essentially having the highest cellular uptake and then giving the highest
non-cytotoxic in the absence of light, but become cytotoxic photocytotoxicity toward HepG2 cells. Compound 4 shows a
upon illumination with red light. The IC50 values, defined as comparable photoactivity relative to 2 due to its higher singlet
the photosensitizer concentration demanded to kill 50% of the oxygen yield, although the cellular uptake of 4 is slightly lower
cells, can be obtained from the dose-dependent survival curves than that of 2.
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Fig. 3 Bright-field (row 1) and intracellular fluorescence (row 2) images of HepG2 cells after incubation with 1 (column 1), 2 (column 2), 3 (column 3), and
4 (column 4) (all at 2 μM) for 2 h, respectively.
The subcellular localization of compounds 1–4 in
HepG2 cells was investigated by confocal microscopy. Since
mitochondria are an important target of the initiation of apop-
tosis induced by PDT,20 it would be interesting to reveal
whether the photosensitizer has an affinity to the subcellular
component. We stained the cells with MitoTracker Green,
which is a specific fluorescence dye for mitochondria, together
with 1–4. As shown in Fig. S4,† in HepG2 cells, the fluo-
rescence caused by MitoTracker Green (excited at 488 nm,
monitored at 499–529 nm) is mainly superimposed with the
fluorescence caused by 1 (excited at 637 nm, monitored at
640–700 nm). Similarly, the fluorescence images of 2–4 and
MitoTracker can also be superimposed (Fig. S5–7 in the ESI†).
These indicate that compounds 1–4 can target the mitochon-
Fig. 4 Comparison of the intracellular fluorescence intensities of SiPcs 1–4 in
dria of HepG2, which is similar to Pc4, a known axially substi-
tuted SiPc.21
HepG2 cells. Data are expressed as mean standard deviation (the number of
cells = 20).
Fig. 5 The intracellular fluorescence images of Annexin V-FITC (in green) and PI (in red) in HepG2 cells after treatment with 1 (8 nM) in combination with light
(1-PDT) or without light (1 alone). The bright field image is given in column 1. Scale bar: 50 μm.
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Due to the high potency of 1, the mode of cell death
induced by 1 was also investigated using double staining with
Annexin V-FITC and propidium iodide (PI) by fluorescence
confocal microscopy.22 As shown in Fig. 5, most of the HepG2
cells are negative for Annexin V-FITC and PI after treatment
with 1 (8 nM) in the absence of light, indicating that 1 is essen-
tially non-cytotoxic toward HepG2 cells in darkness. However,
upon illumination, cells stained with Annexin V-FITC are
obviously observed, and cells stained with PI can also be
seen. This suggests that apoptotic changes of these cells
have occurred after PDT treatment. More than 50% of 1-PDT-
treated HepG2 cells were stained with both Annexin V-FITC
and PI, implying that the pathway of cell death was mainly
apoptosis.
In conclusion, we have reported the first synthesis of
silicon phthalocyanines bearing nucleosides at the axial posi-
tions. The axial nucleoside moieties can effectively reduce the
self-aggregation of these phthalocyanines not only in organic
solvent, but also in cell culture medium. The photodynamic
activities of these compounds depend on the kind of nucleo-
sides as the result of different cellular uptake properties
toward cancer cells. The uridine-containing derivative
(compound 1) is the most potent one. The IC50 value of 1 is as
low as 6 nM toward HepG2 cells. As revealed by confocal
microscopy, compound 1 shows a high localization in the
mitochondria of HepG2 cells and causes predominately apop-
tosis upon illumination. These results indicate that 1 is a
highly promising photosensitizer for photodynamic therapy.
The actual role of the nucleoside moieties and in vivo PDT
efficacies of these compounds are under investigation.
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16 Compounds 1–4 were first dissolved in DMF (1.0 mM) and
the solutions were diluted to 80 μM with 1% (wt) aqueous
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