Investigation of Binding Behavior between Drug Molecule 5-Fluoracil and M4L4-Type Tetrahedral Cages: Selectivity, Capture, and Release

Article abstract of DOI:10.1002/chem.201606060

Two analogous M₄L₄-type tetrahedral cages (smaller: MOC-19; larger: MOC-22) were synthesized and investigated for their interactions with the anticancer drug 5-fluoracil (5-FU) by NMR spectroscopy, high-resolution electrospray-ioniza

Full text of DOI:10.1002/chem.201606060

A Journal of
Accepted Article
Title: Investigation of Binding Behavior Between Drug Molecule 5-
Fluoracil and M4L4 Type Tetrahedral Cages: Selectivity, Capture
and Release
Authors: Ji-Jun Jiang, Wei-Qin Xu, Yan-Zhong Fan, Hai-Ping Wang,
Jun Teng, Yu-Hao Li, Cheng-Xia Chen, Dieter Fenske, and
Cheng-Yong Su
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To be cited as: Chem. Eur. J. 10.1002/chem.201606060
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Investigation of Binding Behavior Between Drug Molecule 5-Fluoracil
and M4L4 Type Tetrahedral Cages: Selectivity, Capture and Release
Wei-Qin Xu[a,b], Yan-Zhong Fan[a], Hai-Ping Wang[a], Jun Teng[a], Yu-Hao Li[a], Cheng-Xia Chen[a], Dieter
Fenske[a], Ji-Jun Jiang[a]*, Cheng-Yong Su[a]*
extended ligand (L2, Scheme S1-2) and Zn2+ for comparison of the size
Abstract: Two analogue M4L4 type tetrahedral cages (smaller MOC-19 and
selectivity. The binding property of two M4L4 cages with 5-FU drug
larger MOC-22) have been synthesized and investigated for their
molecule has been investigated in solution, revealing that 5-FU is
interactions with an anticancer drug 5-fluoracil (5-FU) by NMR, HRESI-
preferentially captured by MOC-19 due to the right size of cavity
MS and molecular simulation. The cage’s size and window are of
windows. Furthermore, the nanoparticles of MOC-19 can adsorb 5-FU
importance for the host-guest binding, of which the smaller MOC-19 with
and significantly delay release of 5-FU into the simulated body liquids.
just right size of cavity window is found to have much strong H-bond
interactions with 5-FU. The porous nanoparticle of MOC-19 exhibits
outstanding behaviors to control release of 5-FU in simulated human body
liquid PBS buffer.
Research in the field of metal-organic cage (MOC, also known as
container, sphere, capsule or flask) have undergone remarkable
progress and continuously attracted much attention due to their
applications brought by well-defined cavity,[1] where size/shape
selective binding or transport of specific guests can occur.[2–4] This
host-guest property offers fascinating potentials for supramolecular
reactor, transporter or container, with which controllable drug delivery
could be a promising target.[5]
Scheme 1. Self-assembly of two M4L4 tetrahedral cages: left, capture and release of 5-
Despite numerous examples of host-guest container molecules,
FU by MOC-19. Right, simulated crystal structures of MOC-22 and MOC-23 and
structural conversion.
investigation on clinical drug molecules uptake and release remains
limited.[6] Cis-platin (cis-PtCl2(NH3)2) has been reported as a very
successful example in drug delivery system.7 Nevertheless, 5-
fluorouracil (5-FU) of small size (5.3 × 5.0 Å) as one of the broad
spectrum anticancer drugs[8] used in the treatment of malignancies like
glioblastoma[9] and breast cancer,[10] has rarely been thorough studied
in respect to its interactions with containers in the field of host-guest
chemistry. In contrast, the dynamical behavior of 5-FU release from
metal-organic frameworks (MOFs), which is of interest because of the
high drug loading and controllable release property,[11] has been
explored. However, MOFs as crystalline solid is well known to be
indissolvable and easy to disintegrate in solvents, leading to difficulty
in seeking clear and accurate interacting information between the drug
molecules and host by methodologies like mass spectrometry or NMR,
and the binding site analysis has to resort to molecular simulation.[6d]
On the other hand, MOCs usually maintain their whole cavity in
solution and give rise to comparable porosity in solid-state via regular
arrangement, thus offering a good chance for better understanding of
host-guest binding chemistry in solution,[12a, 12b] as well as drug release
MOC-19•X8 (X = OTf-, BF4 and ClO4 ) is prepared as previously
reported[13] from ligand L1 and different zinc salts at room temperature.
-
-
MOC-22•X8 (X = OTf- and BF4 ) is synthesized by the reaction of L2
-
with corresponding zinc salts at 70 °C in acetonitrile. Interestingly, the
same reaction at room temperature (RT) results in a new M3L2
sandwiched cage, MOC-23, no matter 1:1 or 2:3 (L2:Zn2+) ratios are
used. However, MOC-23 can be converted to MOC-22 by constantly
heating at 70 °C for 12 hours (Scheme 1). For MOC-19•(OTf)8, the
high resolution electrospray ionization mass spectrometry (HR-ESI-
MS) presents salient peaks at m/z 342.2205, 412.2440, 505.7729,
833.1948 and 1160.5074, the isotope patterns of which match well
with the simulations of M4L4 cage species, namely [MOC-19]8+,
[MOC-19•(OTf)1]7+, [MOC-19•(OTf)2]6+, [MOC-19•(OTf)4]4+ and
[MOC-19•(OTf)5]3+, respectively (Figure 1a and S1). Similarly, the
peak series at m/z 456.1362, 542.5754, 657.8302, 819.1819 and
1061.2172 for [MOC-22•(OTf)n](8-n)+ (n = 0-4) verify formation of the
1
behavior of MOCs nanoparticles as nanocarriers with intrinsic
same M4L4 tetrahedral cage (Figure 1b and S2). H DOSY spectrum
[12c]
membrane permeablity and biodegradability.
While only a little
give diffusion coefficient D = (5.62 ± 0.03) × 10-10 and (4.10 ± 0.03)
× 10-10 m2/s for MOC-19•(OTf)8 and MOC-22•(OTf)8, respectively,
indicating the single product in solution (Figure S3). According to
Stokes-Einstein equation, the dynamic radius of the naked cages of
MOC-19 and MOC-22 are calculated to be 14.7 and 21.4 Å
respectively, which are coincident with the sizes judged from crystal
structure of MOC-19•(ClO4)8 and simulated cage model of MOC-22.
The M3L2 cage MOC-23•(OTf)6 is formed at R.T. and evidently
characterized by 1H NMR and HR-ESI-MS (Figure S4-6),
representing a kinetic product since it can be completely transformed
into M4L4 cage MOC-22•(OTf)8 upon heating at 70 °C and remaining
unchanged after cooling to R.T. The VT-1H NMR monitoring of the
conversion from Zn3(L2)2 to Zn4(L2)4 unveils a critical temperature of
the structural transformation at 45 °C (Figure S7). Therefore, the
absolute Gibbs free energy of such conversion is estimated in the
range of 60.22 to 67.13 KJ/mol (Table S1) according to equation
∆G(Tc) = RTc(22.96 + ln(Tc/∆v) (Tc = 318 K, ∆v is the chemical shift
difference for the same proton in Zn3(L2)2 and Zn4(L2)4,
respectively).[14]
attention has been paid to investigate the interaction between 5-FU and
MOCs compound.
In a previous paper, we demonstrated the capture and release of
iodine molecules in solution and crystalline states by an M4L4
tetrahedral cage MOC-19 (Scheme 1),[13] which inspires our interest to
study the drug loading and delivery by its analogue containers. A new
tetrahedral cage MOC-22 of bigger cavity has been synthesized with an
[a]
W. -Q. Xu, Y. -Z. Fan, H. -P. Wang, J. Teng, Y. -H. Li, C. -C. Xia,
Prof. D. Fenske, J. -J. Jiang, Prof. C. -Y. Su
MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn
Institute of Functional Materials, School of Chemistry
Sun Yat-Sen University, Guangzhou 510275 (China)
E-mail: jiangjj@mail.sysu.edu.cn; cesscy@ mail.sysu.edu.cn
W. -Q. Xu, Department of Chemistry,
[b]
Guangdong University of Education, Guangzhou 510303, China
Supporting information for this article is given via a link at the end of
the document.
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(Ka) are estimated by the hill equation15 based on the 19F NMR.
Derived from the hill function plot of the 5-FU@MOC-19 system
(Figure S19), a hill coefficient (n) of 2.07 indicates that a strong
positive cooperative binding mode between 5-FU and MOC-19.
Meanwhile, the measured apparent association constant Ka is 2.61 ×
102 M-1 .
Figure 1. Positive-ion electrospray ionization mass spectrum of (a) MOC-
19•(OTf)8 and (b) MOC-22•(OTf)8
Figure 2. 1H NMR spectra of titration of MOC-19 with 5-FU (CD3CN, 400 MHz, 243
K). The red dots correspond to the signals of 5-FU. Enlargement of the 1H-NMR
spectrum in the range of 8.5 to 9.7 ppm was present on the right side.
Before starting the drug delivery exploration, the binding behaviors
of 5-FU with MOC-19 and MOC-22 are investigated in solution. As
shown in Figure S8 and S9, HR-ESI-MS shows a series of binding
species between MOC-19 and 5-FU with a general formula of [(5-
FU)n@MOC-19] (n ≤ 6), indicating up to six 5-FU molecules can
interact with one MOC-19 cage. The 1H NMR is used to further
understand the host-guest interaction between MOC-19 and 5-FU
(Figure S10). By adding 5-FU in stoichiometry into the CD3CN
solution of MOC-19•(BF4)8 step by step, the chemical shift of N-H(J)
in 5-FU is shifted steadily downfield till reaching a host:guest ratio of
1:6 (Figure 2), which is attributed to the host-guest stoichiometric
number and coincide with the aforementioned result of ESI-MS.
Further addition of 5-FU leads to serious signals broadening and
precipitation of excess free 5-FU. 1H DOSY spectrum of the drug-cage
mixture shows two distinct lines of diffusion coefficient, corresponding
to the free cage and the drug binded species of (5-FU)6@MOC-19
Molecular simulation is applied in this drug-cage supramolecular
system of 5-FU@MOC-19. From H NOESY study we speculate that
1
the 5-FU molecules interact with MOC-19 at the pockets of cage
windows, which demonstrates the possible existence of a stable
conformation. A further precious refinement provides a much available
structure by geometry optimization to continue the analysis of
hydrogen bonds. The distance between Hi of 5-FU and Hf in aromatic
ring is calculated at 2.993 Å shows moderate strength. The distance
between Hj of 5-FU and the center of nearby aromatic ring is calculated
at 2.511 Å, which indicates the presence of N-H…π interaction[16] for
this drug-cage system (Figure 3). Meanwhile, a distance of 2.738 Å is
found between Hi of 5-FU and Hf’ of L1, consistent with the 1H
NOESY finding. According to Yang’s method[17]
, the stable
conformation and the plots of reduced density gradient (RDG) versus
sign(λ2)ρ are depicted in Figure S20, which gives a numerical evidence
on the existence of hydrogen bond. The energy of the hydrogen bond is
calculated to be 27.27 KJ/mol totally. To display graphically by
isosurface coloring, it is defined that the bluer region of isosurface is,
the stronger withdrawing interaction presents. A slight blue region
which indicates medium hydrogen bond is found between the cage and
the guest, which further proves existence of hydrogen bonds (Figure
S21).
1
(Figure S11a). H NOESY spectrum reveals interaction between Hf of
host and and N-Hi of guest (Figure S11b).
19F NMR spectrum is also used to examine the binding interaction
between 5-FU with MOC-19 (Figure S12). To exclude the influence of
the concentration to the chemical shift of F atom, a control experiment
1
with pure 5-FU is performed to confirm that H and 19F signals have
little shift in varied concentration of pure 5-FU (Figure S13-14). As
expected, continuous shift of F signal is observed upon adding 5-FU
into the solution of MOC-19 up to a molar ratio of 1:6. In striking
contrast, similar titrations of 5-FU into the solution of MOC-22•(BF4)8
1
show no chemical shift of both H and F signals in their H and 19F
NMR spectra. These findings suggest that MOC-22 has too large size
of cavity window to capture 5-FU molecules which may undergo free
ingress and egress of the MOC-22 cavity (Figure S15-16).[6d] Although
both cages have similar tetrahedral structure, the size of MOC-22 is 1.4
times larger than MOC-19 by comparing the diameter of the cavity
window (Scheme 1). Moreover, the window of MOC-22 is about 21.9
Å × 7.5 Å in prismatic diagonal line, which has less steric hindrance of
guest molecule 5-FU (5.3 × 5.0 Å). Thereby the observed binding
between 5-FU and small cage MOC-19 underline the size selectivity
may due to the cavity window.
Figure 3. The location of 5-FU on the windows pocket of MOC-19 showing the
distances of N-H…π hydrogen bonds and shortest H…H separation between MOC-19
and 5-FU.
The binding stoichiometry between 5-FU and MOC-19 is
determined by Job’s methods using 19F NMR at 243 K since the
variation of guest’s chemical shift in 19F NMR spectra is more distinct
1
compared to H NMR. As listed in Table S2, the resonance of F atom
A common strategy to achieve effect drug delivery by drug-carrying
materials is to scale down to the nanometer size. Recently, Fujita
demonstrate the dynamic behaviour of two M6L4 capsules in solution
and crystalline state to host guest molecules in similar way, which offer
a good example of “cream-skimming” of the dynamic solution and
shifts upfield as the molar fraction of MOC-19 increase (Figure S17).
The maximum of 0.857 is obtained in the Job’s curve, indicating that a
complexation stoichiometry of 1:6 (Figure S18), in agreement with
1
above (5-FU)6@MOC-19 stoichiometry obtained from H NMR and
HR-ESI-MS studies. The coefficient value (n) and binding constant
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solid-state host-guest chemistry.[18] Since MOC-19 has preferential
binding interaction with 5-FU in comparison to MOC-22, we choose
MOC-19 as candidate to test its drug delivery property. Nanoparticles
of MOC-19•(ClO4)8 have been prepared by the nanoprecipitation
method with suitable size around 200 nm (Figure 22). The loading
procedure follows the literature[11a] to immerse nanoparticles in
methanol solution of 5-FU for one week. The loading amount is
determined by thermogravimetric analyses (TGA) and derivative
thermogravimetric analysis (DTG). The TGA curve shows two steps of
weight lost in the ranges of 200-320 and 320-400 °C, which correspond
to the departure of 5-FU and the decomposition of the cage,
respectively (Figure S23a). Comparison of the DTG curves of 5-FU,
MOC-19 and 5-FU@MOC-19 confirms that the relation of weight
losses to the temperature are in good agreement with TGA curves
(Figure S23b). The loading amount of 5-FU was estimated to be
11.6 ± 0.2 wt%, higher than that in Cu(pi) PEG5k.[12a] Fourier
transformed infrared spectroscopy (FTIR) is carried out to further
confirm the inclusion of 5-FU (Figure S24). The characteristic peaks at
1692 and 1237 cm-1 are attributed to the stretching vibration of the
C=O and C-N groups from 5-FU loaded in MOC-19. The shift of the
v(C=O) band of 5-FU from 1652 to 1688 cm-1 is due to influence of the
host-guest interaction.[10a]
verifies the hydrogen bonding between the host MOC-19 and guest 5-
FU, in agreement with the spectroscopic results. These binding
behaviour studies provide clues to understand drug loading origin in
crystalline state, and the TGA analysis reveals a loading amount of
11.6 ± 0.2 wt%. Drug release experiment in PBS buffer solution
demonstrates that the release of drug molecules process can last for
108 hours, significantly retarding burst release of 5-FU solid. This
works provides a new path towards design and screen drug release
MOC system based on insight understanding of the dynamic solution
and solid-state host-guest chemistry.
Experimental Section
MOC-19•(OTf)8: Zn(OTf)2•6H2O (18.0 mg, 0.050 mmol) and L1 (31.0
mg, 0.050 mmol) were dissolved in 4.0 ml of acetonitrile at ambient
temperature. The solution was stirred for 0.5 hr to obtain a yellow
solution. Followed by additional 10.0 ml of Et2O, yellow precipitate
was formed and isolated by centrifugation. After washing with
chloroform, yellow powder was isolated by centrifugation.
MOC-19•(BF4)8: Zn(BF4)2•6H2O (9.0 mg, 0.026 mmol) was dissolved
in 5.0 ml of acetonitrile, followed by adding L1 (15.5 mg, 0.025 mmol)
under continuous stirring for 1 hr. The product was precipitated by
adding 10 ml of Et2O and isolated by centrifugation. After wishing
with chloroform (6 ml×3), the pure product was obtained as a yellow
powder.
MOC-22•(OTf)8: Zn(OTf)2•6H2O (18.0 mg, 0.050 mmol) and L2
(42.0 mg, 0.050 mmol) were dissolved in 5.0 ml of acetonitrile. The
mixture was stirred at 70 °C for 12 hr to obtain a yellow solution. After
cooling to ambient temperature, 10 ml of Et2O was added to precipitate
crude product, which was washed with chloroform (6 ml×3) and drying
under the high vacuum, the pure product was obtained as a yellow
powder.
The release of 5-FU is carried out in simulated human body liquid of
phosphate buffer solution (PBS) and detected by UV/vis spectrum.10a
For a comparison, the pure 5-FU in solid state was dialyzed as a
control-experiment which indicates that up to 95 % of the total 5-FU is
burst released within 7 hours. On the contrary, 5-Fu released from 5-
FU@MOC-19•(ClO4)8 can be distinguished in four stages within 108
hours (Figure 4). The release amount is calculated according to the
calibration plots of standard curve of pure 5-FU in PBS (Figure S25).
In the first stage, about 11.09 % of the loaded 5-FU is released during
the early burst release in 2 hours, followed by 30.78% of 5-FU release
in 13 hours in the second stage. The third step exhibits a steadily
release speed in 36 hours contributes about 50.03% of drug release.
The fourth step shows a very slow release speed up to 108 hours
contributing about 60% of drug release (Table S3). The release stages
are similar to that of the reported 5-FU@MIL101. [11n] Meanwhile, the
delayed releasing effect of 5-FU@MOC-19 is more significant in
comparison with that in Cu-PEG5k (24 hours).[12a] The initial burst
release is deduced to departure of 5-Fu located in the outer channel
since the weak interaction between 5-FU and ligand along the channels.
Then the following slow release may due to the slow diffusion rate of
5-FU from inner channels and the windows of the cavities since the
strong interaction of N-H…π hydrogen bonds and the π-π interactions
between 5-FU and the aromatic skeleton of MOC-19•(ClO4)8.[10a]
MOC-23•(OTf)6: L2 (4.2 mg, 0.005 mmol) and Zn(OTf)2•6H2O
(3.6 mg, 0.010 mmol) were dissolved in 0.5 ml of acetonitrile-d3 and
stirred at ambient temperature to obtain a yellow solution for 1D and
2D H1 NMR and HR-ESI-MS measurements (see supporting
information).
Acknowledgements
§This work was supported by the STP Project of Guangzhou
(15020016, 201607010378) and NSF of China (91222201, 21173272).
Keywords: cage compound • 5-fluoracil capture • control release •
structural conversion
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10.1002/chem.201606060
Chemistry - A European Journal
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COMMUNICATION
Wei-Qin Xu, Yan-Zhong Fan, Hai-Ping
Wang, Jun Teng, Yu-Hao Li, Cheng-Xia
Chen, Dieter Fenske, Ji-Jun Jiang*, Cheng-
Yong Su*
Page No. – Page No.
Investigation of Binding Behavior
Between Drug Molecule 5-Fluoracil and
M4L4 Type Tetrahedral Cages:
Selectivity, Capture and Release
5-fluorouracil can be selectively captured by an M4L4 cage in solution and crystalline state, and be controlled release in PBS buffer for 60% with
108 hours.
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