Lactose substituted zinc phthalocyanine: A near infrared fluorescence imaging probe for liver cancer targeting

Article abstract of DOI:10.1016/j.bmcl.2012.12.103

A near infrared fluorescence probe, lactose substituted zinc phthalocyanine, [2,9(10),16(17),23(24)-tetrakis((1-(β-d-lactose-2-yl)-1H-1, 2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II), was synthesized via click reaction. Structural characterization

Full text of DOI:10.1016/j.bmcl.2012.12.103

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1878–1882
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Lactose substituted zinc phthalocyanine: A near infrared
fluorescence imaging probe for liver cancer targeting
⇑
Feng Lv, Xujun He, Li Wu, Tianjun Liu
Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A near infrared fluorescence probe, lactose substituted zinc phthalocyanine, [2,9(10),16(17),23(24)-tetra-
Received 8 October 2012
Revised 20 December 2012
Accepted 29 December 2012
Available online 9 January 2013
kis((1-(b-D-lactose-2-yl)-1H-1,2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II), was synthesized via
click reaction. Structural characterization and optical experiment demonstrated its excellent biocompat-
ibility and fluorescence imaging ability. Near infrared fluorescence imaging in vivo for liver cancer, lung
cancer and melanoma cancer with tumor bearing nude mice as models demonstrated that lactose substi-
tuted zinc phthalocyanine has specifically targeting ability to liver cancer while no targeting to lung can-
cer or melanoma, which implied its potential in liver cancer diagnosis as a near infrared optical probe.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Near infrared fluorescence imaging
Phthalocyanine
Lactose
Liver cancer
Medical imaging in vivo plays an important role in the diagnosis
of liver cancer, the fifth most frequent common malignant neo-
plasms worldwide. Although ultrasonography (US), computed
tomography (CT), magnetic resonance imaging (MRI) or digital
subtraction angiography (DSA) are usually applied in liver cancer
diagnosis,1 optical imaging as a novel imaging modality would
have more wider applications due to its low cost, low-energy radi-
ation, high sensitivity, non-invasive or minimally invasive.2,3 Near
infrared (NIR) fluorescence imaging can be used for the diagnosis
in deep tissues and organs owning to its sensitivity and penetra-
tion depth in biological tissues.4–6 As a key issue for NIR imaging,
an ideal optical probe should meet several properties including
suitable optical efficiency, water solubility, good biocompatibility,
targeting ability as well as specificity to the tissues.6,7 In order to
obtain perfect fluorescence imaging, some scientific efforts have
been focused on the development of the novel near infrared fluo-
rescence probes with cancer targeting.8,9
Among near infrared fluorescence probes, indocyanine green
(ICG), an approved agent for human by FDA, has been used in
breast cancer and liver cancer diagnosis,10,11 but it has some limi-
tation in liver cancer diagnosis due to the deficiency of targeting
ability.12 In order to improve the specificity and sensitivity of
imaging, antibody as a functional targeting group for liver cancer
was usually conjugated to NIR optical probe. Li et al. reported that
anti-sperm protein monoclonal antibody conjugated with ICG
could serve for liver cancer imaging in vivo as an optical probe.13
Except for antibody conjugated ICG, Liu et al. reported epidermal
growth factor receptor (EGFRmAb) conjugated nanoparticles could
target to the liver cancer effectively in vivo by fluorescence imag-
ing.14 Chen et al. reported that alpha-fetoprotein (AFP) monoclonal
antibody conjugated semiconductor quantum dots can be used for
the targeting imaging of cancer.15 Other targeting molecules for li-
ver cancer was few reported in NIR imaging. Although antibody
conjugation can enhance the targeting ability for liver cancer, the
cost and easy inactivation of antibody limited the future clinical
application of these conjugated probes.
Saccharide is a valuable and pragmatic targeting molecule with
some advantages such as tolerance of harsh chemical reaction con-
dition, favorable chemical stability, rich source to achieve and eas-
ily preparation. It has been applied in the diagnosis and treatment
of liver cancer as a targeting group.16 Because the hepatic asialo-
glycoprotein (ASGP) receptors are over-expressed on hepatocyte
membranes, the endothelial membrane of the liver can stick func-
tional molecule such as lactose or galactose to the hepatocyte sur-
face and make it transport successfully due to the lactose-receptor
mediated endocytosis.17,18 So lactose or galactose as a targeting
molecule for liver cancer can obviously enhance the diagnostic
and therapeutic effect of cancer drugs or agents.19–22 Recently, gal-
actose conjugated imaging probe has been utilized in PET/CT
probe.23 Hawary et al. reported lactose substituted chitosan as a li-
ver-targeted carrier of 99mTc in vivo for nuclear imaging and bio-
distribution.24 Here we take advantage of lactose’s targeting ability
to design a NIR imaging probe for liver cancer.
Zinc phthalcyanine, a kind of fluorescence agent with large vis-
ible to NIR absorption and acceptable fluorescent efficiency, has
been applied in a wide variety of research areas, including materi-
als science, photo chemistry and biomedical science.25–27 Coupling
⇑
Corresponding author.
E-mail address: liutianjun@hotmail.com (T. Liu).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.103

F. Lv et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1878–1882
1879
with saccharide moieties, zinc phthalocyanine can be improved in
the water solubility, biocompatibility and cell specificity. These
properties expand its applications in biomedical fields as photod-
yanmic sensitizer or imaging probe.28–31 We have demonstrated
that zinc phthalocyanine as an optical imaging probe can show
excellent imaging in vivo.32 The approach for monosaccharide con-
jugation can be easily achieved by substitution reaction,33 however
it is not so convenient for disaccharide or polysaccharide. Click
reaction, with simple, easy workup procedure for the resulting
products,34,35 has been exploited and applied for the generation
of neoglycoconjugates in material science, polymer chemistry,
and pharmaceutical sciences. It is particularly suitable for biocon-
jugations due to the tolerance of biological conditions and most
polar functional groups].36,37 In this Letter, lactose substituted zinc
and NaOMe to give target compound (1) in 53% yield. Direct syn-
thesis of the target compound like glucose counterpart failed in
giving the compound (1). The possible interpretation may be that
the more hydroxy moieties in precursor block the effective forma-
tion of phthalocyanine. 1H NMR spectrum shows typical peaks of
phthalcyanine at 9.34 ppm (dd, J = 17.8, 8.7 Hz, 4H), 9.12 ppm (d,
J = 12.4 Hz, 4H), 8.70 ppm (d, J = 5.9 Hz, 4H) and 7.967.86 (m, 4H)
as triazole protons. Peaks from 3.45 to 5.81 are assigned as lactose
protons and related methylene. HRMS with m/z of 2261.775 re-
corded by Bruker autoflex Tof/Tof confirms the target compound.
Modification with lactose has obviously enhanced the water
solubility of zinc phthalocyanine. In the absorption spectrum in
DMSO solution (Fig. 1), the B-band at 350–370 nm also shows
the characteristic peaks of phthalocyanine. The typical intense
and sharp Q-bands in the near-infrared area at 618 and 670 nm
signify the non-aggregated state of lactose substituted zinc phtha-
locyanine. The observed red shift of the Q-band is typical for
phthalocyanine with substituents of lactose units. Fluorescence
emission is shown at 690 nm in DMSO with excitation at 618 nm
phthalocyanine, [2,9(10),16(17),23(24)-tetrakis((1-(b-D-lactose-2-
yl)-1H-1,2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II), as a
near infrared fluorescence probe for liver cancer, was synthesized
via click reaction and fluorescence imagings in vivo were reported
with three different kinds of tumor-bearing athymic nude mice as
animal models.
(Uf = 0.269). These results signify that the lactose substituted zinc
Target compound, lactose substituted zinc phthalocyanine,
[2,9(10),16(17),23(24)-tetrakis((1-(b-D-lactose-2-yl)-1H-1,2,3-
phthalocyanine has near infrared optical signal obviously. How-
ever, when measured in water solution, lactose substituted zinc
phthalocyanine differs remarkably from that in DMSO. Detailed
investigation confirms that the aggregation occurs with increase
of water ratios in the mixed of water and DMSO (Fig. S1). Intensity
decreases sharply at 690 nm and concurrently increases slowly at
640 nm, and it forms a symmetric M shape peak in total. The
absorption peak in water is much lower and broader than in DMSO
and weak fluorescence signal is obtained in water. These results
can be attributed to the cofacial aggregation of phthalocyanine in
water.38,39 The same phenomenon was reported before in our lab
and others group.40,41 Probe aggregation in water solution does
not limit the application of fluorescence imaging and strong emis-
sion from optical imaging in vivo confirms this.
Because the probe need to be subjected in biological system
with optical irradiation, both chemical and optical stability are
important for optical probe. Chemical stability of probe was evalu-
ated in physiological solution for 1 h at 37 °C. The recorded absorp-
tion and emission spectra show no obviously reduction, which
indicates that the probe is very stable at 37 °C (Fig. 2). Optical
triazol-4-yl)methoxyl)phthalocyaninato]zinc(II), was obtained via
click reaction, cyclotetramerisation and deprotection (Scheme 1).
The synthetic approach can be briefly described as following. Reac-
tion of 4-chlorophthalonitrile (3) with propiolic alcohol (2) in DMF
in the presence of potassium carbonate afforded 4-propyne oxide
phthalonitrile (4). Lactose was transformed to 2,3,6,20,30,40,60-hep-
ta-O-acetyl-b-D-lactose azide (7) as a white solid in 89% yield after
acetylation and bromination, reaction with NaN3 in water. Click
reaction of compound (4) and compound (7) gave compound (8)
4-(2,3,6,20,30,40,60-hepta-O-acetyl-b-
D-lactose)-1H-1,2,3-triazol-4-
yl)methoxy)phthalonitrile in 60% yield in presence of anhydrous
CuSO4 and sodium ascorbate in dichloromethane/methanol at
room temperature for 48 h. Then compound (8) reacted in a mix-
ture of DMAE (1 mL), n-butanol and zinc chloride under N2 for
24 h at 100 °C to achieve compound (9) [2,9(10),16(17),23(24)-
tetrakis((1-(2,3,6,20,30,40,60-hepta-O-acetyl-b-
D-lactose-2-yl)-1H-
1,2,3-triazol-4-yl)methoxyl)phthalocyaninato]zinc(II). Without
further purification, compound (9) was deprotected in dry MeOH
Scheme 1. Synthetic route of lactose substituted zinc phthalocyanine. Reagents and conditions: (i) DMF, K2CO3, 60 °C; (ii) CH2Cl2, 33% HBr/AcOH, 0 °C; (iii) CHCl3, NaN3, PTC,
70 °C; (iv) CuSO4, Na ascorbate, CH2Cl2/MeOH (4:1), rt; (v) DMAE, n-butanol, ZnCl2, N2, 100 °C; (vi) MeOH, NaOMe, rt.

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F. Lv et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1878–1882
Figure 1. Lactose substituted zinc phthalocyanine in DMSO or water solution (A), absorption spectrum and fluorescence spectrum of lactose substituted zinc phthalocyanine
in DMSO (Abs in black; FL: in blue) or water (Abs in red, FL in green) solution.
costs just 1–2 min, the photo stability of this compound is suffi-
cient as a fluorescence imaging probe.
To determine the cell biocompability of lactose substituted zinc
phthalocyanine, cellular survival rates were measured by MTT
method (Fig. 4). Incubated with lactose substituted zinc phthalocy-
anine at the concentration of 12.5 lmol/L in dark, the cellular via-
bility of HepG2 is about 88%, while the cell still retains 81%
viability with continued irradiation by 6 J/cm2 laser light at wave-
length of 630 nm for 20 min. These results show the excellent bio-
compatibility of probe in vitro either in dark or in optical
irradiation. Good water-solubility and low cytotoxicity imply that
lactose substituted zinc phthalocyanine could serve as a potential
probe for in vivo fluorescence imaging.
NIR fluorescence imaging in vivo was conducted with HepG2 li-
ver tumor-bearing athymic nude mice as animal models. Two
groups of model mice were measured. One group was injected
Figure 2. Chemical stability of lactose substituted zinc phthalocyanine at 37 °C.
(Dark: absorption at 618 nm in DMSO solution; red: absorption at 684 nm in DMSO
solution; blue: absorption at 630 nm in water; green: fluorescence emission at
696 nm in DMSO solution with excitation wavelength at 618 nm.)
with 200
lL
of lactose substituted phthalocyanine at
2 ꢀ 10ꢁ4 mol/L through the tail vein, another was injected with
equal amount of saline as control. The in vivo imagings at 12 h post
injection (P.I.) were acquired respectively using a Kodak In Vivo FX
Professional Imaging System equipped with fluorescence filter sets
(excitation/emission, 625/700 nm). Figure 5 shows the real-time
imaging of near infrared fluorescence agent in the representative
tumor-bearing mice. The probe shows strong near infrared fluores-
cence in vivo although there is no intense fluorescence of probe in
water in vitro. This phenomenon possibly comes from in vivo de-
aggregation by the reaction between the probe and the organs.
But regrettably we cannot prove the mechanism by reasonable
stability was evaluated by continued irradiation with laser light at
the wavelength of 630 nm for 70 min in DMSO solution or water
solution. The results show that the optical density has a 20% de-
crease in DMSO solution while it changes slightly with 8% decrease
in water solution with continued irradiation time of 20 min. Even if
continued irradiation time for 70 min in water solution, the optical
density still remains at 82% (Fig. 3). Since optical imaging recording
Figure 3. Optical stability of lactose substituted zinc phthalocyanine with irradiation in DMSO solution (A) or water solution (B). The arrows signify the decrease of
absorption with the increase of irradiation time.

F. Lv et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1878–1882
1881
infrared probes, however liver tumor targeting imaging of them
shows difference. Lactose or galactose substituted phthalocyanine
shows obviously fluorescence imaging for liver tumor targeting be-
cause of lactose-receptor mediated endocytosis, while glucose
substituted porphyrin or phthalocyanine displays little targeting
ability.32,40,42,43 The targeting ability of lactose units has been con-
firmed by comparison of lactose substituted zinc phthalocyanine
with glucose conjugated zinc phthalocyanines, even though the
unmodified zinc phthalocyanine does not conducted as the control
probe because its lower water solubility limits the administration
intravenously.
To further investigate the probe distribution in various organs,
the mice were then sacrificed, and kidney, heart, liver, lung, spleen,
muscle and tumor were harvested for analysis of probe biodistri-
bution ex vivo (Fig. 5). The biodistribution of probe could be quan-
titatively analysis with this mean intensity of organs, which is the
sum intensity divided by the interior area of each organ. In the
experimental group, strong fluorescence could be observed clearly
in the kidney, liver and tumor, while a little in heart, lung and mus-
cle. Although there is considerable liver uptake after 12h, the
retention of probe in liver would decrease with the increase of
metabolism time while the drug aggregation in tumor would not
decrease rapidly. The results reveal that probe is not distributed
uniformly, with the highest fluorescence signal from the core of
the tumor contrast to other organs. Quantification of mean fluores-
cence signals of organs in probe group shows that the highest
intensity is detected in the tumor while the heart, lung and muscle
had less than 50% of tumor, which suggests an effective accumula-
tion of probe at liver tumor. These results could be attributed to the
lactose receptor mediated active target to the liver cancer, in good
agreement with the real-time imaging in vivo. Histological analysis
shows that the lactose substituted zinc phthalocyanine has no
Figure 4. Cytotoxicity of lactose zinc phthalocyanine on HepG-2 cells in dark or
irradiation.
experiments. From Figure 5, considerable fluorescence is detected
in the experimental group after injecting near infrared fluores-
cence agent, while little fluorescence is detected in control group.
And in the experimental group, strong luminescence signal is
shown in liver cancer site of animal model while weak lumines-
cence signals at other organs. These results indicate that lactose
substituted zinc phthalocyanine has targeting ability to liver can-
cer because of tumor targeting ability of lactose. The tumor imag-
ing effect is depended on the chromorphore and the ensemble
structure. Saccharide substituted zinc phthalocyanines and por-
phyrin can be applied for fluorescence imaging in vivo with accept-
able biocompatibility and fluorescence imaging ability as near
Figure 5. Optical imaging in vivo (A), distribution (B) and fluorescence quantitative analysis of dissected organs (C) with lactose substituted zinc phthalocyanine as probe,
liver cancer bearing mice as model (injected with 200
l
L of 2 ꢀ 10ꢁ4 mol/L with an exposure time of 1 min; filters: excitation 625 nm, emission 700 nm).
Figure 6. Optical imaging in vivo (A), distribution (B) and fluorescence quantitative analysis of dissected organs (C) with lactose substituted zinc phthalocyanine as probe,
lung cancer or melanoma bearing mice as models (injected with 200
l
L of 2 ꢀ 10ꢁ4 mol/L with an exposure time of 1 min; filters: excitation 625 nm, emission 700 nm).

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F. Lv et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1878–1882
3. Luker, G.; Luker, K. J. Nucl. Med. 2008, 49, 1.
damage to the organs according to the HE staining, which proves
the safety of this NIR fluorescence probe in vivo. As shown in imag-
ing by confocal laser scanning microscope (Fig. S2), the large
amounts of fluorescence agent aggregates in the tumor, which is
in accord with the fluorescence imaging of organs. All these con-
firm the lactose substituted phthalocyanine could be applied to
the near infrared fluorescence imaging of liver cancer.
Tumor specificity is another key issue to molecular probe. In or-
der to investigate the specificity of lactose substituted zinc phtha-
locyanine, fluorescence imagings in vivo were conducted with
A549 lung cancer and A375 melanoma as tumor models. As shown
in Figure 6, weak signals are obtained in the experimental groups
after intravenous injection of probe for 12 h, and there are no obvi-
ous differences in the tumor site. Further organs distribution anal-
ysis reveals that the probe mainly accumulates in liver and kidney
while little in tumor of lung cancer or melanoma bearing mice.
These results signify the lactose substituted zinc phthalocyanine
is short of recognition and targeting retention to lung cancer or
melanoma tumor tissues. The fluorescent imagings in vivo for
these three kinds of tumor mice models confirm that lactose
substituted zinc phthalocyanine has targeting ability and specific-
ity to liver cancer, which implies the promising and potential
application in liver cancer diagnosis.
In summary, water-soluble lactose substituted zinc phthalocya-
nine was synthesized via click reaction. Optical imagings in vivo
reveal that lactose substituted zinc phthalocyanine has specificity
and targeting ability to liver cancer while no obvious recognition
to lung cancer or melanoma with nude mice bearing liver cancer,
lung cancer or melanoma as animal models. Organs distribution,
quantitative analysis as well as histological analysis further con-
firm this. The above results demonstrate that lactose substituted
zinc phthalocyanine has the promising and potential application
as a targeting near infrared optical probe in the diagnosis of liver
cancer in future.
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This work has been supported by the National Natural Science
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Supplementary data
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