Double targeting of tumours with pyrenyl-modified dendrimers encapsulated in an arene-ruthenium metallaprism

Article abstract of DOI:10.1002/chem.201002634

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene-ruthenium building blocks and 5,8-dioxido-1,4-naphthoquinonato (donq) bridges, in the presence of pyrenyl-containing dendrimers of different generations (P<

Full text of DOI:10.1002/chem.201002634

DOI: 10.1002/chem.201002634
Double Targeting of Tumours with Pyrenyl-Modified Dendrimers
Encapsulated in an Arene–Ruthenium Metallaprism
Anaꢀs Pitto-Barry,[a] Nicolas P. E. Barry,[a] Olivier Zava,[b] Robert Deschenaux,[a]
Paul J. Dyson,[b] and Bruno Therrien*[a]
Abstract: The self-assembly of 2,4,6-
tris(pyridin-4-yl)-1,3,5-triazine (tpt) tri-
angular panels with p-cymene–rutheni-
um building blocks and 5,8-dioxido-1,4-
naphthoquinonato (donq) bridges, in
the presence of pyrenyl-containing
dendrimers of different generations
(P0, P1 and P2), affords the triangular
cavity of the cage and the dendritic
functional group pointing outwards,
was confirmed by NMR spectroscopy
(1H, 2D and DOSY). The host–guest
properties of these systems were stud-
ied in solution by NMR and UV/Vis
spectroscopic methods, allowing the de-
termination of their affinity constants
(Ka). Moreover, the ability of these
water-soluble host–guest systems to
carry the pyrenyl-containing dendrim-
ers into cancer cells was evaluated on
human ovarian cancer cells. The host–
guest systems are all more cytotoxic
than the empty cage [1]
ꢀ4 mm), with the most active com-
pound, [P0ꢁ1][CF3SO3]6, being an
order of magnitude more cytotoxic.
ACTHGNURTNE[NUNG CF3SO3]6 (IC50
prismatic
host–guest compounds
ACHTUNGTRENNUNG
[PnꢁRu6A(p-cymene)
N
R
(donq)3]6+
Keywords: antitumor agents · den-
drimers · drug delivery · host–guest
systems · metallaprisms
Introduction
(EPR) effect. This effect is believed to play a major role in
the selectivity of nanomedicines towards cancer cells, which
causes an intratumour drug delivery efficacy up to 100 fold
greater than that observed in healthy cells.[3] There are
many types of nanomedicine, including antibodies and poly-
meric drugs, but also large drug-delivery vectors, such as mi-
celles and nanoparticles. Indeed, an EPR effect has been ob-
served for proteins,[4] micelles composed of block copoly-
mers,[5] encapsulated drugs,[6] liposomes,[7] and even bacteria
with diameters of 1–2 mm.[8]
Hypervasculature and the defective vascular architecture of
the endothelial layer of blood vessels contribute to the en-
hanced permeability of cancer cells.[1] In addition to this en-
hanced vascular permeability of tumours, the lymphatic
drainage system is substantially modified in cancer cells, and
it appears that it does not operate efficiently.[2] Consequent-
ly, macromolecular drugs and large vectors are retained in
the tumour interstitium for longer periods than in healthy
tissues. The combination of poor tissue drainage and in-
creased tumour vascular permeability results in a phenom-
enon termed the enhanced permeability and retention
We have synthesised
a number of arene–ruthenium
metalla-assemblies, in particular hexanuclear metallaprisms
AHCTUNGTRENNUNG
that form hexacationic cages, which potentially use the EPR
effect to target cancer cells.[9] These water-soluble assem-
blies have been found to be active against cancer cells,[10]
and their cavities have been used to encapsulate various
guest molecules permanently[11] or reversibly.[12] Tetranuclear
arene–ruthenium rectangles were found to be cytotoxic
against human ovarian A2780 cancer cell lines,[13] and may
also encapsulate guest molecules.[14] These compounds ex-
hibit a size effect, with the smaller rectangular molecules
being only moderately cytotoxic, whereas the larger are
more cytotoxic (IC50 ꢀ4 mm).[13] The same size effect was ob-
served with arene–ruthenium metallacubes incorporating
different tetrapyridylporphyrin panels, with the larger as-
[a] A. Pitto-Barry, N. P. E. Barry, Prof. R. Deschenaux, Dr. B. Therrien
Institut de Chimie, Universitꢀ de Neuchꢁtel
Avenue de Bellevaux 51, 2000 Neuchꢁtel (Switzerland)
Fax : (+41)32-7182511
E-mail: bruno.therrien@unine.ch
[b] Dr. O. Zava, Prof. P. J. Dyson
Institut des Sciences et Ingꢀnierie Chimique
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
1015 Lausanne (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002634.
1966
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Chem. Eur. J. 2011, 17, 1966 – 1971

FULL PAPER
semblies being more cytotoxic than the smaller octanuclear
assemblies.[15]
protons H23 and H24 of the linker unit leads to a significant
upfield shift of 0.44 ppm in the case of the resonance of
proton H24, and of 0.05 ppm for H23, confirming the forma-
tion of P0, P1 and P2.
To determine the impact of the size of a guest, a series of
large pyrenyl-containing dendrimers of different generations
has been prepared (generation zero: P0, generation one: P1
and generation two: P2). The pyrenyl units were encapsulat-
ed in the hydrophobic cavity of a hexanuclear arene–ruthe-
Encapsulation of the pyrenyl moiety into metallaprism
[1]6+ (see Scheme 2) is straightforward for P0 and P1; addi-
tion of silver triflate to the dinuclear metallaclip [Ru2ACHTUNGTRENNUNG(p-
nium cage complex [Ru
cymene)6A(tpt)2A
(donq)3]6+ ([1]6+
tpt=2,4,6-tris(pyridin-4-yl)-
1,3,5-triazine; donq=5,8-
dioxido-1,4-naphthoquinonato),
and the cytotoxicity of these re-
6ACHTUNGERTN(NUNG p-
C
E
;
ACHTUNGTRENNUNG
sulting
host–guest
systems,
and
[P0ꢁ1]6+
,
,
[P1ꢁ1]6+
[P2ꢁ1]6+
was evaluated and
correlated to their size.
Results and Discussion
Synthesis: The synthesis of
guest molecules P0, P1 and P2
Scheme 2. Encapsulation of P0, P1 and P2 in metallaprism [1]6+
.
involves three generations of
cyanobiphenyl dendritic precur-
sors (G0, G1 and G2), the synthesis of which has been report-
ed previously.[16] P0, P1 and P2 were prepared by an esterifi-
cation reaction between 1-pyrenebutyric acid and the differ-
ent generations of cyanobiphenyl dendrimer (see Scheme 1).
Dendrimers, such as those described here, are interesting
materials as their size can be controlled and adjusted pre-
cisely through a convergent synthetic methodology.[17] In the
case of G2, an arm comprising an aliphatic C10H20 chain was
included to add flexibility to this large dendritic moiety and
to increase the yield of the coupling reaction.
cymene)
guest molecule leads to the formation of [P0ꢁ1]
[CF3SO3]6, respectively. In the case of P2, direct
encapsulation necessitates 2 days and dichloromethane is re-
quired to solubilise P2 to afford the desired carceplex system
(donq)Cl2] in the presence of tpt panels and the
AHCTUNGTRENNUNG
and [P1ꢁ1]
ACHTUNGTRENNUNG
[P2ꢁ1]
ACHTNUGTNERN[UGN CF3SO3]6. All of the complexes are isolated as tri-
flate salts and are highly soluble in solvents such as di-
chloromethane and water.
Characterisation: The host–guest compounds were unambig-
uously characterised by IR, UV and NMR spectroscopy, as
well as MS spectrometry, and their purity was assessed by
elemental analysis.
1
The esterification reactions were monitored by H NMR
spectroscopy, with observation of the signals of the pyrenyl
protons (H26, H27 and H28) as these are shifted slightly up-
field (by up to 0.05 ppm relative to 1-pyrenebutyric acid)
after coupling (see Scheme 1 for assignment). Additionally,
a significant modification of the chemical environment of
The IR spectra of [Pnꢁ1]
ACHTNUGTRENN[UGN CF3SO3]6 are dominated by
peaks between 1500 and 1600 cmꢂ1, due to stretching of the
C=C bonds of the tpt panels, and the C=N stretching vibra-
tions around 1200 cmꢂ1. The bands associated with the donq
bridges, including the strong C=O stretching vibration
(ꢀ1630 cmꢂ1), are only slightly altered compared with the
(donq)Cl2].[12a] More-
dinuclear complex [Ru2ACHTNUTRGENNG(U p-cymene)2CAHTUNGTRENNUGN
over, strong stretching vibrations due to the triflate anions
(1260(s), 1030(s) and 638(m) cmꢂ1) are also observed in the
IR spectra of these salts. Additional absorptions originating
from the guest molecule are also observed, notably, a signal
at 1730 cmꢂ1 corresponding to C=O stretching vibrations,
signals at around 1500 cmꢂ1 assigned to valence vibrations
of aromatic Csp2–Csp2 centres and a characteristic signal at
2228 cmꢂ1 assigned to the CꢃN triple bond in the dendritic
arms.
The electronic absorption spectra of host–guest systems
[Pnꢁ1]6+ are characterised by an intense high-energy band
centred at around 250 nm, probably corresponding to
Scheme 1. Syntheses of P0, P1 and P2 (DCC=N,N’-dicyclohexylcarbodi-
ACHTUNGTRENNUNGimide, DPTS=4-(dimethylamino)pyridinium para-toluenesulfonate).
Chem. Eur. J. 2011, 17, 1966 – 1971
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www.chemeurj.org
1967

B. Therrien et al.
ligand-localised or intra-ligand p!p* transitions. Broad
low-energy bands associated with metal-to-ligand charge
transfer (MLCT) transitions are also observed at 450 nm
These host–guest systems were further confirmed by ESI-
MS. Their mass spectra contained a peak corresponding to
[Pnꢁ1+
(CF3SO3)3]3+ at m/z=1263.3 (P0), 1469.3 (P1) and
ACHTUNGTRENNUNG
and between 600 and 800 nm, which is consistent with the
1973.5 (P2).
[12a]
electronic absorption spectra of metallaprism [1]6+
.
In the 1H NMR spectra, the resonances of protons H26,
H27 and H28, those of the different protons of the pyrenyl
part of the guest molecule and of the pyridyl protons of the
tpt panels are shifted upfield upon formation of the encap-
sulated systems [Pnꢁ1]6+, whereas the resonances of the CH
protons of the bridging donq ligands are shifted downfield.
The proton resonances of the p-cymene ligands, located at
the periphery of the prism, are not significantly altered by
the presence of a pyrenyl moiety in the cavity of [1]6+. Simi-
larly, the resonances of the protons located at the end of the
dendritic arms are not affected following encapsulations.
Diffusion-ordered NMR spectroscopy (DOSY)[18] con-
firms the encapsulation of the functionalised pyrenes (Pn)
into the cavity of [1]6+ (see Figure 1 for the DOSY spec-
HyperChem simulations: Since it was not possible to obtain
an X-ray crystal structure of [P0ꢁ1]6+ or the other host–
guest systems, molecular modelling was performed with Hy-
perChem software[29] to estimate the shape and size of all of
these complexes in the gas phase (see Figure 2). As expect-
Figure 2. HyperChem simulation of the structure of [P2ꢁ1]6+, arene lig-
AHCTUNGTERGaNNUN nds were omitted for clarity.
ed, the HyperChem simulations show that the dendritic arm
extends from the cavity with the pyrene moiety encapsulat-
ed inside the cavity of the prism. The complexes also possess
two distinct regions, a hydrophilic head, consisting of the
hexacationic metallacage, and a lipophilic tail, formed by
the dendritic part of the complex. Such amphiphilicity is of
potential relevance to the biological properties of these
compounds.[20]
Figure 1. DOSY NMR spectra of P2, [1]6+ and [P2ꢁ1]6+ in CD3CN at
218C.
Properties of the host–guest system: The host–guest proper-
ties of the complexes were studied in solution by a combina-
tion of NMR, UV/Vis and fluorescence spectroscopy.
1H NMR titrations of P0 and P1 in the presence of [1]6+
were performed in CD3CN at room temperature, whereas,
in the case of P2, broadening of the signals precludes such
an analysis.
trum of [P2ꢁ1]6+). DOSY measurements of P2
(2871 gmolꢂ1), the empty cage [1]6+ (2457 gmolꢂ1) and the
inclusion system [P2ꢁ1]6+ (5328 gmolꢂ1) gave diffusion
coefficients (D) of 6.16ꢃ10ꢂ10
,
6.91ꢃ10ꢂ10 and 4.89ꢃ
10ꢂ10 m2 sꢂ1, respectively, these values being indicative of en-
capsulation. The DOSY measurements of [P0ꢁ1]6+ and
[P1ꢁ1]6+ gave similar results for these compounds. More-
over, from D, the radius (r) of the [Pnꢁ1]6+ systems was
evaluated by using the Stokes–Einstein equation[19] (see
Table 1).
Upon gradual addition of guest P0 or P1 (0.1–3.0 equiv) to
1
a solution of [1]
N
spectra show displacement of the chemical shifts of some
resonances of both the host and the guest. The broadening
of and change in chemical shifts of the signals support a
rapid inclusion of the guest molecule into the cavity of [1]6+
as observed previously with [pyreneꢁ1]
,
[CF3SO3]6.[12a] Plots
ACHTUNGTRENNUNG
Table 1. The molecular weight, radius and diffusion coefficients of P0, P1,
P2, [1]6+, [P0ꢁ1]6+, [P1ꢁ1]6+ and [P2ꢁ1]6+, as determined by DOSY ex-
periments.
of these chemical shift changes (Dd) of the b proton of the
tpt ligands versus the molar ratio of P0 or P1 to prism [1]6+
indicate a 1:1 stoichiometry of the host–guest systems (see
Figure 3).[21] From these plots, stability constants of associa-
tion (Ka) were estimated by using the non-linear least-
squares fitting program winEQNMR2[22] (see Table 2). The
binding free energies (DG8) for [P0ꢁ1]6+ and [P1ꢁ1]6+ were
determined from the corresponding association constants
obtained at 218C in CD3CN and for both DG8 was below
ꢂ5.80 kcalmolꢂ1.
Mw [gmolꢂ1
]
r [10ꢂ10 m][a]
D [10ꢂ10 m2 sꢂ1
]
P0
P1
741.91
1359.60
2871.34
2600.79
3342.70
3960.39
5472.13
5.25
6.70
7.95
7.09
7.14
8.13
10.01
9.33
7.31
6.16
6.91
6.86
6.02
4.89
P2
[1]6+
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Radius determined by DOSY experiments.[19]
1968
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Chem. Eur. J. 2011, 17, 1966 – 1971

Targeting Tumours
FULL PAPER
[1]6+ with P2), and applying the Rose–Drago equation,[24]
the association constants of [P0ꢁ1]6+, [P1ꢁ1]6+ and [P2ꢁ1]6+
were estimated (see Table 2). The Ka values for [P0ꢁ1]6+
and [P1ꢁ1]6+, obtained by using UV/Vis spectroscopy, are
1
consistent with the values estimated by using H NMR titra-
tions.
A decrease in the stability of encapsulation is observed
with an increase in the generation of the dendrimer precur-
sor grafted onto the pyrenyl moiety. This can easily be un-
derstood since the pyrenyl part of the molecule is less acces-
sible for encapsulation if it is attached to a higher genera-
tion. The association constants are quite high and the free
energies (DG8 up to ꢂ5.36 kcalmolꢂ1) demonstrate a prefer-
ence for the encapsulated system over the dissociated one,
which is consistent with the DOSY measurements.
Figure 3. 1H NMR chemical shift changes for the b proton of the tpt lig-
6+
&
^
A
( ) and P1 ( ) to [1] in CD3CN at
Pyrene has been intensively used as a fluorescent probe
and its fluorescence is well documented.[25] Encapsulation of
pyrene in metallaprism [1]6+ quenches its fluorescence com-
pletely.[10b] Therefore, it is not surprising to observe quench-
ing upon encapsulation of the pyrenyl moiety of the pyren-
yl-containing dendrimers Pn. Spectral overlap between the
emission of the pyrenyl moiety of P0 and the absorbance of
the metallaprism [1]6+ is observed (see Figure 5), which cor-
responds to an energy transfer effect between the pyrenyl
moiety and the metallaprism.[26]
Table 2. The association constants (Ka) and free energies (DG8) of en-
capsulation of P0, P1 and P2 in [1]6+, as determined by 1H NMR titration
(in CD3CN at 218C, 4 mm concentration of [1]6+) and by a UV/Vis
method (CH2Cl2 at 218C).
[a]
[b]
Ka [104 mꢂ1
]
Ka [104 mꢂ1
]
DG8 [kcalmolꢂ1
]
P0!
P1!
[P1ꢁ1]6+
P2!
[P2ꢁ1]6+
G
4.1
1.9
n.a.
7.8
2.7
0.8
ꢂ6.29
ꢂ5.83
ꢂ5.36
ACHTUNGTRENNUNG
[a] Determined by NMR titration; n.a.=not applicable. [b] Determined
by UV/Vis spectroscopy.
Since the association constant of [P2ꢁ1]6+ could not be
determined by NMR titration because of broadening of the
signals, the association constants were also estimated by
UV/Vis spectroscopy, a widely used method for the study of
binding phenomena that is particularly suited to 1:1 host–
guest systems.[23] Aliquots of a solution of [1]
ACHTUNGRTNEU[GN CF3SO3]6 in
CH2Cl2 were added to a solution of the guest molecule Pn in
CH2Cl2 ([1]/[Pn]=0 to 2 equiv), and the mixtures were ana-
lysed by UV/Vis spectroscopy at 218C. Based on changes in
the absorbance (see Figure 4 for the UV/Vis titration of
Figure 5. Normalised absorbance spectrum of metallaprism [1]6+ and
fluorescence spectrum of P0.
As the guest molecule enters the cavity of the metalla-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
cited and cannot re-emit the same energy as in the free
state. This loss of excitation and energy transfer between the
pyrenyl component and the metallaprism leads to a decrease
in the emission energy of pyrene and ultimately to fluores-
cence quenching of the pyrenyl moiety.[27] Quenching of the
fluorescence of pyrenyl-containing dendrimers in [1]6+ is il-
lustrated by the emission spectra from fluorescence titra-
tions. Upon gradual addition of [1]ACHTUNGTRNEUNG[CF3SO3]6 (0.1–
10.0 equiv) to a solution of P0 or P1 in CH2Cl2 (10ꢂ7 m), a
strong quenching of the fluorescence is observed (see
Figure 6 for the emission titration of P0).
Figure 4. UV/Vis titration of [1]6+ in a solution of P2 in CH2Cl2 (10ꢂ5 m)
at 218C.
Chem. Eur. J. 2011, 17, 1966 – 1971
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1969

B. Therrien et al.
To verify whether the host–guest systems remain intact
before internalisation by the cancer cells, their stability was
studied, by NMR spectroscopy, in D2O and CD3CN at room
and elevated temperatures (>508C). These studies reveal
that the host–guest compounds [Pnꢁ1]6+ are stable in solu-
tion for several hours. Moreover, upon addition of DMSO
to the D2O solution of [Pnꢁ1]
ACHTNUGTRNEN[NUG CF3SO3]6, no loss of the guest
molecule was observed. Similarly, UV/Vis studies of the
host–guest systems in the biological media at 378C for 24 h
show no spectral changes, thus confirming the strong encap-
sulation of the pyrenyl group within the cavity of [1]6+. Con-
sequently, the high stability of the host–guest systems sug-
gests that intact [Pnꢁ1]6+ systems enter the cells.
Figure 6. Fluorescence emission titration of [1]6+ in a solution of P0 in
CH2Cl2 (10ꢂ7 m) at 218C, with excitation at 350 nm.
Conclusion
The synthesis of three new pyrenyl-containing dendrimers
and their encapsulation into a water-soluble arene–rutheni-
um metallaprism is described. The host–guest systems,
Antiproliferative activity: The antiproliferative activity of
pyrenyl-containing dendrimers P0, P1 and P2, the complex
[1]
[CF3SO3]6 and the host–guest systems [Pnꢁ1]
E
[Pnꢁ1]
ACHTNUGERTN[NUGN CF3SO3]6, are remarkably stable in solution, as
were evaluated against the A2780 (cisplatin sensitive) and
A2780cisR (cisplatin resistant) human ovarian cancer cell
lines. Their cytotoxicities, in comparison to cisplatin, are
presented in Table 3.
shown by NMR, UV/Vis and fluorescence spectroscopic
studies. The cytotoxicity of the host–guest systems has been
evaluated on human ovarian A2780 and A2780cisR cancer
cell lines and an increase of one order of magnitude in cyto-
toxicity is observed for [P0ꢁ1]
empty metallaprism. The cytotoxicities of the higher genera-
tions of encapsulated dendrimers, [P1ꢁ1][CF3SO3]6 and
[CF3SO3]6, were found to be equivalent to that of the
cage alone. Notably, for the first time, this study has shown
that metallacage host systems are able to deliver hydropho-
bic guest molecules with extremely large appendages into
cancer cells.
ACHTNUGTRNEN[NUG CF3SO3]6 compared with the
Table 3. IC50 values of pyrenyl-containing dendrimers P0, P1, P2 and com-
AHCTUNGTRENNUNG
plexes [1]
lines.
[CF3SO3]6 and [Pnꢁ1]
ACHTNUGRTEN[NUGN CF3SO3]6 on A2780 and A2780cisR cell
[P2ꢁ1]
ACHTUNGTRENNUNG
A2780 (IC50 [mM])
A2780cisR (IC50 [mM])
P0
P1
P2
inactive
inactive
inactive
3.1ꢄ1.0
0.4ꢄ0.1
2.2ꢄ1.1
2.6ꢄ0.8
1.6ꢄ0.6
inactive
inactive
inactive
4.6ꢄ0.5
0.5ꢄ0.4
2.4ꢄ0.8
2.8ꢄ1.0
8.6ꢄ0.6
[1]
[P0ꢁ1]
[P1ꢁ1]
[P2ꢁ1]
cisplatin
ACHTUNGTRENNUNG
T
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
R
ACHTUNGTRENNUNG
Acknowledgements
R.D. thanks the Swiss National Science Foundation (Grant No 200020-
129501) for financial support. A generous loan of ruthenium chloride hy-
drate from the Johnson Matthey Technology Centre is gratefully ac-
knowledged.
The pyrenyl-containing dendrimers P0, P1 and P2 are in-
ACHTUNGTRENNUNG
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are even more cytotoxic, in the case of [P0ꢁ1]
ACHTNUGERTN[NUGN CF3SO3]6 the
IC50 value (0.4 mm) shows it to be an order of magnitude
more cytotoxic than the empty cage. The IC50 values of
[P1ꢁ1]
G
ACHTUGNTRENUN[GN CF3SO3]6 are similar to those of
the empty cage. High generations of dendritic systems are
known to be biocompatible, and tend to show different
levels of cytotoxicity,[28] however due to the lipophilic nature
of Pn, their intrinsic cytotoxicity could not be established in
this study. It is notable that [1]6+ and the host–guest systems
show similar cytotoxicities for both the cisplatin-sensitive
and cisplatin-resistant cancer cell lines, which indicates that
they do not share the same mechanism of action as the ref-
erence drug, cisplatin.
1970
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Chem. Eur. J. 2011, 17, 1966 – 1971

Targeting Tumours
FULL PAPER
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Received: September 13, 2010
Published online: January 5, 2011
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