In Vitro Anticancer Activity of Nanoformulated Mono- and Di-nuclear Pt Compounds

Article abstract of DOI:10.1002/asia.202100901

Nanoformulations of mononuclear Pt complexes cis-PtCl₂(PPh₃)₂ (1), [Pt(PPh₃)₂(L?Cys)] ? H₂O (3, L?Cys=L-cysteinate), trans-PtCl₂(PPh₂PhNMe₂)₂ (4;

Full text of DOI:10.1002/asia.202100901

doi.org/10.1002/asia.202100901
Full Paper
In Vitro Anticancer Activity of Nanoformulated Mono- and
Di-nuclear Pt Compounds
Pan Wang,[a] Jian-Wei Wang,[b] Wen-Hua Zhang,*[a] Hongzhen Bai,*[b] Guping Tang,[b] and
David J. Young[c]
Dedicated to Prof. Tzi Sum Andy Hor on the occasion of his 65th birthday.
Abstract: Nanoformulations of mononuclear Pt complexes
cis-PtCl2(PPh3)2 (1), [Pt(PPh3)2(LÀ Cys)]·H2O (3, LÀ Cys=L-cystei-
nate), trans-PtCl2(PPh2PhNMe2)2 (4; PPh2PhNMe2 =4-(dimeth-
ylamine)triphenylphosphine), trans-PtI2(PPh2PhNMe2)2 (5) and
dinuclear Pt cluster Pt2(μ-S)2(PPh3)4 (2) have comparable
cytotoxicity to cisplatin against murine melanoma cell line
B16F10. Masking of these discrete molecular entities within
the hydrophobic core of Pluronic® F-127 significantly boosted
their solubility and stability, ensuring efficient cellular uptake,
giving in vitro IC50 values in the range of 0.87–11.23 μM.
These results highlight the potential therapeutic value of Pt
complexes featuring stable PtÀ P bonds in nanocomposite
formulations with biocompatible amphiphilic polymers.
Introduction
through the enhanced permeability and retention (EPR) effect
with a simultaneous reduction of adverse side effects.[7a,8a,9]
In addition to the EPR effect (passive targeting),[10] nano-
technology allows for multiple therapeutic modalities to be
integrated into one formulation. These combinative therapies[11]
can achieve targeting capability[12] and may combine with gene
therapy, radiotherapy, photodynamic therapy and/or
immunotherapy.[3,5e,11c,13] In this work, we have studied the
nanoparticle formation of a class of mononuclear and dinuclear
Pt-based complexes featuring P- and/or S-based ligands using
amphiphilic polymer Pluronic® F-127.[14] These complexes
Since the seminal discovery that cisplatin exhibited anti-
proliferative behavior against Escherichia coli in 1965,[1] and its
approval by the US Food and Drug Administration (FDA) in
1978 for the treatment of metastatic testicular, ovarian, and
bladder cancers, cisplatin and related Pt-based complexes have
been a mainstay of chemotherapeutic antitumor regimens.[2]
Other FDA or regionally approved Pt-based drugs include
carboplatin,
oxaliplatin,
nedaplatin,
heptaplatin,
and
lobaplatin.[3] In addition to these clinically approved chemo-
therapeutic drugs, a huge number of Pt-based coordination
complexes supported by diverse ligand types have proven
effective in cellular and animal cancer models.[2,4]
included
mononuclear
cis-PtCl2(PPh3)2
LÀ Cys=L-cysteinate),
(1),[15]
[Pt-
(PPh3)2(LÀ Cys)]·H2O
(3,
(4,
trans-
PtCl2(PPh2PhNMe2)2
PPh2PhNMe2 =4-(dimethylamine)
Small molecular drugs, including Pt-based drugs, have been
widely integrated with nanotechnology to improve their
therapeutic efficacy.[5] One successful example is the liposomal
formation (e.g. SPI-77,[6] Lipoplatin,[7] LiPlaCis[8]) of cisplatin
within nano-sized hydrophilic bilayers of phospholipids.[8a,9]
Liposomal encapsulation enhances the circulation time of the
drug, leading to increased drug accumulation at the tumor site
triphenylphosphine)[16] and trans-PtI2(PPh2PhNMe2)2 (5), as well
as a dinuclear Pt cluster Pt2(μ-S)2(PPh3)4 (2).[17] We hypothesized
that the use of a strong-field P-based ligand would facilitate the
dissociation of PtÀ Cl (1), PtÀ S (2, 3), or PtÀ N (3) bonds at the
trans position to facilitate DNA cross-linking, similar to the
action mechanism of cisplatin.
Glutathione (GSH), an S-based reducing species over-ex-
pressed in cancer cells, exhibits similar donor strength to Cl, S,
and N, and may also serve to accelerate dissociation of PtÀ Cl
(1), PtÀ S (2, 3) and PtÀ N (3) bonds to enhance DNA binding. We
herein report the synthesis and structural relationships of 1–5,
their nanoparticle formulation using Pluronic® F-127 and anti-
cancer properties against murine melanoma B16F10 cells line.
The favorable results obtained with these nanocomposites
indicate that formulations of Pt complexes bearing stable PtÀ P
bond may be promising leads for new anticancer chemo-
therapies.
[a] P. Wang, Prof. W.-H. Zhang
College of Chemistry, Chemical Engineering and Materials Science
Soochow University
Suzhou 215123 (P. R. China)
E-mail: whzhang@suda.edu.cn
[b] Dr. J.-W. Wang, Dr. H. Bai, Prof. G. Tang
Department of Chemistry
Zhejiang University
Hangzhou 310028 (P. R. China)
E-mail: hongzhen_bai@zju.edu.cn
[c] Prof. D. J. Young
College of Engineering Information Technology & Environment
Charles Darwin University
Darwin, Northern Territory 0909 (Australia)
Results and Discussion
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100901
There is still an intense research interest in developing novel Pt-
based therapeutics for cancer treatment four decades after the
This manuscript is part of a special collection on Metals in Functional Ma-
terials and Catalysis.
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approval of cisplatin.[4c,5a,9] A primary challenge is to improve
patient benefit by reducing damage to normal tissues resulting
in nausea and hair loss among other side effects. This can
potentially be achieved through nanotechnology to provide
stable and biocompatible particles of suitable size (e.g. in the
range of 50–200 nm) for targeted drug delivery.[18] Multiple
therapeutic and/or diagnostic modalities have been integrated
to try and achieve synergistic and spatiotemporal treatment.[19]
Aside from nanomaterial assembly, carefully designed Pt-based
complexes can also be used to achieve fine-tuning of the drug-
biomolecule interaction.[4c,e,f,20]
A central Pt(II/IV) coordinated by specific ligand types can
achieve nucleic acid selectivity and apoptosis.[4b,21] A well-known
example is oxaliplatin that can induce immunogenic cell death
(ICD) in the treatment of colon cancer, while cisplatin and other
clinically adapted platinum drugs fail to do so.[4e,22] ICD is a
critical step in immunotherapy by priming T-cell activation. Its
combination with immunotherapeutic modalities, such as PD-1/
PD-L1 therapy is expected to show clinical potential for the
treatment of tumors that are resistant to immunotherapy alone
(cold tumor).[23] Ang et al.[4e,24] screened a series of Pt-complexes
and found that those bearing a biscarbene ligand, which they
termed ‘PlatinER’ exhibit superior ICD properties.
It is well-established that the major mechanism of cisplatin
chemotherapy is that the complex becomes activated intra-
cellularly by the aquation of one of the two ClÀ ‘leaving’ groups,
and subsequently binds to DNA, forming metallated DNA
adducts.[2,25] The driving force is the superior donor strength of
NH3 relative to ClÀ and thus the PtÀ Cl bond trans to Pt-NH3 is
more susceptible to H2O exchange. By analogy, we speculate
that for Pt-based species with phosphine ligands, such as cis-
PtCl2(PPh3)2 (1, Scheme 1), the two PtÀ Cl bonds that are trans to
the two PtÀ P bonds should labile, facilitating DNA cross-linking,
leading to cell apoptosis. The lower ClÀ concentration of 10–
20 mM in the cytoplasm relative to blood (0.1 M) also contrib-
utes to PtÀ Cl bond dissociation.[26]
Syntheses and structural characterization of 1–5
Mononuclear 1 and dinuclear cluster 2 were readily synthesized
from the reaction of K2PtCl4 and PPh3 following reported
protocols (Scheme 1).[27] The facile inclusion of the S atom into
the coordination sphere of 1 to give dinuclear cluster 2
prompted us to study its reaction with S-based amino acids
contain SH, as the transactivator of transcription (TAT) peptide
and internalizing arginine-glycine-aspartic acid (iRGD) cyclic
peptide have demonstrated transmembrane and/or tumor-
targeting, in addition to other useful properties.[28] The reaction
of 1 and LÀ Cys in toluene at room temperature gave rise to
zwitterionic 3 in 40% yield. The positive charges of Pt2+ in 3 are
balanced by the deprotonated SH and one deprotonated and
uncoordinated carboxylate.
The hyperpolarized membrane potential of mitochondria in
cancer cells has been exploited in anticancer drug design by,
for example, incorporating cationic functionality.[4c,29] In this
regard, the use of ligand PPh2PhNMe2 is preferred as the À NMe2
function in the ligand is assumed to readily react with MeI to
give the À [NMe3]+ cation.[30] The reaction of K2PtCl4 and
PPh2PhNMe2 gave rise to 4 (33% yield) wherein a pair of
PPh2PhNMe2 ligands and a pair of Cl is in an unexpected trans
configuration (Scheme 1).[27]
Notably, the reaction of 4 with a large excess of MeI in
CH2Cl2 failed to produce the cationic compound as expected
(Scheme 1), but gave mononuclear complex 5 wherein the two
ClÀ of 4 were replaced by IÀ (63% yield) with the retention of
the trans configuration. It is notable that 5 was insoluble in
most solvents such as DMSO, DMF, MeCN, and CHCl3, and only
slightly soluble in CH2Cl2 and MeOH. The strong propensity of
Pt2+ toward soft IÀ coupled with the low solubility of 5 might
be the reason for the unsuccessful formation of the cationic
species.
1
Complexes 1–4 were characterized by H, 13C, and 31P NMR
spectroscopy in CDCl3 (Figures S1–S4; 5 was too insoluble).
Single proton decoupled 31P resonances at 14.3 ppm (1, Fig-
ure S1c), 28.0 ppm (2, Figure S2c), 10.7/18.4 ppm (3, doublet,
Figure S3c), and 18.3 ppm (4, Figure S4c) indicated high purity.
It should be noted that when the single crystals of 4 were
immersed in CD2Cl2 overnight, its 31P NMR indicated that the
Scheme 1. Synthesis of 1–5 using K2[PtCl4] as the starting material.
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cycle. The two CÀ O bond distances of the carboxylate have
nearly identical values (C3À O1=1.251(13) Å; C3À O2=1.241(13)
Å), an indication of a conjugated, deprotonated, and uncoordi-
nated carboxylate, and thus consistent with the zwitterionic
nature of 3.[32]
The synthesis of 5 (Figure 1e) from 4 (Figure 1d) was
confirmed by their distinctive PtÀ Cl (2.3074(14) Å; 4) and PtÀ I
(2.6177(4) Å; 5) distances. The XÀ PtÀ X bonds (X=Cl and I)
exhibited torsional freedom concerning the PÀ PtÀ P axis. The
°
CÀ PÀ PtÀ Cl and CÀ PÀ PtÀ I torsional angles were À 133.8 (4) and
°
104.7 (5), respectively.
Nanoparticle self-assembly of 1–4 using Pluronic® F-127
Figure 1. Single crystal structure of 1 (a), 2 (b), 3 (c), 4 (d), and 5 (e). Colour
codes: Pt (dark magenta), P (orange), S (yellow), Cl (green), I (purple), O
(red), N (blue), C (black). All hydrogen atoms and solvates are omitted for
clarity.
One of the key obstacles when using Pt-based drugs, including
cisplatin, for chemotherapy is their limited solubility. As a
consequence, Pt drugs generally exhibit short circulation times
with low accumulation at the tumour site, leading to side
effects. Cisplatin, for example, has notable nephron- and
ototoxicity.[33] Nano-carriers based on the self-assembly of
amphiphilic small molecules or block copolymers, such as
singlet at 18.6 ppm shifted to 12.0 ppm, suggesting a trans-to-
cis structural change (Figure S5a, and S5b). Similar observation
was also made by Brune et al.[16] who demonstrated that 4
undergoes a trans-to-cis structural change in CH2Cl2 at r.t. The
purities of all five complexes were confirmed by microanalyses
and Fourier-transform infrared (FT-IR) spectra. Solid-state struc-
tures were elucidated by single-crystal X-ray diffraction (Table 1,
Figure 1).
The cis configuration of 1 (Figure 1a) and the dimeric
structure of 2 (Figure 1b) have been reported previously.[15,31]
Both the S and N atoms in the LÀ Cys ligand of 3 coordinate to
the Pt2+ (Figure 1c) to give a stable five-membered metallo-
DSPE-PEG2K[34]
and
PEO-PPO-PEO
(Pluronic
polymer
micelles)[14,35] have been widely used to improve the solubility
of Pt drugs. When assembled in aqueous solution with these
(usually lipophilic) drugs, the hydrophobic segment of the
amphiphilic molecules aggregates to form the core of the
micelle, functioning as the host region to encapsulate the drug,
while the hydrophilic end exposed to water endows water
solubility, stability, and biocompatibility.
We employed Pluronic® F-127 (PEO99-PPO67-PEO99) as the
host material to prepare nanoparticles of 1–4 (the nanoparticle
Table 1. Summary of crystallographic data for 1–5.
Compounds
1
2
3
4
5
Formula
FW
Crystal system
Space group
a (Å)
b (Å)
c (Å)
C36H30Cl2P2Pt
790.52
monoclinic
P21/c
32.373(2)
9.5967(6)
19.4538(12)
90.00
94.520(2)
90.00
6025.0(6)
8
C72H60P4Pt2S2
1503.38
Triclinic
P-1
12.1221(7)
13.2267(8)
21.1703(12)
83.9490(17)
77.3162(17)
77.3162(17)
3293.1(3)
2
C39H37NO3P2PtS
856.78
Orthorhombic
P212121
10.430(3)
16.109(4)
20.459(5)
90.00
90.00
90.00
3437.6(15)
4
1.655
C40H40Cl2N2P2Pt
876.67
Triclinic
P-1
9.9846(9)
10.0248(9)
10.4448(10)
86.043(3)
68.439(3)
65.086(3)
877.25(14)
1
C40H40I2N2P2Pt
1059.57
Triclinic
P-1
8.4088(4)
10.5983(5)
11.1794(6)
99.188(2)
97.398(2)
104.277(2)
938.30(8)
1
°
α ( )
°
β ( )
°
γ ( )
V (Å3)
Z
1calc, gcmÀ 3
μ, mmÀ 1
F(000)
1.743
8.029
3104
1.516
4.444
1480
1.659
4.275
436
1.875
5.500
508
4.275
1704
Total reflns.
Uniq. reflns.
Reflns. (I�2σ(I))
Rint
153469
13291
12222
0.0517
739
0.0274
0.0707
1.079
0.831/À 2.356
190861
16370
9750
0.2123
721
0.0500
0.0851
1.013
117966
8555
6514
0.2332
425
0.0485
0.0917
1.008
92195
3868
3681
0.1014
214
0.0396
0.0885
1.098
20171
3300
2675
0.1101
216
0.0343
0.0527
1.062
1.359/À 1.365
Parameters
[a]
R1
[b]
wR2
GOF[c]
1max/1min, e ÅÀ 3
0.904/À 1.290
2.690/À 2.377
2.235/À 1.775
[a] R1 =Σj jFo jÀ jFc j j/ΣjFo j, [b] wR2 ={Σ[ω(Fo À Fc2)2]/Σ[ω(Fo )2]}1/2, and [c] GOF={Σ[ω(Fo À Fc2)2]/(nÀ p)}1/2, where n is the number of reflections, and p the
2
2
2
total number of parameters refined.
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of 5 could not be prepared due to its low solubility).[14] Stirring a
DMSO or CH2Cl2 solution containing Pt complex and Pluronic®
F-127 with excess water gave a homogenous solution. Dialysis
(molecular weight cut-off: 3500) and lyophilization gave the
target materials.
ing 10% fetal bovine serum (FBS) and 1% penicillin/streptomy-
cin (P/S), and then transferred to a 96-well cell culture plate (1×
104 cells per well) in DMEM (10% FBS and 1% PS) and cultured
for 16 h for attachment. The culture medium was then
removed, followed by the addition of the nanoformulations of
1–4 in DMEM (with free DMEM as the control, n=5) for an
additional 20 h. MTT (0.5 mgmLÀ 1) in DMEM was then added to
replace the cell culture medium, this was followed by replace-
ment of the medium by DMSO to dissolved the formazan
crystals formed for spectrophotometric measurement at
570 nm.
Nanoformulations of 1–4 exhibited obvious cytotoxicity
(20 h) against melanoma cells (Figure 3) with IC50 of 5.32 μM (1,
Figures 3a and 3b), 0.87 μM (2, Figures 3c and 3d), 11.23 μM (3,
Figures 3e and 3f), and 2.82 μM (4, Figures 3g and 3 h). These
values are comparable to that of cisplatin (7.4 μM, 24 h),[36] Pt-
Pyrazole complexes [Pt(PzÀ CH3)2Cl2] (8.3 μM, 72 h),[37] [Pt-
(PzÀ F)2Cl2] (17.7 μM, 72 h),[37] PtÀ Cu heterometallic cluster [CuCl
(isad)Pt(NH3)Cl2] (0.63 μM, 24 h),[38] β-cyclodextrin encapsulated
trans-dichloro-(dipyridine)platinum(II) (0.71 μM, 20 h),[39] and
cisplatin human serum albumin nanoparticles (150 μM, 24 h).[40]
It is interesting to note that dinuclear cluster 2 exhibited the
lowest IC50 value, indicating that the presence of S atoms in the
cluster might play a non-innocent role (e.g. as a convenient
leaving group). By contrast, compound 3 bearing the LÀ Cys
ligand exhibited the highest IC50 value presumably due to the
tight binding of this chelating ligand. It is also notable that the
mononuclear compound 4 with trans stereochemistry also
Transmission electron microscopy (TEM, Figure 2) showed
that 1–4 formed regular, spherical particles with Pluronic® F-
127, of ca 300 nm (1), 300 nm (2), 80 nm (3), and 500 nm (4) in
diameter. The size of these particles was suitable for in vitro
cytotoxicity analysis. The zeta potential of the nanoparticles of
1 (0.13 mV, Figure S6a), 2 (12.5 mV, Figure S6b), 3 (À 3.79 mV,
Figure S6c), and 4 (6.47 mV, Figure S6d) was close to zero which
is conducive for long circulation times to elicit the EPR effect.
The 31P NMR of these nanoparticles in CDCl3 show that there
is no obvious chemical shift for those of 1 (Figure S7a) and 3
(Figure S7c), indication of structural retention upon particle
formation. However, for that of 2 (Figure S7b), the singlet at
28.0 ppm disappeared, accompanied by the generation of two
new peaks at 21.4 ppm and 14.3 ppm. This is likely due to
decomposition of the complex (e.g. by PtÀ S bond breaking).
Furthermore, for that of 4 (Figure S7d), the singlet at 18.3 ppm
also shifted to 12.3 ppm, this resembles that for the single
crystal of 4 in CD2Cl2 and indicating a trans-to-cis conversion
during the particle preparation.
Cytotoxicity evaluation by MTT assay
Murine melanoma B16F10 was used as the model cell line to
evaluate the anti-proliferation potential of the nanoformula-
tions of 1–4 using the MTT assay (MTT=3-[4,5-dimethylthiazol-
2-yl]-2,5 diphenyl tetrazolium bromide). B16F10 cells were first
cultured in Dulbecco’s Modified Eagle Medium (DMEM) contain-
Figure 2. TEM images of 1 (a), 2 (b), 3 (c), and 4 (d) nanoparticles formed
with Pluronic® F-127.
Figure 3. Cell viability and IC50 (μM) results for nanoformulations of 1 (a, b),
2 (c, d), 3 (e, f), and 4 (g, h) against murine melanoma B16F10 cells (n=5).
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solution of 1. Elemental analysis (%) for C36H30Cl2P2Pt: Calcd: C
54.67, H 3.79; found: C 54.63, H 3.79. IR (KBr disc, cmÀ 1): 3051(w),
1480(m), 1434(m), 1314(w), 1183(w), 1163(w), 1097(m), 1090(m),
exhibited good cytotoxicity. This might be due to a facile trans-
to-cis configurational change in solution or within the cells.[41]
1
1072(w), 999(w), 925(s), 755(vs), 744(vs), 694(vs). H NMR (400 MHz,
CDCl3): δ 7.56–7.42 (m, 12H), 7.33 (t, J=7.3 Hz, 6H), 7.17 (t, J=
7.1 Hz, 12H). 13C NMR (100 MHz, CDCl3) δ 135.0 (t, J=5.2 Hz), 130.9,
129.9 (t, J=25.8 Hz), 128.0 (t, J=5.7 Hz). 31P NMR (162 MHz, CDCl3):
δ 14.3.
Conclusion
We have reported the synthesis of a class of Pt-based nano-
formulations as potential cancer chemotherapies. We observed
that the use of strong-field ligands such as non-toxic PPh3
made for easier material preparation to yield stable products.
Synthesis of Pt2(μ-S)2(PPh3)4 (2)
Compound
1
(0.50 g, 0.63 mmol) and Na2S·9H2O (0.75 g,
Given
a large number of P-based ligands, such as the
3.12 mmol) were stirred in toluene (70.0 mL) at r.t. for 2 days to
obtain yellow-orange precipitate, which was filtered, washed with
Et2O and water, and air-dried to give the title compound. Orange-
yellow single crystals were obtained by evaporating a MeOH
solution of 2 at r.t. Yield 0.41 g (87% based on Pt). Elemental
analysis (%) for C72H60P4Pt2S2: Calcd: C 57.52, H 4.02; found: C 55.77,
3.98. IR (KBr disc, cmÀ 1): 3047(w), 1571(w), 1477(w), 1433(m), 1311
(w), 1181(w), 1095(s), 1028(w), 997(w), 743(s), 735(s), 688(s). 1H NMR
(400 MHz, CDCl3) δ 7.42 (d, J=6.9 Hz, 24H), 7.07 (t, J=7.3 Hz, 12H),
6.93 (t, J=7.6 Hz, 24H). 13C NMR (100 MHz, CDCl3) δ 135.1, 128.9,
126.9. 31P NMR (162 MHz, CDCl3) δ 28.0.
monotopic PPh3 and chelating phosphines, many PtÀ P com-
plexes can be expected with the auxiliary ligands trans to P
readily removed to influence the cytotoxicity of the drug. In
addition, the very low IC50 value for 2 indicates that the
presence of S atoms in the compound may be important.
Moreover, diverse chemistry can be explored by taking
advantage of the nucleophilicity of S, as elegantly demon-
strated by Hor et al.[17,42] It should also be noted that the in vitro
data obtained herein is still preliminary and substantial amount
work is still need in the future, such as the drug loading in the
cells, DNA binding kinetic studies, the possibly subtle biological
roles of S, as GSH and related biomolecules bearing S atoms are
found to coordinate with Pt ions and sequester them from the
cell, leading to drug resistance.[43]
Synthesis of [Pt(PPh3)2(LÀ Cys)]·H2O (3)
Compound
1
(0.15 g, 0.19 mmol) and L–Cysteine (0.11 g,
0.95 mmol) were suspended in 10.0 mL toluene. The resulting
mixture was stirred at r.t. for three days to give a light-yellow
precipitate, which was isolated by centrifugation. The precipitate
was dissolved in CH2Cl2 and centrifuged, evaporation of the CH2Cl2
solution provided 3 as a crude product, which was then purified by
column chromatography using CH2Cl2/MeOH (10:1; v/v) as the
eluent. Yield 64.8 mg (40% based on Pt). Elemental analysis (%) for
C39H37NO3P2PtS: Calcd: C 53.52, H 4.15, N 1.60; found: C 52.42, H
4.58, N 1.56. IR (KBr disc, cmÀ 1): 3051(w), 2920(w), 2854(w), 1607(vs),
Experimental Section
General
Compounds 1 and 2 were synthesized following the reported
protocols with slightly modified procedures.[27] Potassium tetra-
chloroplatinate(II) (Pt>46.5%, Laajoo), triphenylphosphine (PPh3,
1
1481(s), 1435(w), 1333(s), 1186(w), 1094(s), 997 (w), 744 (s). H NMR
(400 MHz, CDCl3) δ 7.46–7.27 (m, 24H), 7.21 (td, J=7.8, 2.6 Hz, 6H),
4.78–4.55 (m, 1H), 3.63 (s, 2H), 3.07–2.85 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 172.4, 134.4 (dd, J=55.2, 11.1 Hz), 131.6 (dd, J=44.0,
2.2 Hz), 128.7 (dd, J=106.0, 11.2 Hz), 69.0, 35.7. 31P NMR (162 MHz,
CDCl3) δ 18.4 (d, J=21.6 Hz), 10.7 (d, J=21.0 Hz) ppm.
>95%,
Aladdin),
4-(dimethylamine)triphenylphosphine
(PPh2PhNMe2, 95%, Yuanye), Iodomethane (MeI, 98%, Energy
Chemical), Pluronic® F-127 (molecular weight: 12600, Sigma-
Aldrich), Platinum standard solution (>95%, Aladdin) and other
reagents were obtained from commercial sources and used as
1
received. The nuclear magnetic data of H, 13C, and 31P NMR were
obtained from the Varian UNITY plus-400/plus-600 NMR spectrom-
Synthesis of trans-PtCl2(PPh2PhNMe2)2 (4)
eter. FT-IR spectra were measured on
a Varian 1000 FT-IR
spectrometer as KBr disks (400–4000 cmÀ 1). Elemental analyses for
C, H, and N were performed on a Carlo-Erba CHNOÀ S micro-
analyzer. The transmission electron microscope (TEM) images were
obtained by dropping the sample in water onto the copper net
under the HT7700 transmission electron microscope. The determi-
nation and analysis of Pt element content were measured on the
inductively coupled plasma mass spectrometry (ICP-MS) of Varian
710-ES. Zeta potential is measured on LA-95052 laser particle size
analyzer using dynamic light scattering technology (DLS).
Compound 4 was synthesized using a method similar to that
described for 1, except that PPh2PhNMe2 was used instead of PPh3.
PPh2PhNMe2 (1.47 g, 4.83 mmol) was dissolved in refluxing EtOH.
K2PtCl4 (1.00 g, 2.41 mmol) in 12.5 mL H2O was then slowly
introduced to form a pale yellow precipitate immediately. The
°
mixture was stirred overnight at 60 C to give a large amount of
light yellow precipitate which was filtered and washed with hot
water, hot ethanol and ether, and air-dried to give the crude
product. Purification was achieved by column chromatography
using CH2Cl2/MeOH (2:1; v/v) as the eluent. Yield: 0.69 g (33%
based on Pt). Pale yellow single crystals of 4 were obtained by slow
evaporation of a CH2Cl2 and MeOH mixed solution. Elemental
analysis (%) for C40H40Cl2N2P2Pt: Calcd: C 54.80, H 4.60; found: C
54.33, H 4.60. IR (KBr disc, cmÀ 1): 3051(w), 2852(w), 1595(s), 1513(m),
1476(w), 1433(m), 1361(s), 1292(w), 1227(w), 1201(s), 1104(s), 1094
(s), 999(w), 943(w), 811(s), 740(s), 690(vs), 623(w). 1H NMR (400 MHz,
CDCl3): δ 7.74–7.59 (m, 12H), 7.44–7.29 (m, 12H), 6.74–6.65 (m, 4H),
2.99 (s, 12H).13C NMR (100 MHz, CDCl3) δ 137.0 (t, J=6.9 Hz), 135.0
Synthesis of cis-PtCl2(PPh3)2 (1)
PPh3 (2.50 g, 9.53 mmol) was added to anhydrous ethanol (30.0 mL)
and the mixture heated to boiling. K2PtCl4 (2.00 g, 4.8 mmol) in
25.0 mL aqueous solution was then slowly added to immediately
°
give white precipitate. The mixture was stirred at 60 C for 2 hours
and then filtered, washed with hot water, hot ethanol and ethyl
ether to obtain the title compound. Yield: 3.58 g (94% based on Pt).
Colorless crystals were grown by diffusing ether into a CH2Cl2
(t, J=5.9 Hz), 130.1, 127.8 (t, J=5.3 Hz), 111.4 (t, J=5.8 Hz), 40.1. 31
NMR (162 MHz, CDCl3): δ 18.3.
P
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micellar solution. 31P NMR (162 MHz, CDCl3): δ 12.3. The Pt
concentration was determined to be 8.4 μgmLÀ 1 by ICP-MS. The
solution was lyophilized for the in vitro experiments.
Synthesis of trans-PtI2(PPh2PhNMe2)2 (5)
Compound 4 (49.8 mg, 0.057 mmol) and CH3I (40.0 μL, 92.0 mg,
0.65 mmol) were mixed in 20.0 mL CH2Cl2 and the mixture stirred at
reflux for 2 days. The solvent was then evaporated under vacuum
to give the crude product, which was purified by column
chromatography using CH2Cl2/petroleum ether (5:4; v/v) as the
eluent. Yield: 37.3 mg (63% based on Pt). Yellow single crystals of 5
were obtained by slow evaporation of a CH2Cl2/MeOH solution of 5
at r.t. Elemental analysis (%) for C40H40I2N2P2Pt: Calcd C 45.34, H
3.81, N 2.64; found: C 44.84, H 3.68, N 2.6. IR (KBr disc, cmÀ 1): 3076
(vw), 2895(vw), 1594(vs), 1518(m), 1445(m), 1435(m), 1373(vs), 1293
(m), 1236(w), 1181(s), 1102(s), 1000(m), 949(w), 811(s), 745(s), 695(s),
624(s). NMR was not available due to the poor solubility of this
compound.
X-ray crystallographic determination of 1–5
Single crystals of 1–5 were analyzed on a Bruker APEX III CCD X-ray
diffractometer with graphite monochromated Ga Kα (λ=1.34138 Å
for 1) and Mo Kα (λ=0.71073 Å for 2–5) radiations. Refinements
and reductions of the collected data were achieved using the
Bruker SAINT program and applied to all complexes with
absorption correction (multi-scan).[44] All crystal structures were
solved by direct methods and refined on F2 by full-matrix least-
squares techniques with the SHELXTL-2016 program.[3]
In complex 2, a large amount of spatially delocalized electron
density in the lattice was found but acceptable refinement could
not be obtained for this electron density. The solvent contribution
was then modeled using SQUEEZE in the Platon program suite.[45] In
complex 3, the hydrogen atoms on the H2O solvate were located
from the difference Fourier map with their OÀ H distances fixed to
OÀ H=0.83 Å and thermal parameters constrained to Uiso(H)=1.2
Ueq(O). The H2O molecule was then refined as a rigid group. The
hydrogen atoms on the N atom were added by using HFIX 23.
Preparation of the nanoparticle of 1
Compound 1 (6.9 mg, 8.7 μmol) was dissolved in 2 mL DMSO at
°
60 C, and then 1 mL of DMSO solution containing Pluronic® F-127
(20.1 mg, 1.6 μmol) was added. Dichloromethane (2.0 mL) was
added to assist the dissolution and the mixture was stirred
°
overnight at 60 C to evaporate the CH2Cl2. The resulting solution
was added to stirring water at a rate of 60 μL per minute (rotating
speed 1400 rpm). After stirring for an additional 6 hours, the
mixture was dialyzed (molecular weight cut-off: 3500) for 12 hours
to obtain 15.0 mL of micellar solution. 31P NMR (162 MHz, CDCl3): δ
14.3. The Pt concentration was determined to be 1.9 μgmLÀ 1 by
ICP-MS. The solution was lyophilized for the in vitro experiments.
Crystallographic data for 1–5 have been deposited in the Cam-
bridge Crystallographic Data Center (CCDC) as supplementary
publication numbers 2092988–2092992. These data can be
obtained free of charge either from the CCDC via www.ccdc.cam.a-
c.uk/data_request/cif or from the Supporting Information.
A
summary of the key crystallographic data for 1–5 are listed in
Table 1.
Preparation of nanoparticles of 2
Compound 2 (6.9 mg, 4.6 μmol) and Pluronic® F-127 (21.1 mg,
1.7 μmol) were mixed in CH2Cl2 (2.0 mL). After stirring for 10 hours,
this mixture was added to 8.0 mL H2O (rotating speed 1400 rpm) at
a rate of 30 μL per minute. After stirring for 12 hours, the CH2Cl2
had evaporated, and the mixture was dialyzed (molecular weight
cut-off: 3500) for 12 hours to obtain 8.0 mL of micellar solution. 31P
NMR (162 MHz, CDCl3): δ 14.3, 21.4. The Pt concentration was
determined to be 41.3 μgmLÀ 1 by ICP-MS. The solution was
lyophilized for in vitro experiments.
Cytotoxicity evaluation by MTT assay
The B16F10 cell line was purchased from the Shanghai Institute of
Cell Biology, Chinese Academy of Sciences. Fetal bovine serum
(FBS), penicillin, streptomycin, and trypsin were purchased from
Zhejiang Tianhang Biotechnology Co. Ltd. and used as supplied.
The B16F10 cell lines were cultured in DMEM containing 10% FBS
and 1% penicillin/streptomycin (P/S). Cells grew as a monolayer
and were detached upon confluence using trypsin (0.5% w/v in
PBS). The cells were harvested from the cell culture medium by
incubating in trypsin solution for 3 min. The cells were centrifuged,
and the supernatant discarded. A 3 mL portion of serum-supple-
mented cell culture medium was added to neutralize any residual
trypsin. The cells were re-suspended in serum-supplemented
DMEM at a concentration of 5×104 cells per 1 mL. Cells were
Preparation of nanoparticle of 3
Compound 3 (3.9 mg, 4.6 μmol) was dissolved in 1 mL of CH2Cl2,
and 2.0 mL of DMSO containing Pluronic® F-127 (20.1 mg,
°
1.6 μmol). The mixture was stirred at 60 C overnight to evaporate
°
cultured at 37 C and 5% CO2 for the MTT studies.
the CH2Cl2, and the resulting DMSO solution was added to stirring
water (3.0 mL) at a rate of 30 μL per minute (rotating speed
1400 rpm). The mixture was stirred for a further 6 hours and then
dialyzed (molecular weight cut-off: 3500) for 12 hours to obtain
8.0 mL micelle solution. 31P NMR (162 MHz, CDCl3): δ 18.4, 10.7. The
Pt concentration was determined to be 8.3 μgmLÀ 1 by ICP-MS. The
solution was lyophilized for the in vitro experiments.
B16F10 cells were seeded at a density of 1×104 cells per well in
200 μL of DMEM (10% FBS+1% P/S), and cultured for 16 h for
attachment. The culture medium was then replaced by a serum-
free medium containing various concentrations of the nanoformu-
lations of 1–4. After incubation with a period of 20 h, the MTT
solution (100 μL, 0.5 mgmLÀ 1 in serum-free DMEM) was added to
°
replace the cell culture medium. After incubating the cells at 37 C
for 4 h, the MTT solution was removed and DMSO (100 μL) added
to dissolve the formazan crystals formed, and the microplates were
agitated for 5 min at a medium rate before spectrophotometric
measurement at 570 nm on a microplate reader. The untreated
cells served as the 100% cell viability control, while the completely
dead cells served as the blank. All experiments were carried out
with five replicates (n=5). The relative cell viability (%) related to
control cells was calculated by the formula below:
Preparation of the nanoparticle of 4
Compound 4 (5.3 mg, 6.0 μmol) was dissolved in a mixture of
DMSO (4.0 mL) and CH2Cl2 (2.0 mL) and heated at 60 C. A DMSO
(1.0 mL) solution containing Pluronic® F-127 (20.0 mg, 1.6 μmol)
was then introduced with stirring. The resulting mixture was stirred
°
°
at 60 C overnight to evaporate the CH2Cl2, and then added to
stirring water at a speed of 30 μL per minute (1400 rpm). After
stirring for an additional 6 hours, the mixture was dialyzed
(molecular weight cut-off: 3500) for 24 hours to obtain 18.0 mL
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: anticancer drug · Pt drugs · B16F10 · PtÀ S cluster ·
crystal structure · trans effect
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Manuscript received: August 4, 2021
Accepted manuscript online: August 12, 2021
Version of record online: ■■■, ■■■■
Chem Asian J. 2021, 16, 1–9
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Full Paper
FULL PAPER
P. Wang, Dr. J.-W. Wang, Prof. W.-H.
Zhang*, Dr. H. Bai*, Prof. G. Tang,
Prof. D. J. Young
1 – 9
In Vitro Anticancer Activity of
Nanoformulated Mono- and Di-
nuclear Pt Compounds
Nanoformulations of a class of
mononuclear and dinuclear Pt-based
complexes bearing PtÀ P bonds have
been developed as efficient chemo-
therapeutic reagents against murine
melanoma cell line B16F10.