Synthesis of aspirin-ligated cisplatin derivatives and its slow release study over MIL-101(Fe)

Article abstract of DOI:10.1007/s11696-020-01114-4

An aspirin-ligated cisplatin derivative, biasplatin, was prepared from acetylsalicylic anhydride and oxoplatin in DMF. Biasplatin was synthesized from oxoplatin and aspirin anhydride as starting materials by a substitution reaction of hydroxo leaving groups in its axial position. The obtained biasplatin was fully characterized by FTIR, ¹HNMR, ¹³CNMR, and ESI mass spectroscopy. Biasplatin entrapped into MIL-101(Fe) by suspended in DMF and stirring for 72?h at ambient temperature, known as biasplatin@MIL-101(Fe). The slow release of biasplatin and biasplatin@MIL-101(Fe) was conducted in PBS solution pH 7.20, 37?°C as media and measured by UV–Vis spectrophotometer. The release of biasplatin without loaded into MIL-101(Fe) is persistent for 3%, and biasplatin@MIL-101(Fe) is 0.05% over 72?h. A significant slow release of biasplatin@MIL-101(Fe) only 1% compared with time release of biasplatin without loaded into MIL-101(Fe).

Full text of DOI:10.1007/s11696-020-01114-4

Chemical Papers
https://doi.org/10.1007/s11696-020-01114-4
ORIGINAL PAPER
Synthesis of aspirin‑ligated cisplatin derivatives and its slow release
study over MIL‑101(Fe)
Venansia Avelia Rosari · Witri Wahyu Lestari2,3 · Maulidan Firdaus3
1
Received: 8 August 2019 / Accepted: 19 February 2020
©
Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract
An aspirin-ligated cisplatin derivative, biasplatin, was prepared from acetylsalicylic anhydride and oxoplatin in DMF. Bias-
platin was synthesized from oxoplatin and aspirin anhydride as starting materials by a substitution reaction of hydroxo leav-
1
13
ing groups in its axial position. The obtained biasplatin was fully characterized by FTIR, HNMR, CNMR, and ESI mass
spectroscopy. Biasplatin entrapped into MIL-101(Fe) by suspended in DMF and stirring for 72 h at ambient temperature,
known as biasplatin@MIL-101(Fe). The slow release of biasplatin and biasplatin@MIL-101(Fe) was conducted in PBS
solution pH 7.20, 37 °C as media and measured by UV–Vis spectrophotometer. The release of biasplatin without loaded into
MIL-101(Fe) is persistent for 3%, and biasplatin@MIL-101(Fe) is 0.05% over 72 h. A signiꢀcant slow release of biasplatin@
MIL-101(Fe) only 1% compared with time release of biasplatin without loaded into MIL-101(Fe).
Keywords Cisplatin derivatives · Biasplatin · Aspirin · MIL-101(Fe) · Time release
Introduction
Juhász et al. 2011). To overcome these problems, cisplatin
which contains platinum(II) as metal center needs to be
modiꢀed in a complex containing platinum(IV), in order to
achieve products which are less toxic and more stable (Shi
et al. 2012). Conjugation of cisplatin(IV) with other organic
prodrugs such as nab-Paclitaxel and 5-ꢂuorouracil drugs
demonstrated a low relapse rate of human papillomavirus
(Adkins et al. 2016). Pt(IV)–polymer conjugations such
as Pt(IV)/MPEG-b-PCL-b-PLL conjugation into micelles
(Xiao et al. 2011), MPEG-P(LA-co-MCC)/Pt(IV)/DRB and
MPEG-P(LA-co-MCC-NHS)/Pt(IV)/DRB micelles (Xiao
et al. 2012), and Pt(IV)/PCL-b-PABPA-POEGMEA/cur-
cumin micelles (Scarano et al. 2015) have lower IC50 value
and suppress cancer cells growth compared with Pt(II) and
Pt(IV) complexes.
One of the most known cancer treatments is chemother-
apy, based on drugs which suppress the cell proliferation.
Platinum derivatives are well-known as eꢁective cancer
medication, and cisplatin is one of the most commonly used
platinum derivative drugs. Despite the fact that cisplatin
possesses anticancer activity because of its inhibitor activ-
ity to cancer cells (Theiner et al. 2015), it also has some
limitations due to toxicities and resistances (Amable 2016;
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-020-01114-4) contains
supplementary material, which is available to authorized users.
*
Witri Wahyu Lestari
witri@mipa.uns.ac.id
The axial ligand substitution on cisplatin derivatives
could modify the pharmacokinetic effects of prodrugs,
including lipophilicity, toxicity, and solubility (Escola et al.
1
Magister of Chemistry Programme, Universitas Sebelas
Maret, Jl. Ir. Sutami No. 36A, Kentingan, Jebres,
Surakarta 57126, Indonesia
2
016; Arafath et al. 2017; Wexselblatt et al. 2015). Aspirin,
one of the most widely used medicines, has anti-inꢂamma-
tory activity (Clissold 1986), and its ligation with oxoplatin
has allowed the achievement of asplatin, a novel platinum
prodrugs for cancer treatment (Pathak et al. 2014). Asplatin
has lower toxicity than cisplatin. It is proven by less reduc-
tion in body weight in asplatin, and in small dose (0.5 mg/
kg), there is no inꢂuence in the reduction of body weight
2
3
Research Group of Porous Materials for Sustainability,
Chemistry Department, Universitas Sebelas Maret,
Jl. Ir. Sutami No. 36A, Kentingan, Jebres, Surakarta 57126,
Indonesia
Chemistry Department, Universitas Sebelas Maret,
Jl. Ir. Sutami No. 36A, Kentingan, Jebres, Surakarta 57126,
Indonesia
Vol.:(0
1
123456789)
3

Chemical Papers
(
Cheng et al. 2014). In addition to possessing good activity
of cisplatin on pH 6.0–7.2 is rapidly converted to cisplatin;
meanwhile, monohydrate form of cisplatin on pH higher
than 7.2 is more stable (Yachnin et al. 1998).
against cancer cells proliferation, asplatin enhanced apopto-
sis cancer cells by increasing mitochondrial outer membrane
permeability. This causes cytochrome c release from mito-
chondria into the cytosol and enhances cancer cell apopto-
sis (Cheng et al. 2016). Cisplatin has fast release properties
(
Catanzaro et al. 2018). On the other hand, aspirin has slow
Experimental
Materials
release properties (Budd et al. 1993), and therefore we could
suppress cisplatin fast release by ligated aspirin into cispl-
atin. However, two-side aspirin-modiꢀed cisplatin has not
been further investigated. This respective compound hypo-
thetically is also active as an anticancer agent.
Chemicals
Recently, metal–organic frameworks (MOFs) have
revealed to be useful for applications in various ꢀelds includ-
ing biosensor (Wang et al. 2015; Jing et al. 2016), catalyst
All chemicals used in the synthesis were of commercial
grade and used without further purification. Potassium
tetrachloroplatinate(IV) (K PtCl ) was purchased from
2
4
(
Xu et al. 2015), imaging and drug delivery (Taylor-Pashow
Carbolution Chemical Gmbh. Potassium iodide (KI), silver
et al. 2009; Liu et al. 2014). Thus, it has been reported
several examples about good eꢃciency of MOFs in drug
release, as well as studies proving enhancement of drugs
eꢃciency thanks to encapsulation and conjugation of drugs
into MOFs (Mocniak et al. 2015). Aspirin is generally used
in host–guest encapsulation in MOFs not only because of the
high selectivity to MOFs, but also because molecular size of
aspirin (0.41 nm) ꢀts easily in the cavity of MOFs (1.8 and
nitrate (AgNO ), potassium chloride (KCl), 1,4-benzen-
3
edicarboxylic acid (H BDC), and FeCl ·6H O were pur-
2
3
2
chased from Sigma-Aldrich. Hydrogen peroxide (H O ),
2
2
ammonia (NH ), and ethyl acetate (EtOAc) were purchased
3
from VitLab. o-acetylsalicylic acid (aspirin) was purchased
from Alfa Aesar. N,N′-dicyclohexylcarbodiimide (DCC)
and sodium chloride (NaCl) were purchased from Across
Organic. All solvent, ethanol, diethyl ether, dichloromethane
(DCM), dimethylformamide (DMF), and acetonitrile were
purchased from VWR Chemical Prolab. FTIR spectra were
2
.3 nm) (Singco et al. 2016). This drug design has shown
good capability for controlled release of aspirin by the
intermolecular non-covalent interaction, such as hydrogen
bonding, van der Waals, ion–dipol, and dipol–dipol interac-
tion between MOFs and the drug (Xu et al. 2015). On the
other side, cisplatin derivatives have also shown eꢃciency
as anticancer drugs (He et al. 2014; Taylor-Pashow et al.
−
1
recorded as KBr disks in the range of 4000–400 cm with
1
a Perkin Elmer System 2000 FTIR spectrometer. H and
1
3
C NMR spectra were recorded with a Bruker AVANCE
III HD 400 MHz NMR spectrometer at room tempera-
ture. Mass spectrometry measurements were carried out as
ESI–MS with a Bruker Daltonics FT-ICR-MS spectrom-
eter and UV–Vis spectrophotometer by PerkinElmer UV/
VIS/NIR Lambda 900. Elemental analysis (C, H, and N)
were performed with a Heraeus VARIO EL oven. X-ray dif-
fractogram was recorded by Bruker tipe D8, Cu Kα anode
λ=1.54060 Å, range 2θ=10–50.
2
009). Another interesting alternative has been investigated
by introducing a cisplatin derivative-based biphosponate as
linker in a coordination polymer for treatment of ovarian
cancer (He et al. 2015).
In this study, biasplatin was synthesized by substituting
the two hydroxyl axial ligand. Singco et al. (2016) reported
aspirin release from MIL-101(Fe) matrix was slower in
acidic medium and faster in basic medium. NSAID drug
loaded into MIL-101(Fe) also has slower release than loaded
into MIL-100(Fe) (Horcajada et al. 2006). Commonly cis-
platin derivatives were modiꢀed with adding organic com-
plexes, copolymer linker or loaded into nanoparticles and
Synthesis of cisplatin
Cisplatin was prepared from K PtCl according to the pro-
2
4
cedure suggested by Alderden et al. (2006).
liposomes, encapsulation in UiO-66-NH , has shown slower
2
its release. From fact that MIL-101(Fe) can slow down drug
release, herein we tried to study how far MIL-101(Fe) could
suppress biasplatin release to reduce its toxicity. Due to
the large pore volume of MIL-101(Fe) which reach up to
Synthesis of oxoplatin
H O (60 mL, 30% w/v) was added to cis-
2
2
3
−1
0
.75 cm g (Tang et al. 2015), incorporation biasplatin,
diamminedichloroplatinum(II) (1 g, 3.3 mmol). The mixture
was stirred for 5 h at 75 °C. The resulting yellow solution
was kept overnight to crystallize. The precipitate was ꢀltered
and washed with cold water, ethanol, and diethyl ether, then
dried in vacuum.
aspirin-ligated cisplatin derivatives on its two axial sides,
would ꢀt the pore size of MIL-101(Fe). Neutral to base
buꢁer solution is used to mimicking the human cell environ-
ment. Neutral to base pH is used due to monohydrate form
1
3

Chemical Papers
Synthesis of aspirin anhydride
Aspirin anhydride was synthesized according to Pathak et al.
72 h at ambient temperature. The biasplatin-containing sol-
ids, biasplatin@MIL-101(Fe), were recovered by ꢀltration,
washed with DMF and dried for 24 h at ambient tempera-
ture. The remaining ꢀltrate was collected and then meas-
ured its absorbance by UV–Vis spectrophotometer. Loading
of biasplatin into the porous solids amount was calculated
using the equation from the calibration plot.
(
2014) and Liu et al. (2013).
Synthesis of biasplatin
The reaction was carried out under diꢁerent solvent without
lyophilization and using diꢁerent puriꢀcation method. Oxo-
platin (50 mg, 0.15 mmol) was suspended in DMF (10 mL).
A solid aspirin anhydride (378 mg, 1.1 mmol) was added to
oxoplatin suspension. The mixture was stirred at 65 °C for
Time release of two‑side‑modiꢁed aspirin‑ligated
to cisplatin derivate
Biasplatin@MIL-101(Fe) (10 mg) was dispersed in 250 mL
of PBS, pH = 7.20, stirred at 37 °C for 72 h. At predeter-
mined intervals, 5 mL samples were collected (every 2 min
at ꢀrst 10 min, every 5 min at ꢀrst 30 min, every 10 min
at ꢀrst 60 min, 30 min in 2 h, 1 h in the next 3 h, 6 h (day)
or 12 h (night) in the rest time) and analyzed the content
of released biasplatin by UV–Vis spectroscopy. The same
amount of fresh PBS solution was added to keep the volume
constant.
4
8 h then the solvent was removed. The product was puriꢀed
by resuspended in acetonitrile and precipitated in diethyl
ether. This step was repeated until the product completely
soluble in acetonitrile then washed with diethyl ether. The
remaining solvent was then evaporated and dried in vacuum.
Synthesis of MIL‑101(Fe)
MIL-101(Fe) was synthesized according to modiꢀed litera-
ture procedure Santiago-Portillo et al. (2015).
Results and discussion
Dilution of phosphate buꢀer saline (PBS) solution
Successively, cis-[Pt(NH ) Cl ] was oxidized with H O in
3
2
2
2
2
PBS was prepared following promega protocol (Anon
water, two hydroxyl groups coordinated Pt(IV) in axial posi-
tion forming oxoplatin (1). The achievement of the desired
product was confirmed by FTIR spectroscopy (Fig. 2),
observing the presence of not only amine groups and chlo-
ride ions, but also hydroxyl groups due to oxidation with
n.d.). Salts NaCl (8 g), KCl (0.2 g), Na HPO (1.44 g), and
2
4
KH PO 0.24 g were dissolved in 750 mL of warm water
2
4
(
37 °C). The pH was controlled by adding HCl (1 M) drop
wise until the pH becomes 7.20, and water was added until
the volume become 1 L. The rest of the procedures were
done referring to Lestari et al. (2018) with some modiꢀca-
tions on pH.
−
1
H O . Sharp peak at 3515 cm indicated O–H stretching.
2
2
−
1
Peaks assigned to Pt–O stretching at 1039 cm and to Pt–N
−1
stretching at 554 cm conꢀrm the presence of hydroxyl and
ammonia ligands coordinating Pt(IV). The FTIR result is in
full accordance with those reported by Wang et al. (2015)
and Pathak et al. (2014).
Calibration plot of standard two‑side‑modiꢁed
aspirin‑ligated cisplatin derivate
The preparation of the target anhydride was performed
in the presence of N,N′-dicyclohexylcarbodiimide (DCC)
as condensing agent. The reaction might occur between the
aspirin molecule through the carboxylic group, and the cen-
tral carbon in DCC allows the formation of the o-acylurea
intermediate, and then the synthesis proceeds with a nucleo-
philic attack by another aspirin molecule on the highly elec-
trophilic carboxylate, aꢁording the desired product aspirin
anhydride (2) as shown in Scheme 1 (Otera 2003).
Biasplatin (10 mg) was dissolved in PBS (50 mL), and this
solution, 0.20 mg/mL concentration, is called mother liq-
uor. The mother liquor was diluted into various concentra-
tion 0.02 mg/mL, 0.04 mg/mL, 0.06 mg/mL, 0.08 mg/mL,
0
0
.10 mg/mL, 0.12 mg/mL, 0.14 mg/mL, 0.16 mg/mL, and
.18 mg/mL. All these solutions were measured the absorb-
ance using UV–Vis spectrophotometer. The absorbance data
at maximum wavelength was plotted into graph.
The formation of product (2) has been conꢀrmed by infra-
red spectroscopy, where the expected band due to the anhy-
Incorporation of two‑side‑modiꢁed aspirin‑ligated
cisplatin derivate into MIL‑101(Fe)
−
1
dride C–O–C stretching at 1043, 1009, and 977 cm are
−
1
observed, and also peak 1130 cm of C–O stretching acetic
anhydride (Fig. 2). No O–H bond in the spectra indicates
that aspirin has lost its hydrogen ion from hydroxyl group.
Another strong evidence proving the success of the reac-
Biasplatin was entrapped into the porous solids MIL-
1
01(Fe) by 3:1 ratio of biasplatin/MIL-101(Fe). Biasplatin
(
30 mg) was dissolved in DMF (10 mL), and then 10 mg
1
of MIL-101(Fe) was added. The suspension was stirred for
tion can be found in H NMR spectrum (Fig. 1), in which
1
3

Chemical Papers
Scheme 1 Synthesis step of aspirin anhydride (2)
Fig. 1 1H NMR spectra of aspirin anhydride in CDCl
3
1
3

Chemical Papers
the absence of the signal attributable to OH group in aspi-
rin molecule conꢀrms that the starting material has totally
reacted.
acetyl salicylate can be confirmed by FTIR spectrum
(Fig. 2); in fact, the bands due to the C–O–C stretching
in anhydride (2) and to O–H in oxoplatin (1) cannot be
1
The reaction of anhydride (2) with oxoplatin (1) leads to
the formation of biasplatin (3) by substitution of hydroxyl
groups in axial position (Scheme 2). Reaction mechanism
is analogue to Pathak et al. (2014). Aspirin anhydride
substitute the hydroxo groups of oxoplatin and coordi-
nate with Pt(IV) in the axial position forming biasplatin.
Aspirin anhydride becomes carbocation and carbanion.
OH as leaving group is substituted by carbanion, while
carbocation attach to another hydroxo group (Otera 2003).
Evidence of the displacement of the hydroxyl groups with
observed. The H NMR spectrum (Fig. 3) exhibits a mul-
tiplet peak at 6.19–5.84 ppm attributable to the proton in
1
3
NH group. The C NMR spectrum (Fig. S2) shows the
3
signals that can be assigned to COO–C
shifted if
aromatic
compared with compound 2 as prove of anhydride cleav-
age. Finally, the ESI mass spectrum (Fig. S3) conꢀrms
the achievement of the new compound (3), exhibiting the
+
[M + H] peak with the highest intensity and m/z value in
accordance with predicted chemical structure of biasplatin.
Scheme 2 Synthesis step of
biasplatin (3)
Fig. 2 FTIR spectra of bias-
platin
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3

Chemical Papers
Fig. 3 1H NMR spectra of biasplatin in DMSO
Biasplatin stability was studied by TG/DTA. TG/DTA
graph in Figure S4 shows biasplatin start to decompose at
1
80 °C by elimination of aspirin ligand.
Biasplatin loading and release over MIL‑101 (Fe)
The typical characteristic FTIR absorption peaks of the
−
1
MIL-101(Fe) are observed at around 1600–1400 cm (Fig.
S5). Those peaks are from carboxylic group of the linker
−
1
dicarboxylic ligand. Sharp peaks at 1671–1281 cm cor-
respond to C–O stretching of carboxyl groups. The peak at
−
1
7
40 cm assigned to C–H vibration of the benzene in the
linker. The MOF structure is cubic with characteristic peaks
observed at 2θ: 5.9; 6.3; 10.3; and 11.2° in accordance with
CCDC No 605510 (Fig. S6).
The UV–Vis spectra of biasplatin in DMF show maxi-
mum absorbance at 300 nm (Fig. 4). This absorbance has
related to Tao et al. (2010) that cisplatin has intense absorb-
ance in several bands including 300–330 nm. The highest
absorbance happened in this range because of d–d transi-
Fig. 4 Calibration curve of biasplatin in DMF
Biasplatin incorporation into MIL-101(Fe) was high. This
might because the large pore size of MIL-101(Fe) (accord-
ing to pore volume analysis, Figure S7) could easily capti-
vate molecule of biasplatin.
4
+
tions of Pt ion. Calibration curve is used to calculate the
amount of biasplatin incorporated into MIL-101(Fe). The
amount of biasplatin loaded into MIL-101(Fe) was calcu-
lated based on the unloaded biasplatin to MIL-101(Fe).
The entrapped biasplatin into MIL-101(Fe) matrix is 93%.
The release of biasplatin was carried out in vitro in phos-
phate buꢁer saline (PBS). The PBS solution pH 7.20 at 37 °C
was used to mimicking intercellular human body environment.
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3

Chemical Papers
Fig. 5 Biasplatin release in PBS
pH 7.20 at 37 °C
biasplatin
biasplatin@MIL-101(Fe)
3
2
2
1
1
0
0
.0
.5
.0
.5
.0
.5
.0
time release
Figure 5 shows biasplatin, and biasplatin@MIL-101(Fe) had
very slow release compared with other cisplatin modiꢀcation
drugs and other drugs contained in MIL-101(Fe). Cisplatin
loaded in polymeric nanoparticles release was almost 100%
before 120 h in acidic but lower in basic (Ahmad et al. 2018).
The release time of cisplatin cross-linked polymer in base
was 50% after 120 h (Fu et al. 2015). Time release of cisplatin
encapsulated copolymer and was loaded into UiO-66 achieved
dissolved 40% in 24 h and fully dissolved in 144 h. Aspirin
4+
ligand increases the stability of Pt so that biasplatin could
interact with MIL-101(Fe) better than cisplatin. The stability
of biasplatin also aꢁected the diꢁusion process from biaspl-
atin inside MIL-101(Fe) matrix into PBS solution. The release
of biasplatin without loaded into MIL-101(Fe) is constant for
about 3%, and biasplatin@MIL-101(Fe) is 0.05% over 72 h.
Slow release of biasplatin@MIL-101(Fe) only 1% compared
with time release of bisplatin only. These signiꢀcant results
show the slow diꢁusion rate of biasplatin release from MIL-
101(Fe) into buꢁer solution due to low solubility of biasplatin
in the water.
2
5% and UiO-67 achieved 35% at ꢀrst 50 h and fully release
after 400 h; otherwise, cisplatin only in UiO-66 achieved 70%
and UiO-67 achieved 90% at ꢀrst 50 h (Filippousi et al. 2016).
Horcajada et al. (2006) reported ibuprofen in MIL-101(Fe)
Fig. 6 Nanotracking analysis of biasplatin solubility
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3

Chemical Papers
Nanoparticle tracking analysis was performed to inves-
tigate the low-solubility phenomenon of biasplatin. From
nanoparticle tracking analysis result (Fig. 6), biasplatin
only partially dissolves in PBS even after 1 h sonication,
and pale yellow solution with some particles are ꢂoating.
After 2 h standing, the particles are almost entirely deposited
on the bottom of the ꢂask (shown in blue circle), so that the
solution itself looks mostly clear. After 24 h the solution
becomes clear, and there is precipitate at the bottom (shown
in blue circle). There are aggregates in the solution of diꢁer-
ent sizes from 120 to 560 nm. The concentration of particles
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Programme associated with Institute für Anorganische Chemie Uni-
versität Leipzig Germany and Ministry of Research, Technology and
Higher Education of The Republic of Indonesia (RISTEK DIKTI), in
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M, Nanaki SG, Vizirianakis IS, Bikiaris DN, Van Der Voort
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4
74/UN27.21/PP/2018 and Fundamental Research Grant project No.
19/UN27.21/PN/2019 (Kementerian Riset Teknologi Dan Pendidikan
7
Tinggi Republik Indonesia). The author wishes to thank Sara Durini
Ph.D. and Prof. Dr. Dr. hc. mult. Evamarie Hey-Hawkins for their help-
ful assistance and suggestion during research stay at Institute für Anor-
ganische Chemie Universität Leipzig Germany, and we would like to
thank Rafaella Precker (Institute für Anorganische Chemie, Universität
Leipzig, Germany) for providing MIL-101(Fe).
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Compliance with ethical standards
He C, Lu K, Liu D, Lin W (2014) Nanoscale metal-organic frameworks
for the co-delivery of cisplatin and pooled siRNAs to enhance
therapeutic eꢃcacy in drug-resistant ovarian cancer cells. J Am
Chem Soc 136:5181–5184. https://doi.org/10.1021/ja4098862
Conflict of interest The authors declare that they have no conꢂict of
interest.
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