Encapsulation of Pt(IV) prodrugs within a Pt(II) cage for drug delivery

Article abstract of DOI:10.1039/c4sc01892c

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host-guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host-guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host-guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.

Full text of DOI:10.1039/c4sc01892c

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Encapsulation of Pt(IV) prodrugs within a Pt(II) cage
for drug delivery†
Cite this: DOI: 10.1039/c4sc01892c
Yao-Rong Zheng, Kogularamanan Suntharalingam, Timothy C. Johnstone
*
and Stephen J. Lippard
This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs
using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that
can host four Pt(IV) prodrug guest molecules. Relying on host–guest interactions between adamantyl units
tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This
host–guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR
spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular
uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host–
guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled
complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines,
whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential
of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.
Received 25th June 2014
Accepted 8th October 2014
DOI: 10.1039/c4sc01892c
www.rsc.org/chemicalscience
though a large number of systems have been explored, delivery
systems with well-dened size and shape and consistent drug
Introduction
loading are limited. These features are critical for clinical
development and are therefore highly sought-aer.
Cisplatin, carboplatin, oxaliplatin are FDA-approved platinum-
based anticancer drugs used in clinics worldwide.1–5 About 50%
of cancer patients receiving chemotherapy are treated with one
of these Pt drugs. Their drawbacks are well known and include
lack of selectivity, dose-limiting toxic side effects, low bioavail-
ability, and short retention in the bloodstream. The conversion
of cisplatin to a Pt(IV) prodrug has been recognized as a prom-
ising approach to improve the therapeutic index of Pt-based
anticancer agents and reduce side effects.6 Pt(IV) prodrugs are
generally more inert than their Pt(II) counterparts, resulting in
lower potency and higher toxicity.7,8 To achieve their potential
as anticancer agents, Pt(IV) prodrugs are reduced intracellularly
to the Pt(II) form.9–11 Octahedral Pt(IV) constructs gain two axial
ligands upon oxidation of a square-planar Pt(II) precursor.
These extra ligands can coordinate during intracellular reduc-
tion. Through modication of these axial ligands, Pt(IV) pro-
drugs can acquire new chemical and biological properties that
facilitate drug delivery or improve therapeutic index.12–14 In the
past decade, various nanodelivery systems have been investi-
gated for Pt(IV) prodrug delivery, including polymeric nano-
particles,15,16 gold nanoparticles,17,18 carbon nanotubes,19–21 and
metal–organic frameworks (MOFs)22 among others. Even
Coordination-driven self-assembly represents a well-estab-
lished methodology for constructing ordered, discrete metal-
based nanostructures through controlled aggregation of metals
and organic building blocks.23–27 These structures have well-
dened chemical composition and structural features that can
be resolved by NMR spectroscopy, mass spectrometry, and X-ray
crystallography. Metal-based polyhedra or cages represent a
group of complex inorganic structures accessed through coor-
dination-driven self-assembly.28 They usually have a well-
dened cavity, which can be used to encapsulate small mole-
cules by host–guest interactions.29,30 This property has led to
various novel applications in chemistry.31–33 For example, a
Pd6L4 cage encapsulates anthracene and phthalimide guests to
induce a Diels–Alder reaction with highly unusual regiose-
lectivity.34 A Ga4L6 tetrahedron is reported to be able to stabilize
protonated substrates and catalyze the normally acidic hydro-
lysis of orthoformates in basic solution.35 A well-known, pyro-
phoric species, white phosphorus, can be encapsulated within
an Fe4L6 cage and stably stored in air.36
In cancer research, these structures are of interest because
their unique chemical and host–guest properties distinguish
them from traditional mononuclear metal-based anticancer
agents. Exploration of the use of such complexes in cancer
research is attracting increasing attention.37–39 For instance, a
self-assembled Fe2L3 cylinder provides a novel DNA-binding
motif in which the complex inserts at a three-way DNA
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States. E-mail: lippard@mit.edu
† Electronic supplementary information (ESI) available: Experimental details of
synthesis and characterization of 1–3, cell culture, the MTT assay, ow
cytometric analysis, and uorescence microscopic characterization. See DOI:
10.1039/c4sc01892c
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junction.40,41 Recently, a group of Ru-based trigonal prisms has values, and their integrations (1 : 1 : 1) agree with the structure.
been used to encapsulate small organic anticancer agents for In addition, Diffusion-Ordered Spectroscopy (DOSY) NMR was
delivery.42 This eld is still at an early stage, and the role that used to measure the size of the resulting supramolecular
self-assembled metal complexes will play in cancer research complex. The diffusion coefficient (D) obtained from DOSY46
remains to be determined.
was used in the Stokes–Einstein equation (D ¼ kBT/6phr, kB:
In this article, we describe an innovative design that syner- Boltzmann constant, T: temperature, h: dynamic viscosity, r:
gizes coordination-driven self-assembly and Pt-based anti- hydrodynamic radius) to afford an estimation of the size of the
cancer drugs. In particular, we developed a novel, well-dened structure. D(2) is 1.8 ꢁ 10ꢀ10 m2 sꢀ1 (Fig. S2†), and the hydro-
Pt drug delivery system by employing Pt(IV) prodrug technology dynamic radius for 2 was determined to be 1.4 nm. This value
and coordination-driven self-assembly. This delivery system is agrees with the crystal structure of a previously reported Pd
composed of cytotoxic Pt(IV) prodrugs and a hexanuclear Pt(II) analogue.47 The cage shows good stability under physiological
cage having low toxicity and high cellular uptake. The cage acts conditions in the presence of glutathione (Fig. S3†).
as the delivery vehicle and the Pt(IV) prodrugs as the cargo. As
shown in Scheme 1, host–guest interactions between the ada-
mantyl units and the cage drive association of four Pt(IV)
building blocks with each cage complex. The high positive
charge of the nanoconstruct is proposed to facilitate cellular
uptake. Upon entering cells and reacting with biological
reductants, the self-assembled supramolecular system is
envisaged to release cisplatin and thereby destroy cancer cells.
Assembly of the host–guest system
Formation of the host–guest complex (3) was readily achieved by
mixing the Pt(IV) prodrug (1) and the cage (2) in a 4 : 1 ratio at
80 ꢂC with sonication. The overall charge of 3 is 8+ at neutral pH
owing to deprotonation of the carboxylic acid groups.
Compound 1 has low solubility in water (<500 mM) but becomes
readily soluble when mixed with the cage (Fig. S4†). This
process is attributed to host–guest interactions between 1 and 2,
with the hydrophobic adamantyl moiety of 1 being encapsu-
lated within the hydrophobic cavity of 2. 1D and 2D NMR
Results and discussion
Pt-based molecular components
spectroscopy was applied to characterize the formation of the
1
The adamantyl Pt(IV) prodrug (1) was prepared from
cisplatin. Oxidation of cisplatin by H2O2 forms oxoplatin,
c,c,t-[PtCl2(NH3)2(OH)2]. Oxoplatin was then allowed to react
with 0.9 equiv. of succinic anhydride, resulting in the formation
of c,c,t-[PtCl2(NH3)2(OH)(succinate)]. The hydroxyl group of
this Pt(IV) compound then performs a nucleophilic attack on
1-adamantyl isocyanate to generate the adamantyl Pt(IV) pro-
drug 1 in 67% yield.43,44 The structure of 1 is supported by
multinuclear (1H, 13C, and 195Pt) NMR spectroscopy and ESI
mass spectrometry. The 195Pt NMR spectrum of 1 exhibited a
signal at d ¼ 1250.5 ppm, characteristic of Pt(IV). An isotopically
resolved signal at m/z ¼ 609.9 ([MꢀH]ꢀ) was detected in the
ESI-MS, conrming the chemical composition. Purity was
assessed by elemental analysis (see ESI†).
The hexanuclear Pt(II) cage, 2, was prepared according to a
previously reported procedure.45 In the proton NMR spectrum
of 2 in D2O, only signals corresponding to the platinum bound
pyridyl ligand (d ¼ 8.97 ppm for a-pyridine; d ¼ 8.44 ppm for b-
pyridine) and the ethylenediamine moiety (d ¼ 2.72 ppm) were
observed. The chemical shis for 2 are close to the reported
host–guest complex. In the H NMR spectra (Fig. S5 and S6†),
signals from both 1 and 2 undergo signicant shis upon self-
assembly. The upeld shi (Dd) of the adamantyl signals from
the Pt(IV) species ranges from ꢀ0.71 to ꢀ2.36 ppm, whereas
downeld shis of pyridyl signals for the cage were observed
around 0.25–0.29 ppm. These signicant shis indicate
encapsulation of the adamantyl moiety within the pore and are
consistent with the results reported previously with 1-ada-
mantanol.48 On the other hand, the NMR signals from the
succinate moiety of the Pt(IV) complex display minimal changes
in chemical shi (0.01–0.07 ppm), possibly because this ligand
extends from the periphery of the cage. As a consequence, the
local magnetic environment of the succinate ligand is not
signicantly altered upon encapsulation. This structural feature
was further validated by a 2D NOESY NMR analysis (Fig. S7†).
Cross peaks exist between adamantyl signals and pyridyl peaks,
but no through-space coupling was observed between the
succinate unit and the cage. As shown in Fig. 1a and S8,† a 3D
Scheme 1 Representation of the host–guest complex (3) assembled Fig. 1 (a) A 3D model of the host–guest complex 3 and (b) DOSY NMR
from the Pt(IV) prodrug (1) and the Pt(II) cage (2).
spectrum (400 MHz, R.T.) of 3 (2.8 mM) in D2O (D ¼ 1.3 ꢁ 10ꢀ10 m2 sꢀ1).
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model of 3 generated from Maestro and Spartan reveals these
structural features. Additionally, results from a DOSY NMR
analysis (Fig. 1b) also support the self-assembly. In D2O (hwater
¼ 8.90 ꢁ 10ꢀ4 Pa s), signals from both the Pt(IV) species and the
cage exhibit diffusion coefficients that are almost equivalent,
ꢃ1.3 ꢁ 10ꢀ10 m2 sꢀ1, whereas 1 alone in DMSO-d6 (hDMSO
¼
2.00 ꢁ 10ꢀ3 Pa s) has a diffusion coefficient of 1.6 ꢁ 10ꢀ10 m2
sꢀ1 (Fig. S1†). Taken together, these results conrm that the
Pt(IV) building blocks are encapsulated within the cage. Inte-
grations extracted from the 1H NMR spectra indicate their
binding ratio to be 4 : 1. The composition of 3 was veried by
elemental analysis (see ESI†).
Fig. 3 ESI-MS of the reaction mixture of 3 (0.16 mM), ascorbic acid (17
mM), and guanosine (0.62 mM). The cationic adduct 7 forms from the
reaction of the released cisplatin and guanosine.
Release of cisplatin upon reduction
1H and DOSY NMR spectroscopy. The reaction is depicted in
Fig. 2a. The drug delivery construct is reduced by ascorbic acid
and releases cisplatin (4), 1-adamantylamine (5), and succinic
To exhibit anticancer activity, cisplatin must be released from
this host–guest system upon reduction. We evaluated the
reduction of the system and the release of cisplatin using a
variety of methods, including cyclic voltammetry, NMR spec-
troscopy, and ESI mass spectrometry. The cyclic voltammogram
of 3 has three irreversible reduction features (Fig. S9†). The two
most cathodic signals have peak potentials of ꢀ930 and ꢀ810
mV vs. Ag/AgCl at a scan rate of 200 mV sꢀ1. Electrochemical
analysis of the empty cage 2 suggests that these features arise
from its triazine core. The remaining signal has a peak potential
of ꢀ550 mV at an equivalent scan rate, which we assigned to the
irreversible reduction of the Pt(IV) prodrug encapsulated within
the cage. We also treated 3 (0.8 mM) with 10 equiv. of ascorbic
acid (8 mM), a biological reductant, in deuterated phosphate
buffered saline (PBS) and monitored the reduction process by
ꢂ
acid (6). Upon incubation at 37 C for 12 h, about 40% of the
Pt(IV) species is reduced according to the relative integration of
the NMR signals of 1 and 3. Aer 24 h, the Pt(IV) compound was
fully reduced. Notably, 1-adamantylamine alone does not
encapsulate within the cage (2) because the amine group is
protonated at neutral pH. Disassembly of the supramolecular
system was followed by DOSY NMR spectroscopy (Fig. S10†).
Upon reduction, the diffusion coefficients of the species giving
rise to the succinate and adamantyl signals changed from 1.3 ꢁ
10ꢀ10 m2 sꢀ1 to 5.0 ꢁ 10ꢀ10 m2 sꢀ1. In D2O solution, the 1H
NMR signal from the ammine groups of cisplatin was not
observed. We used ESI mass spectrometry to conrm that
cisplatin was being released. An aqueous solution of 3 (0.16
mM) was incubated with ascorbic acid (17 mM) in the presence
of guanosine (0.62 mM) in a total volume of 1 mL. Upon release
from 3, cisplatin is able to covalently bind to guanosine to form
the cationic adduct, cis-[Pt(NH3)2Cl(guanosine)]+ (7). The pres-
ence of 7 served as marker for cisplatin release. Aer 20 h of
incubation at 37 ꢂC, ESI-MS of the reaction mixture revealed the
formation of 7, indicative of cisplatin release (Fig. 3, m/z ¼
547.1). A control study under identical conditions (20 h, 37 ꢂC)
in the absence of ascorbic acid did not yield 7 (Fig. S11†).
Collectively, the CV, NMR spectral, and ESI-MS data support the
conclusion that cisplatin is released upon reduction.
Cellular response
The anticancer activity of 3 was explored in a group of human
cancer cell lines. Cytotoxicity proles of the Pt(IV) prodrug (1),
the cage (2), and the supramolecular system (3) were evaluated
against A549 (lung carcinoma), A2780 (ovarian carcinoma), and
A2780CP70 (ovarian carcinoma resistant to cisplatin) cells. The
IC50 values (concentration required to reduce viability to 50%)
are summarized in Fig. 4a. To permit a valid comparison, all
values refer to concentrations of platinum rather than molar
concentrations of molecules or complexes. The supramolecular
complex 3 displays micromolar potency against all cancer cell
lines tested, comparable to that of cisplatin. In A2780CP70 cells,
3 exhibits higher cytotoxicity (IC50 ¼ 14.7 ꢄ 2.8 mM) than 1 and 2
Fig. 2 (a) Chemical representation of the reduction of 3 by ascorbic
acid and (b) H NMR (400 MHz, R.T.) spectra showing reduction of 3
(0.8 mM) by ascorbic acid (8 mM) in deuterated PBS over 24 h at 37 ꢂC. (IC50 ¼ 22.3 ꢄ 1.8 mM and 57.7 ꢄ 9.2 mM, respectively), which
1
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Compound 3 prompts A2780 cells to undergo early (5.51%) and
late (7.42%) stage apoptosis. Apoptotic cells normally exhibit
characteristic cellular changes, such as blebbing, chromatin
condensation, and DNA and nuclear fragmentation, all of which
can be probed by uorescence microscopy (see Fig. S14† and
4d). Upon incubation of A2780 cells with 3 ([Pt] ¼ 30 mM for 72
h), red uorescent signals arising from the terminal deoxy-
nucleotidyl transferase dUTP nick end labeling (TUNEL) reac-
tion were apparent, indicative of DNA fragmentation and
apoptosis. The evidence compiled from the cell-based experi-
ments described above supports the proposal that 3 releases
cisplatin in cells to effect anticancer activity.
Summary and conclusions
We present a novel approach for developing a delivery system
for cisplatin based on the use of Pt(IV) prodrugs and a self-
assembled metal-based complex. Pt(IV) building blocks capable
of acting as prodrugs that release cisplatin were loaded into a
Pt(II) cage complex via host–guest interactions. Upon formation
of such a supramolecular system, the cytotoxicity prole of the
prodrug was improved because of the high cellular uptake of the
cage. Structural features of the system are well supported by
NMR spectroscopy, and the biological properties were evaluated
by the MTT assay, cellular uptake studies, ow cytometry, and
uorescence microscopy. As a proof of concept, this report
described an innovative strategy combining platinum-based
medicinal chemistry and coordination-driven self-assembly to
Fig. 4 (a) Cytotoxicity profiles of cisplatin and 1–3 against A549 (lung
cancer), A2780 (ovarian cancer), and A2780CP70 (ovarian cancer produce a well-dened system that delivers cisplatin. The
resistant to cisplatin) cell lines, (b) whole cell uptake of the Pt
success of this system not only demonstrates the potential for
applications of self-assembled metal-based complexes in cancer
research, but also provides new concepts for designing novel
drug delivery systems.
compounds in A2780CP70 cell line ([Pt] ¼ 30 mM, 4 h, 37 ꢂC, 5% CO2),
(c) flow cytometric analysis of cell cycle of A2780 cells treated with 3
([Pt] ¼ 30 mM) for 72 h, and (d) cellular images of the TUNEL assay
results from A2780 cells treated with 3 ([Pt] ¼ 30 mM) for 72 h (scale
bar: 20 mm).
Acknowledgements
highlights the advantages of the host–guest complex. The
elevated cytotoxicity prole of 3 is attributed to high cellular
uptake of the cationic cage. We evaluated directly the cell
uptake of cisplatin and 1–3 in A2780CP70 cells. The results,
shown in Fig. 4b, reveal that 2 and 3 have 10 times greater
uptake than either cisplatin or the Pt(IV) prodrug (1).
This work was supported by National Cancer Institute Grant
CA034992 and the Kathy and Curt Marble Cancer Research
Fund from the Frontier Research Program of the Koch Institute
at MIT. Spectroscopic instrumentation at the MIT DCIF is
maintained with funding from NIH Grant 1S10RR13886-01.
The cytotoxic effect of 3 is attributed to intracellular release
of cisplatin, a conclusion supported by observation of effects
characteristic of cisplatin on cells. DNA-ow cytometric studies
Notes and references
were conducted to identify the incidence of cell cycle arrest
upon treatment of cancer cells with 3. As shown in Fig. 4c and
S12,† 3 induces cell cycle arrest in the A2780 cell line. Aer 72 h
incubation, cells arrested at the G2/M phase (40% increase in
G2/M population compared to the untreated control). This
behavior is consistent with the G2/M cell cycle arrest response
evoked by cisplatin.49 The host–guest complex 3 is able to kill
cancer cells by triggering programmed cell death, or apoptosis.
By using a dual staining annexin V/PI ow cytometry assay, the
occurrence of apoptosis was investigated in A2780 cells treated
with 3. The results (Fig. S13†) show that 3 can induce apoptosis
in A2780 cells aer 72 h, similar to the treatment with cisplatin.
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