Facile synthesis of highly biocompatible folic acid-functionalised SiO2 nanoparticles encapsulating rare-earth metal complexes, and their application in targeted drug delivery

Article abstract of DOI:10.1039/c7dt03000b

Mesoporous silica core-shell nanospheres encapsulating a rare-earth metal complex (RC) were first synthesised through a facile W/O (water in oil) inverse microemulsion method. In order to achieve targeted complex delivery, folic acid (FA) was used as the targeting component due to its high affinity for over-expressed folate receptors (FRs) in cancer cells. The RC₂@SiO₂-FA nanospheres were characterised via ultraviolet-visible light absorption spectroscopy (UV-vis spectroscopy), dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A microwave method was used to synthesise five RC cores based on 4-chlorophenoxyacetic acid, and their crystal structures were further confirmed using X-ray diffraction. The five RC cores have the following chemical formulae: [Er₂(p-CPA)₆(H₂O)₆] RC₁, [Ho₂(p-CPA)₆(H₂O)₆] RC₂, [Sm(p-CPA)₃(H₂O)] RC₃, [Pr(p-CPA)₃(H₂O)]·3H₂O RC₄ and [Ce(p-CPA)₃(H₂O)₂]·2H₂O RC₅. The carboxyl groups showed two kinds of coordination modes, namely μ₂-η¹:η¹ and μ₂-η¹:η², among RC₁-RC₅. The flexible -OCH₂COO- spacer group, which can undergo rotation of its C-O and C-C bonds, offered great potential for structural diversity. In vivo experiments revealed that the nanospheres exhibited no obvious cytotoxicity on HepG2 cells and 293 T cells, even at concentrations of up to 80 μg mL^-1. Nevertheless, all of the RC cores showed a certain degree of anti-tumour efficacy; in particular, RC₂ showed the strongest cytotoxicity against HepG2 cells. Interestingly, the cytotoxicity of all of the RC₂@SiO₂-FA nanospheres was higher than that of lone RC₂. These types of FA-targeted mesoporous silica nanocarriers can be used for the delivery of anti-tumour RC, and provide a basis for the further study of affordable non-platinum-based complexes.

Full text of DOI:10.1039/c7dt03000b

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ISSN 1477-9226
PAPER
Joseph T. Hupp, Omar K. Farha et al.
Efficient extraction of sulfate from water using
framework
a Zr-metal–organic
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ARTICLE
Facile synthesis of highly biocompatible folic acidꢀfunctionalized
SiO2 encapsulated rareꢀearth metal complexes nanoparticles and
its application on targeted metalꢀbased complex delivery
Received 00th January 20xx,
Accepted 00th January 20xx
Xiuling Xu, Fan Hu and Qi Shuai*
DOI: 10.1039/x0xx00000x
Mesoporous silica encapsulated rareꢀearth metal complex (RC) shellꢀcore nanospheres were first synthesised
through a facile W/O (water in oil) inverse microemulsion method. In order to achieve targeted complexes
delivery, folic acid (FA) was used as the targeting component for its high affinity to overꢀexpressed folate
receptor (FR) in cancer cell. The RC2@SiO2ꢀFA was characterized via ultravioletꢀvisible light absorption
spectra (UVꢀvis spectra), dynamic light scattering (DLS), scanning electron microscope (SEM) and
transmission electron microscopy (TEM). Microwave method were used to synthesize five RCs cores based on
4ꢀchlorophenoxyacetic acid, and crystal structure was further confirmed by Xꢀray diffraction, namely, [Er2(pꢀ
CPA)6(H2O)6] RC1, [Ho2(pꢀCPA)6(H2O)6] RC2, [Sm(pꢀCPA)3(H2O)] RC3, [Pr(pꢀCPA)3(H2O)]·3H2O RC4 and
[Ce(pꢀCPA)3(H2O)2]·2H2O RC5. Carboxyl group showed two kinds of coordination modes of µ2ꢀη1:η1
www.rsc.org/
and µ2ꢀη1:η2 among RC1ꢀRC5
of the C O and C C bonds gave great potential to structural diversity. In vivo experiments revealed that
. The flexible ꢀOCH2COOꢀ spacer group which was caused by rotation
ꢀ
ꢀ
there was no obvious cytotoxicity on HepG2 cell and 293T cell even at up to 80ug/mL of SiO2ꢀFA spheres.
Nevertheless, all the RC1ꢀRC5 cores had certain antitumor efficacy, in particular, RC2 showed the strongest
cytotoxicity against HepG2. Interestingly, all the cytotoxicity of RC2@SiO2ꢀFA was higher than that of
single RC2. These kinds of FAꢀtargeted mesoporous silica nanocarriers can be used for the delivery of
antitumor RC, and provide a basis for the further study of affordable nonꢀplatinumꢀbased complex.
entire body upon administration after intravenous infusions, and thus
often results in doseꢀlimiting nephrotoxicity, hepatoxicity and elicits
Introduction
other side effects.13,
Finally, platinumꢀbased anticancer drugs,
especially nedaplatin, carboplatin and oxaliplatin, are expensive and
For the past few years, there has been a growing trend of people
suffering from cancer and this disease has become one of the major
causes for death worldwide.1ꢀ4 Rosenburg’s crucial discovery opened
the door of complex used for anticancer agents, which led to the
production of Ptꢀbased complexes for anticancer drugs.5, The
therapeutic effects of Ptꢀbased complexes are mainly based on the
inhibition of cancer cell proliferation through the distortion of
doubleꢀstranded DNAs.7, Its secondꢀgeneration analogues (i.e.
oxaliplatin and carboplatin) have also been extensively studied in
recent years.9, 10 However, the flowing mentioned to a certain extent
limit the use of platinumꢀbased anticancer drugs. Firstly, cisplatin
undergoes a range of nonselective binding events in the presence of
a vast number of biomolecules, including phospholipids and proteins.
Thus, only a small amount of cisplatin reaches a targeted tumour,
where the drug ultimately induces apoptosis by binding to the DNA
of the tumour.11, 12 Secondly, the drug is distributed throughout the
14
16
thus usually inaccessible to cancer patients.15,
Recent studies
showed that lowꢀcost rareꢀearth metals and their derivatives exhibit a
variety of biological activities in vitro and in vivo.17ꢀ19 They could
modify the fluidity and permeability of cell membranes, reduce
membrane ATPase activity, inhibit cell mitosis and DNA
synthesis.20 Since Anyhilelri reported the anticancer activities of
rareꢀearth amino acid complex La(gly)3·Cl3·H2O in 1975, rareꢀearth
complexes (RCs) have been comprehensively studied in tumor
treatments.21 When RCs enter a human body, they easily accumulate
in tumour tissues or plasmas, showing a certain specific affinity for
tumour tissue and antitumour activity.22ꢀ24 Furthermore, when
coordinating with rareꢀearth metals, the amino acid, pyridine and
indole derivatives show an improved inhibitory effects on breast,
cervical or liver cancer cells.25ꢀ29 Developing affordable RCsꢀbased
anticancer drugs which can effectively target the DNAs of cancerous
cells is urgently needed.
6
8
Specific modifications for the reduction of side effects are favorable
for
cancer
treatment.30
Folate
receptors
(FRs)
are
Electronic supplementary information (ESI) available: 1HNMR and 13CNMR spectra of
compounds. IR spectrum of complexes 1ꢀ5. For ESI and crystallographic data in CIF or
other electronic format See DOI:10.1039/x0xx00000x
glycosylphosphatidylinositolꢀlinked membrane proteins that have a
high affinity (association constants in the order of 109–10) towards
folic acid (FA) and play an essential role in cell growth.31ꢀ34 FRs
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mediate the cellular uptake of FA and drug conjugate via receptorꢀ events during drug distribution in the body while facilitating the
mediated endocytosis.35 As cancerꢀrelated biomarkers, FRs was transport of the drug across the cell membrane via endocytosis at the
expressed at high frequency in numerous kinds of human tumours, site of action.47 Therefore, the increase in therapeutic efficiency by
such as ovarian, breast, brain, lung, liver tumours.36 Conversely, FR the enhanced permeation retention effect (EPR effect) in tumour
scarcely exists in the majority of normal tissues and organs. Thus, tissues can be easily achieved.48, 49
information on FR is of great importance in both clinical diagnosis
In this study, we used a novel strategy in which SiO2 encapsulated
and drug development. A great number of optimistic outcomes were
RCs were delivered to HepG2 cancer cells. The RCs were
achieved by FA modification on the surface of multiple materials for
synthesized through facial microwave methods, which exhibit rapid
targeted drug therapy.37ꢀ39
reaction time and produce high yield and uniform product. Tritonꢀ
As novel delivery vehicles, mesoporous silica nanoparticles (MSNs) 100 was selected as a template and surfactant. A thin layer of silica
have recently been a focus of several studies.40ꢀ43 Mesoporous silica obtained through the hydrolysis and condensation of TEOS was used
functionalized with a variety of pendant organic groups was to prevent the rapid dissolution of complex spheres and regulate the
fabricated via coꢀcondensation between organotrialkoxysilanes with release of the anticancer drug effectively. The outer sphere of the
another silicon source, such as tetraethoxysilane (TEOS) and 3ꢀ mesoporous silica nanocarriers was functionalized with a noticeable
aminopropyltriethoxysilane (APTES).44ꢀ46 During the fabrication, amount of amino groups. To achieve targeted drug delivery, alkyne
surfactants were used as structureꢀdirecting agents. Fortunately, FA was used as the targeting molecule for its high affinity with FR,
these pendant organic groups can be further modified by the target which was upregulated in the HepG2 cancer cells. With the FA
molecule. As a novel strategy for cancer therapy, targeted MSNs conjugation, the spheres can be selectively absorbed by the cancer
enable the protection of metalꢀbased drug from undesirable binding cells through cell surface receptorꢀmediated mechanisms.
Scheme 1 Schematic procedure for preparation and folic acid conjugation of RC@ SiO2ꢀNH2 spheres.
Apparatus
Experimental Section
NMR spectra were recorded on a Bruker 500 MHz spectrometer in
DMSOꢀd6 with tetramethylsilane as an internal standard. Microwave
synthesis was proceeded on a CEM Discover SP singleꢀmode
microwave synthesis reactor. Elemental analyses (C and H) were
performed on a Vario MACRO cube elemental analyzer. IR spectra
were recorded on a BRUKER TENSOR 27 spectrophotometer
within 400ꢀ4000 cmꢀ1 using the samples prepared as pellets with
KBr. Viability was assessed by absorbance at 490 nm using a
Perlong DNMꢀ9062 microplate reader. Field emission scanning
electron microscope measurements were performed on a FEI Nova
Nano SEM 450 from Life Science Research Core Services (LSRCS).
Materials and reagents
All other starting materials were of analytical grade and obtained
from commercial sources without further purification. ErCl3·6H2O,
HoCl3·6H2O, SmCl3·6H2O, PrCl3·6H2O, CeCl3·6H2O, 4ꢀ
chlorophenol, ethyl chloroacetate, Triton Xꢀ100, hexyl alcohol,
cyclohexane,
tetraethyl
orthosilicate,
3ꢀ
(propargylthiopropyl)triethoxysilane, ammonium hydroxide, acetone,
ethanol, folic acid, 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide
hydrochloride, Nꢀhydroxysuccinimide, dimethyl sulfoxide were
obtained from Acros Organics.
2 | J. Name., 2012, 00, 1-3
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Preparation of the ligand pꢀHCPA
Shaking Bath (100 r/min) at room temperature for 24 h. Tetraethyl
orthosilicate (0.10 mL) and 3ꢀ(propargylthiopropyl)triethoxysilane
(0.10 mL) was then added with ultrasonication for another 30 min,
ammonium hydroxide (0.06 mL) slowly added. In the same
conditions, the mixture was placed in the Shaking Bath for another
24 h. Acetone (10 mL) were used to demulsification. After
centrifugation (10000 rpm, 15 min), the solid was washed several
times with water and ethanol, then dried at 25 oC for 16 h.
pꢀHCPA ligands were synthesised by the following microwave
methods: A mixture of 4ꢀchlorophenol (5mmol, 0.64 g), ethyl
chloroacetate (5mmol, 0.61 g), K2CO3 (5mmol, 0.69 g) and KI
(1mmol, 0.17 g) in 3 mL of DMF was stirred for 30 min in
microwave tube. The thoroughly mixed resulting solution was
irradiated in a commercial microwave oven for 4 min at 200 W.
Then followed by adding 5 mL of NaOH (2 mol/L) and continue
irradiated 5 min at 500 W. After cooling to room temperature, the Folic acid conjugation on RC2@SiO2ꢀNH2 spheres
resulting aqueous solution was acidified (pH=6) by addition of a 1
FA (32 mg, 0.072 mmol) was activated by 1ꢀethylꢀ3ꢀ(3ꢀ
mol/L HCl solution under vigorous stirring, extracted and the white
dimethylaminopropyl)carbodiimide hydrochloride (16 mg, 0.084
solid product was purified by column chromatography. Found pꢀ
mmol) and Nꢀhydroxysuccinimide (9.6 mg, 0.084 mmol) which was
HCPA (Yield: 91 %): 1H NMR (500 MHz, DMSO) δ 13.15 (s, 1H),
dissolved in dimethyl sulfoxide (10 mL) solution, and stirred for 24
7.45 – 7.38 (m, 2H), 7.07 – 6.98 (m, 2H), 4.78 (s, 2H). 13C NMR
h. Then, 40 mg of RC2@SiO2ꢀNH2 spheres were redispersed in
(126 MHz, DMSO) δ 169.96, 156.64, 129.19, 124.72, 116.27, 64.71.
ethanol solution (60 %, 10 mL) and added to the activated FA
solution to react for 24 h with stirring at room temperature. The
mixture was centrifuged at 8000 rpm and washed with ethanol
several times and dried at 35 oC under vacuum.
Scheme 2 Synthesis of the pꢀHCPA.
In vitro cytotoxicity assay
Preparation of RC1ꢀRC5
The in vitro cytotoxicity studies of RC1ꢀRC5 was assessed by means
of MTT assay. The HepG2 and 293T cells were incubated in 96ꢀwell
plates with cell density was 7×103 cells/well in cell culture media
(1640+10% FBS) in a humid environment with 5% CO2 at 37 oC for
24 h. The RC2@SiO2ꢀFA nanoparticles, free RC2 and blank
nanoparticles solutions were treated with cells for 24 h, 48 h, and 72
h. After incubating, each wells added 10 ꢁl MTT solution (5 mg/mL
in PBS) and the cells was incubated for 4 h. Finally, the crystals
were dissolved by DMSO after removing the media. The OD
(optical density) value was measured with the microplate reader.
Cell viability (%) was calculated as [(OD of test group ꢀ OD of blank
group) / (OD of control group ꢀ OD of blank group)] × 100.
An appropriate amount of NaOH (0.2 mmol/L) solution was added
dropwise to pꢀHCPA ethanol solution under stirring to adjust the pH
value to approximately 7. Then the LnCl3 (Ln = Er, Ho, Sm, Pr, Ce)
ethanol solution was added into this mixture under stirring with the
molar ratio of Ln3+:pꢀHCPA=1:3. Then, the mixtures was
transferred into a 25 mL microwave tube and heated by microwave
under autogenous pressure at 100 oC for 1 h at 100ꢀ200W. After
cooled to room temperature and filtered, the colourless crystals of
RC1ꢀRC5 suitable for the Xꢀray diffraction were obtained directly on
the filter paper or continued to be cultivated by slowly evaporating
the filtrate at room temperature. RC1ꢀRC5 were stable enough which
can retain their structural integrity at room temperature for a
considerable length of time. Anal. calc. For RC1, C48H48Cl6O24Er2:
37.02; H, 3.09 %. Found: C, 37.01; H, 3.11 %. IR data (cmꢀ1): v(Oꢀ
H): 3409 b; vasym(COOꢀ):1630 s, 1580; vsym(COOꢀ): 1488 s, 1429 s;
v(ArꢀOꢀC): 1173s, 1067s; v(ꢀCH2ꢀ): 610m. For RC2,
C48H48Cl6O24Ho2: C, 37.13; H, 3.09 %. Found: C, 37.11; H, 3.09 %.
IR data (cmꢀ1): v(OꢀH): 3409 b; vasym(COOꢀ): 1870; vsym(COOꢀ): 1488
s, 1429 s; v(ArꢀOꢀC): 1173s, 1067s; v(ꢀCH2ꢀ): 611m. For RC3,
C48H40Cl6O20Sm2: C, 39.72; H, 2.76 %. Found: C, 39.71; H, 2.77 %.
IR data (cmꢀ1): v(OꢀH): 3414 b; vasym(COOꢀ): 1875; vsym(COOꢀ): 1491
s, 1431 s; v(ArꢀOꢀC): 1067s, 1008s; v(ꢀCH2ꢀ): 641m. For RC4,
C24H26Cl3O13Pr: C, 37.42; H, 3.38 %. Found: C, 37.41; H, 3.37 %.
IR data (cmꢀ1): v(OꢀH): 3397 b; vasym(COOꢀ): 1875; vsym(COOꢀ): 1491
s, 1425 s; v(ArꢀOꢀC): 1063s, 1008s; v(ꢀCH2ꢀ): 643m. For RC5,
C24H28Cl3O14Ce: C, 36.60; H, 1.78 %. Found: C, 36.59; H, 1.79 %.
IR data (cmꢀ1): v(OꢀH): 3402 b; vasym(COOꢀ): 1873; vsym(COOꢀ): 1490
s, 1431 s; v(ArꢀOꢀC): 1063s, 1012s; v(ꢀCH2ꢀ): 635m.
Xꢀray crystal structure determination
All crystallographic data were collected on a Bruker SMART CCD
area detector diffractometer at 298(2)
K
with graphite
monochromatized MoꢀKα radiation (λ=0.71073 Å) in ω scan mode,
and the data reduction was performed using Bruker SAINT. The
crystal structures were resolved by direct methods and refined with
fullꢀmatrix leastꢀsquares refinement on F2 with anisotropic
displacement parameters for nonꢀH atoms using SHELXTL.50 All
nonꢀhydrogen atoms were refined anisotropically. The hydrogen
atoms except for those of water molecules were generated direct
methods. Structural plots were generated with Diamond. The details
of the crystal parameters, data collection, and refinements for the
RC1ꢀRC5 are summarized in Table 1, selected bond lengths and
angles for RC1ꢀRC5 are listed in Table S1, Supporting Information.
Bond lengths (Å) and angles (°) of hydrogenꢀbond for RC1ꢀRC5 are
listed in Table S2. CCDCꢀ1561435 RC1, CCDCꢀ1561436 RC2,
CCDCꢀ1561438 RC3 CCDCꢀ1561439 RC4 CCDCꢀ1561434 RC5
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Preparation of RC2@SiO2ꢀNH2 nanoparticles
In a 50 mL roundꢀbottom flask, RC2 (0.5umol) was dissolved in
distilled water (0.50 mL). A mixture of Triton Xꢀ100 (1.77 mL),
hexyl alcohol (1.80 mL) and cyclohexane (7.50 mL) was then added
with ultrasonication for 30 min. Then the mixture was placed in the
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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Table 1 Crystallographic Data and Structure Refinement Details for RC1ꢀRC5
Coordination polymer
RC1
RC2
RC3
RC4
RC5
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
a, Å
C48 H48 Cl6 O24 Er2
1556.08
C48 H48 Cl6 O24 Ho2 C24 H20 Cl3 O10 Sm
C24 H26 Cl3 O13 Pr
769.71
C24 H28 Cl3 O14 Ce
786.93
1551.42
298(2)
725.10
298(2)
298(2)
298(2)
293(2)
Orthorhombic
Pbca
Orthorhombic
Pbca
Triclinic
Monoclinic
P2(1)/c
Monoclinic
P2(1)/c
Pꢀ1
14.528(3)
9.303(2)
14.565(3)
9.341(2)
40.155(8)
90
7.836(2)
12.718(4)
13.981(1)
81.30(5)
79.29(5)
77.24(5)
1326.4(10)
2
9.9898(8)
36.886(3)
8.4551(7)
90
19.452(1)
8.797(1)
b, Å
c, Å
39.895(7)
90
18.022(2)
90
α (°)
β (°)
90
90
108.1740(10)
90
99.56(1)
γ (°)
90
90
90
Volume (Å3)
Z
5392.0(19)
4
5463(2)
2960.1(4)
4
3041.0(10)
4
4
Dc/g cmꢀ3
1.917
1.886
1.816
1.727
1.719
µ (mmꢀ1
F (000)
)
3.474
3.253
2.571
1.979
1.826
3064
3056
714
1536
1572
Crystal size (mm)
0.30 x 0.30 x 0.25
ꢀ17<=h<=17
ꢀ11<=k<=9
ꢀ39<=l<=47
23124 / 4795
0.1381
0.30 x 0.30 x 0.28
ꢀ19<=h<=18
ꢀ9<=k<=12
ꢀ52<=l<=53
33412 / 6796
0.0432
0.30 x 0.30 x 0.25
ꢀ10<=h<=9
ꢀ16<=k<=11
ꢀ18<=l<=17
9284 / 6431
0.0338
0.30 x 0.30 x 0.28
ꢀ13<=h<=11
ꢀ49<=k<=48
ꢀ11<=l<=11
20922 / 7365
0.0272
0.30 x 0.30 x 0.21
ꢀ25<=h<=25
ꢀ10<=k<=11
ꢀ18<=l<=23
20848 / 7489
0.0234
Index Range
Reflections collected
R (int)
Completeness (%)
97.6
99.2
98.5
99.5
99.8
Data / restraints / parameters
Goodnessꢀofꢀfit on F2
Final R indices [I>2sigma(I)]
4795 / 12 / 361
1.160
6796 / 0 / 361
1.110
6431 / 0 / 343
1.065
7365 / 0 / 370
1.145
7489 / 6 / 389
1.097
R1 = 0.0972
wR2 = 0.1981
R1 = 0.1166
wR2 = 0.2067
2.354 and ꢀ3.729
R1 = 0.0715
wR2 = 0.2484
R1 = 0794
wR2 = 0.2557
2.814 and ꢀ3.647
R1 = 0.0560
wR2 = 0.1609
R1 = 0.0682
wR2 = 0.1694
3.345 and ꢀ1.621
R1 = 0.0348
wR2 = 0.1041
R1 = 0.0408
wR2 = 0.1121
1.300 and ꢀ2.891
R1 = 0.0247
wR2 = 0.0665
R1 = 0.0337
wR2 = 0.0780
0.624 and ꢀ0.921
R indices (all data)
Largest diff .peak and hole (eÅ ꢀ3
)
Results and Discussion
Description of Crystal Structures.
The crystal structure of [Er2(pꢀCPA)6(H2O)6] RC1
RC1 and RC2 are isostructural differing only with respect to the
metal ion. Take the structure of RC1 to be described in detail here for
example. The centrosymmetric dimer found in the crystal structure
of RC1 is shown in Fig. 1. Singleꢀcrystal Xꢀray diffraction reveals
that complex RC1 crystallizes in triclinic crystal system and
Orthorhombic Pbca space group. As shown in Fig. 1, there are two
crystallographically independent Er (III) ion, six pꢀCPA ligands and
Fig. 1 The coordination environment of Er(III) in RC1.
six coordinated H2O molecules. Each Er (III) ion is coordinated with
six carboxylate oxygen atoms (O1, O2, O4, O7, O8, O8A) and three
oxygen atoms (O1W, O2W, O3W) from coordinated H2O molecules,
giving a tricapped triangular prism coordination geometry, with the
caps (O8, O1W, O1) of the three plane construct by the oxygen
atoms of O7ꢀO3WꢀO8AꢀO2W, O7ꢀO3WꢀO2ꢀO4 and O4ꢀO2ꢀO8Aꢀ
O2W, respectively. The length of the ErꢀO bonds range from
2.255(7) Å to 2.445(6) Å, with the average value of 2.370 Å.51
4 | J. Name., 2012, 00, 1-3
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O2A, O4, O5B, O7, O8, O8B) and one oxygen atoms (O1W) from
coordinated H2O molecule, giving a tricapped triangular prism
coordination geometry, with the caps (O7, O15B, O2A) of the three
plane construct by the oxygen atoms of O8ꢀO1ꢀO1WꢀO4, O1ꢀO8ꢀ
O8BꢀO1A and O1AꢀO8BꢀO4ꢀO1W, respectively. The length of the
SmꢀO bonds range from 2.245(7) Å to 2.456(7) Å, with the average
value of 2.362 Å.52
Fig. 2 The coordination polyhedron (a) and coordination modes (b, c) in RC1.
As is shown in Fig. 2, all the carboxylate groups show two kinds of
coordination modes: µ1ꢀη1:η1 and µ2ꢀη1:η2 and further crosslink the
neighboring Er(III) with coordination water molecules via O2ꢀ
H1WA/O1W, O3ꢀH3WA/O3W and O3WꢀH3WA/O2 hydrogen
bonds, forming the 1D chains with the [Er2(pꢀCPA)6(H2O)6] repeat
units. The carboxyl group oxygen atoms of O2 and O3 serve as
acceptors, and the oxygen atoms of O1W and O3W from
coordinated water molecules play a role of donors in the OꢀH/O
hydrogen bonds for detail.
Fig. 5 The coordination polyhedron (a) and coordination modes (b, c) in RC3.
Fig. 6 A view of the 1D chain along b axis in RC3.
Fig. 3 A view of the 1D chain along a axis in RC1.
In RC3, two Sm (III) are bridged by two carboxylate groups utilized
two kinds of coordinated modes µ2ꢀη1:η1 and µ3ꢀη1:η2, and further
The crystal structure of [Sm(pꢀCPA)3(H2O)] RC3
generate
a binuclear secondary building unit (SBU) [Sm(pꢀ
Refinement data revealed that RC3 crystallized in triclinic Pꢀ1 space
group. The asymmetric unit consists of one Sm (III) ions, three pꢀ
CPA ligands, and three coordinated water molecules. Each Sm (III)
ion is coordinated with eight carboxylate oxygen atoms (O1, O1A,
CPA)3(H2O)]n, producing the Sm···Sm distance of 4.2189(5) Å.
Neighbouring SBUs connect to each other via sharing the
carboxylate of pꢀCPA ligands to produce a 1D chain extending
along the b axis (Fig. 6).
The crystal structure of [Pr(pꢀCPA)3(H2O)]·3H2O RC4
Singleꢀcrystal Xꢀray diffraction analysis revealed that RC4
crystallized in Monoclinic crystal system, P2(1)/c space group. The
asymmetric unit of RC4 possesses one crystallographically
independent Pr (III) ion, three pꢀCPA ligands, one coordinated water
molecule, and three lattice water molecules. The PrꢀO bond lengths
vary from 2.537(2) to 2.560(3).53
Fig. 4 The coordination environment of Sm(III) in RC3.
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water. The coordination geometry around Ce(III) ion could be
described as a dicapped square antiprism coordination geometry,
with the two caps (O1, O5) of the two plane construct by the oxygen
atoms of O2WꢀO2ꢀO1WꢀO1B (top surfaces), and O5AꢀO8AꢀO4ꢀO7
(bottom surfaces), respectively. The length of the CeꢀO bonds were
range from 2.4546(16) Å to 2.8146(17) Å, with the average value of
2.5953 Å.54 In RC5, the totally deprotonated carboxy from pꢀCPA
ligands displays two different coordination modes of µ2ꢀη1:η1 and µ2ꢀ
η1:η2 (Fig. 5(b) and (c)), which linked neighbouring Ce(III) ions
generate a metalꢀbased 1D chain along the b axis (Fig. 10b).
Fig. 7 The coordination environment of Pr(III) in RC4.
Centre Pr (III) is nine coordinated (Fig. 7), connected by eight
oxygen atoms from carboxyl (O1, O1A, O2, O4, O5B, O7, O7B,
O8B) of pꢀCPA ligands, one oxygen atom (O1W) from coordinated
water molecule. As shown in Fig. 8a, similar to RC1, coordination
geometry around Pr (III) ions in RC4 are distorted tricapped
triangular prism, with the caps (O7B, O2, O1A) of the three plane
construct by the oxygen atoms of O5BꢀO8BꢀO1WꢀO1, O1WꢀO1ꢀ
O4ꢀO7 and O5Bꢀ8BꢀO7ꢀO4, respectively. The PrꢀO covalent bond
distances are within the range of 2.420 (3)ꢀ2.621 (2) Å, with the
average value of 2.520 Å, which is consistent quite well with the
other praseodymium complexes reported.
Fig. 10 (a) The coordination polyhedron and (b) A view of the 1D chain along c
axis in RC5.
Structures comparison of RC1ꢀRC5
RC1ꢀRC5, derived from 4ꢀchlorophenoxyacetic acids, have both
many similarities and specific structural features. Carboxyl
group shows two kinds of coordination modes, µ2ꢀη1:η1 (RC1ꢀ
RC5), µ2ꢀη1:η2 (RC1ꢀRC5). Coordinated water were present in
RC1ꢀRC5, but lattice water were only present in RC4 and RC5.
In fact, the ꢀOCH2COOꢀ spacer group of ligands was flexible
through the rotate of C
structural diversity.
ꢀO and CꢀC bonds, which can lead to
Fig. 8 (a) The coordination polyhedron and (b) A view of the 1D chain along c
axis in RC4.
Synthesis and characterization of RC2@SiO2 nanoparticles
Five RCs were easily synthesised by mixing the deprotonationed 4ꢀ
chlorophenoxyacetic acid and rareꢀearth metal (Er3+, Ho3+, Sm3+,
Pr3+, Ce3+) with the assisted of facile microwave method. Microwave
radiation has been widely used to synthesize organic molecules,
zeolites, nanoparticles since 1946. Absolute advantages of rapid
reaction time, higher yields, and uniform product have made
microwave synthesis become one of the most convenient method to
get chemical compounds during this period. However, it still keeps
an unremarkable fields in synthesizing coordination compounds.
Similar to RC3, two Pr(III) are bridged by two carboxylate groups
utilized two kinds of coordinated modes µ2ꢀη1:η1 and µ2ꢀη1:η2, and
sharing the carboxylate of pꢀCPA ligands to produce a 1D chain
extending along the a axis (Fig. 8b).
The crystal structure of [Ce(pꢀCPA)3(H2O)2]·2H2O RC5
It crystallizes in the centrosymmetric monoclinic P2(1)/c space
group. The structure of RC5 contains one Ce(III) ion, three pꢀCPA
ligand, two coordinated water molecules and two lattice water
molecules. As shown in Fig. 9, Ce(III) is tenꢀcoordinated with eight
In this manuscript, W/O microemulsions are a very wisely choice for
the synthesis of silica coated RC2. In order to stabilize the complexes
spheres and make preparation for the modification of targeted
molecules, a thin shell of amorphous silica was used to coat the
surface of the complexes spheres by the reverse microemulsion
method. Fig. 11 shows the SEM and TEM images of the
nanoparticles. The average sizes of the particle are mainly 100 nm.
The thickness of the silica shell is about 5 nm from the TEM
micrograph (Fig. 11b). The size distributions of nanoparticles were
also further confirmed by dynamic light scattering (DLS)
measurements and the results coincide well with those obtained from
Fig. 9 The coordination environment of Ce(III) in RC5.
carboxylate oxygen atoms (O1, O1B, O2, O4, O5, O5A, O7, O8A) the SEM and TEM images (Fig. 12).
from ligands, and two water oxygen (O1W, O2W) from coordinated
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Fig. 11 SEM (a) and TEM (b) images of RC2@SiO2ꢀFA.
Fig. 13 UVꢀvis spectra of FA and RC2@SiO2ꢀFA.
UVꢀvis and fluorescence properties
The complexes of 4ꢀchlorophenoxyacetic acid ligands with rareꢀ
earth metal were first investigated by UVꢀvis absorption
spectroscopy in distilled water. As shown in Fig. 14, we found that
the absorption bands of five complexes mainly located in 230 and
280 nm.
Fig. 12 DLS data of the RC2@SiO2ꢀFA.
Conjugation of folic acid
In order to realize the targeted delivery of metalꢀbased
anticancer drug, folic acid (FA) which was attractive targeting
ligands was covalently linked to amino groups through
carbodiimide coupling to achieve active targeting. The
conjugation of FA on RC2@SiO2ꢀNH2 spheres could be
identified by measuring UVꢀvis absorption. As Fig. 13 shows,
the main characteristic UVꢀvis absorption peak of FA has a
bathochromic shift from 283 nm to 287 nm. The bathochromic
shift reveals the modification in the environment of the FA
between the free and grafted states, which indicates that FA has
been successfully grafted to the surface of the RCs@SiO2
spheres.
Fig. 14 UVꢀvis spectra of five complexes.
Complexes with rareꢀearth metal centers have been widely
investigated for their fluorescence properties. The rareꢀearth metal
usually exhibit weak emissions under direct excitation due to their
low molar absorptivity. Rareꢀearth metal centers emission can be
sensitized by coordinating ligands with πꢀπ conjugated systems,
which can efficiently absorb and transfer the energy. Fluorescences
of five complexes were investigated at room temperature under
excitation and emission wavelengths of 280 and 310ꢀ330 nm. RC2
has abundant coordination waters molecules, which increases the
probability of forming intermolecular and intramolecular hydrogen
bonds to a certain extent, and resulting in a red shift of fluorescence.
Fig. 15.
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Fig. 17 In vitro cytotoxicity of SiO2ꢀFA. Data represent mean ± SD (n=5).
Fig. 15 Fluorescence spectra of five complexes, λex=280 nm.
Fig. 18 shows the cell viabilities against RC2@SiO2ꢀFA at
complexes concentrations of 10, 50, 100, 150 and 200ug/mLꢀ1. That
the cytotoxicity of RC2@SiO2ꢀFA is consistently higher than that of
SiO2@RC2ꢀFA at all tested concentrations is due to the enhanced
cellular uptake that results from the enhance permeability and
retention (EPR) effect as well as the FA receptor mediated
endocytosis, while free coordination polymer shows low cytotoxicity
than RC2@SiO2ꢀFA vesicles because of the different cellular uptake
and drug release behaviour between them. However, RC2@SiO2ꢀFA
can efficiently deliver complexes into HepG2 cells, resulting in
excellent anticancer therapeutic efficacy compared to free RC2,
indicating the successful conjugation of FA to the surface of the
RC2@SiO2ꢀNH2 and the excellent tumor targeting ability.
Effect of the five RC1ꢀRC5 on the growth of HepG2 cancercells
The effect of the five RCs at a concentration of 10umol/mL was
studied on HepG2 cancer cells and the results are displayed in Fig.
16. Among the five investigated RCs, all of them were confirmed to
have a certain activity. Due to higher molecular weight and greater
affinity for cancer cells, RC2 possess better toxicity than other RCs.
(The Cell viability of the five RCs was 86, 63, 88, 84, 92,
respectively).
Fig. 16 In vitro cytotoxicity of five RCs. Data represent mean ± SD (n=5).
For drug delivery systems, it is important to investigate the
cytotoxicity of the vehicles. As MTT assay (Fig. 17) showed, no
obvious cytotoxicity of SiO2ꢀFA spheres on cell viabilities of HepG2
and 293T cells was observed. It can be seen that the SiO2ꢀFA
vehicles are scarcely cytotoxic to HepG2 cells and 293T cells even
at up to 80ug/mL, indicating its good biocompatible characteristics.
All the RC1ꢀRC5 has a certain activity on HepG2 cells. Take the
complex 2 (named RC2) to be described in detail here for example.
The effects of RC@SiO2ꢀFA spheres on cell viabilities of HepG2
cells at 24 h were also investigated and did show obvious
cytotoxicity.
Fig. 18 In vitro cytotoxicity of RC2 and RC2@SiO2ꢀFA. Data represent mean ±
SD (n=5).
Conclusions
In this contribution, by rapid microwave method with the advantages
of shorter reaction time, higher yields, and uniform product, five
novel RCs was prepared. Their structures were well determined by
Xꢀray crystal diffraction. The carboxyl group showed two kinds
of coordination modes of µ2ꢀη1:η1 and µ2ꢀη1:η2 among RC1ꢀRC5
Coordinated water was present in RC1ꢀRC5, but lattice water
was only present in RC4 and RC5. Furthermore, the
.
ꢀ
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OCH2COOꢀ spacer group of ligands was flexible because of the 16 K. Ott, H. Vogelsang, J. Mueller, K. Becker, M. Muller, U.
rotation of the C
structural diversity. A targeted RC delivery system based on
ꢀ
O and C
ꢀ
C bonds, thereby resulting in
Fink, J. R. Siewert, H. Hofler and G. Keller, Clin. Cancer Res.,
2003, 9, 2307ꢀ2315.
encapsulating complexes into the SiO2 spheres was successfully 17 U. Kostiv, I. Kotelnikov, V. Proks, M. Slouf, J. Kucka, H.
constructed by facile W/O reverse microemulsion method. FA was
used as the targeting component for its high affinity with FRs in
Engstova, P. Jezek and D. Horak, Acs Appl. Mater. Inter., 2016,
8, 20422ꢀ20431.
HepG2 cancer cells. The FAs conjuncted to the surfaces of the 18 S. De, S. Mohanty, S. K. Nayak, S. K. Verma and M. Suar,
spheres by the amide reaction. The tumourꢀtargeting conjugated FAs Nano, 2015, 10, 1550091, 1ꢀ14.
and acid responsive spheres exhibited great potential in targeted 19 Chen, E. K. L. Yeow, G. Liu, M. Olivo and B. Xing, Nat.
anticancer drug delivery and cell imaging. The FAꢀtargeted Commun., 2016, 7. 10432, 1ꢀ9.
mesoporous silica nanocarriers can be used to deliver antitumour 20 A. Palasz and P. Czekaj, Acta Biochim. Pol., 2000, 47, 1107ꢀ
RCs and provide a basis for the further study of affordable nonꢀ 1114.
platinumꢀbased complexes. We believe that through further researeh, 21 L. J. Anghileri, ArzneimittelꢀForschung, 1975, 25, 793ꢀ795.
more RC spheres suitable for application in bioꢀimaging and 22 M. Esposito, P. Collecchi, S. Brera, E. Mora, A. Mazzucotelli,
anticancer therapy will be discovered.
M. Cutolo and M. Oddone, Sci. Total. Environ, 1986, 50, 55ꢀ
63.
23 S. Hirano and K. T. Suzuki, Environ. Health Persp., 1996,
1041, 85ꢀ95.
Acknowledgements
The authors gratefully acknowledge the financial supports from the
National Natural Science Foundation of China (Grant No. 21473136,
Grant No. 21103140).
24 G. J. Beyer, W. G. Franke, K. Hennig, B. A. Johannsen, V. A.
Khalkin, M. Kretzschmar, N. A. Lebedev, R. Munze, A. F.
Novgorodov and K. Thieme, Appl. Radiat. Isotopes, 1978, 29,
673ꢀ681.
25 X. Liu, Q. Gan and C. G. Feng, Inorg. Chim. Acta., 2016, 450,
299ꢀ303.
26 R. D. Teo, J. Termini and H. B. Gray, J. Med. Chem., 2016, 59,
6012ꢀ6024.
27 L. Wang, W. J. Li and Y. M. Song, Rsc Adv., 2014, 4, 42285ꢀ
42292.
28 Q. L. Guan, Y. H. Xing, J. Liu, W. J. Wei, R. Zhang, X. Wang
and F. Y. Bai, J. Inorg. Biochem., 2013, 128, 57ꢀ67.
29 B. D. Wang, Z. Y. Yang, P. Crewdson and D. Q. Wang, J.
Inorg. Biochem., 2007, 101, 1492ꢀ1504.
30 V. T. Huynh, P. de Souza and M. H. Stenzel, Macromolecules.,
2011, 44, 7888ꢀ7900.
31 A. C. Antony, Annu. Rev. Nutr., 1996, 16, 501ꢀ521.
32 C. P. Leamon and P. S. Low, Drug Discov. Today., 2001, 6, 44ꢀ
51.
33 C. Müller and R. Schibli, J. Nucl. Med., 2011, 52, 1ꢀ4.
34 B. A. Kamen and A. Capdevila, P. Natl. Acad. Sci. Usa., 1986,
83, 5983ꢀ5987.
35 J. Ming, T. F. Jiang, Y. H. Wang and Z. H. Lv, Sensor Actuat.
BꢀChem., 2017, 252, 450–457.
36 L. R. Coney, A. Tomassetti, L. Carayannopoulos, V. Frasca, B.
A. Kamen, M. I. Colnaghi and V. R. J. Zurawski, Cancer Res.,
1991, 51, 6125ꢀ6132.
37 Q. Liu, N. Xu, L. Liu, J. Li, Y. Zhang, C. Shen, K. Shezad, L.
Zhang, J. Zhu and J. Tao, Acs Appl. Mater. Inter., 2017, 9,
21673ꢀ21687.
38 J. Li, K. Liu, H. Chen, R. Li, M. Drechsler, F. Bai, J. Huang, B.
Z. Tang and Y. Yan, Acs Appl. Mater. Inter., 2017, 9, 21706ꢀ
21714.
Notes and references
1
D. Cirri, S. Pillozzi, C. Gabbiani, J. Tricomi, G. Bartoli, M.
Stefanini, E. Michelucci, A. Arcangeli, L. Messori and T.
Marzo, Dalton Trans., 2017, 46, 3311–3317.
2
A. Eskandari, J. N. Boodram, P. B. Cressey, C. Lu, P. M.
Bruno, M. T. Hemann and K. Suntharalingam, Dalton Trans.,
2016, 45, 17867ꢀ17873.
3
4
5
6
7
8
9
Y. Yang, S. Deng, Q. Zeng, W. Hu and T. Chen, Dalton Trans.,
2016, 45, 18465ꢀ18475.
J. P. Parker, M. Devocelle, M. P. Morgan and C. J. Marmion,
Dalton Trans., 2016, 45, 13038ꢀ13041.
X. F. Zhao, Y. Ouyang, Y. Z. Liu, Q. J. Su, H. Tian, C. Z. Xie
and J. Y. Xu, New J. Chem., 2014, 38, 955ꢀ965.
B. Rosenberg and L. Van Camp, Cancer Res., 1970, 30, 1799ꢀ
1802.
L. R. Kelland and N. P. Farrell, Platinum Based Drugs in
Cancer Therapy, Humana Press, Totowa, NJ, USA, 2000.
Y. F. Dong, L. M. Zhou, Q. Tian. F, Y. Zheng and L. Sanche, J
Phys. Chem. C, 2017, 121, 17505−17513.
T. Andre, C. Boni, L. MounedjiꢀBoudiaf, M. Navarro, J.
Tabernero, T. Hickish, C. Topham, M. Zaninelli, P. Clingan, J.
Bridgewater, I. TabahꢀFisch and A. de Gramont, New Engl. J.
Med., 2004, 350, 2343ꢀ2351.
10 S. Derijcke and Johan Vansteenkiste, Breathe, 2009, 6, 10ꢀ10.
11 V. G. Vaidyanathan and B. U. Nair, Dalton Trans., 2005, 17,
2842ꢀ2848.
12 L. F. Tan, F. Wang, H. Chao, Y. F. Zhou and C. Weng, J. Inorg.
Biochem., 2007, 101, 700ꢀ708.
13 P. Heffeter, U. Jungwirth, M. Jakupec, C. Hartinger, M.
Galanski, L. Elbling, M. Micksche, B. Keppler and W. Berger,
Drug Resist Update., 2008, 11, 1ꢀ16.
14 M. Shimada, H. Itamochi and J. Kigawa, Cancer management
and research, 2013, 5, 67ꢀ76.
39 D. Depan, J. Shah and R. D. K. Misra, Mat. Sci. Eng. CꢀMater.,
2011, 31, 1305ꢀ1312.
40 C. Jo, H. J. Lee and M. Oh, Adv. Mater., 2011, 23, 1716–1719.
41 C. H. Lin, S. H. Cheng, W. N. Liao, P. R. Wei, P. J. Sung, C. F.
Weng and C. H. Lee, Int. J Pharmaceut., 2012, 429, 138ꢀ147.
15 Z. J. Shire and G. R. Loppnow, Anal. Bioanal. Chem., 2012,
403, 179ꢀ184.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Page 10 of 11
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DOI: 10.1039/C7DT03000B
ARTICLE
Journal Name
42 L. L. Zhang, H. J. Yin, Z. Xiong, Y. Q. Xiong and W. J. Xu, J. 49 G. Arrachart, I. Karatchevtseva, D. J. Cassidy, G. Triani, J. R.
Macromol. Sci. B., 2011, 50, 2255ꢀ2270.
Bartlett and M. W. C. Man, J. Mater. Chem., 2008, 18, 3643ꢀ
43 K. Kohara, S. Yamamoto, L. Seinberg, T. Murakami, M.
3649.
Tsujimoto, T. Ogawa, H. Kurata, H. Kageyama and M. Takano, 50 G. M. Sheldrick, Acta Crystallogr. Sect. CꢀCryst. Struct., 2015,
Chem. Commun., 2013, 49, 2563ꢀ2565. 71, 3ꢀ8.
44 J. Wang, Q. Xiao, H. Zhou, P. Sun, Z. Yuan, B. Li and T. Chen, 51 L. A. Galan, B. L. Reid, S. Stagni, A. N. Sobolev, B. W.
Adv. Mater., 2006, 18, 3284ꢀ3288.
45 A. GuerreroꢀMartinez, J. PerezꢀJuste and L. M. LizꢀMarzan,
Adv. Mater., 2010, 22, 1182ꢀ1195.
Skelton, M. Cocchi, J. M. Malicka, E. ZysmanꢀColman, E. G.
Moore, M. I. Ogden and M. Massi, Inorg. Chem., 2017, 56,
8975−8985.
46 C. Tsai, Y. Pan, C. Ting, S. Vetrivel, A. S. T. Chiang, G. T. K. 52 E. Kreidt, C. Dee and M. Seitz, Inorg. Chem., 2017, 56,
Fey and H. Kao, Chem. Commun., 2009, 33, 5018ꢀ5020. 8752−8754.
47 C. Lin, S. Cheng, W. Liao, P. Wei, P. Sung, C. Weng and C. 53 S. K. Gupta, G. A. Bhat and R. Murugavel, Inorg. Chem., 2017,
Lee, Int. J. Pharmaceut., 2012, 429, 138ꢀ147. 56, 9071−9083.
48 D. Chen, L. L. Li, F. Q. Tang and S. O. Qi, Adv. Mater., 2009, 54 A. Karmakar, G. M. D. M. Rubio, A. Paul, M. F. C. Guedes Da
21, 3804ꢀ3807.
Silva, K. T. Mahmudov, F. I. Guseinov, S. A. C. Carabineiro and
A. J. L. Pombeiro, Dalton Trans.,, 2017, 46, 8649ꢀ8657.
10 | J. Name., 2012, 00, 1-3
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Facile synthesis of highly biocompatible folic acid-functionalized SiO2 encapsulated rare-earth
metal complexes nanoparticles and its application on targeted metal-based complex delivery.