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Enhancing the solubility and bioactivity of anticancer drug tamoxifen by
water-soluble pillar[6]arene-based host–guest complexation
Liqing Shangguan, Qi Chen, Bingbing Shi and Feihe Huang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5 DOI: 10.1039/c0xx00000x
Published on 09 August 2017. Downloaded by University of Windsor on 09/08/2017 13:10:42.

ChemComm Accepted Manuscript

A water-soluble pillar[6]arene functions as a solubilizing biotechnological areas, we wonder whether water-soluble
agent to enhance the solubility and bioactivity of poorly pillar[n]arenes can be used as the hosts to complex poorly water-
water-soluble anticancer drug tamoxifen by host–guest 50 soluble drugs to enhance their water-solubility and bioactivity.
complexation between it and tamoxifen. Here tamoxifen (Scheme 1), a poorly water-soluble estrogen
agonist for treatment of breast cancer, was chosen as a model
10 Numerous promising drug candidates suffer greatly from drug for investigation.17d Water-soluble pillar[6]arene WP6
insufficient aqueous solubility, and as a result, incomplete (Scheme 1) was used as the solubilizing agent to enhance its
absorption and low bioactivity hinder their application in clinical 55 water-solubility and bioactivity.17c First, tamoxifen solid was
cases.1 Researchers are constantly searching for new chemical mixed with an aqueous solution of WP6 followed by stirring for
and biotechnological approaches to enhance drug dissolution and 24 hours. With the assistance of host–guest interactions between
15 bioactivity such as using co-solvents,2 solid dispersion,3 lipid host molecule WP6 and tamoxifen, the solubility of tamoxifen in
formulations,4 complexing with cyclodextrin5 or other water was increased remarkably as measured by nuclear magnetic
macrocycles6,7 and preparing prodrugs8 through chemical 60 resonance (NMR) using sodium benzene-1,3,5-tricarboxylate as
modification. Among them, complexation technique using the internal reference.6f,6i Furthermore, in vitro toxicity study by
macrocycles that possess hydrophilic outer surfaces and using MTT assay resulted that complexed tamoxifen showed
20 hydrophobic inner cavities like cyclodextrins,5 cucurbiturils,6 higher efficiency in killing cancer cells including MCF-7 and
calixarenes7 and their derivatives as hosts may improve not only Hela in shorter treatment time than the free drug. The host WP6
the solubility but also the stability of the guest drugs,6e,6g since the 65 itself was harmless to these cells, indicating that it was a non-
drug is encapsulated into the cavity of the host. Yet such method toxic solubilizing excipient. Hence, it is hopeful that WP6 can be
is not universally applicable for all drugs and limited by the a new type of complexation host in enhancing drug water-
25 selective property of host−guest interactions. Therefore, it is of solubility and bioactivity.
essential practical significance to seek new potential complexing
moieties as effective solubilizing agents for poorly water-soluble
drugs.
Pillar[n]arenes have been new supramolecular candidates for
30 the construction of smart bioactive systems since their discovery
in 2008.9,10 Cavities with different sizes can be obtained by
changing n from 5 to 15.10d,10e Compared with other previously
reported macrocycles like crown ethers, cyclodextrins,
calixarenes and cucurbiturils, pillar[n]arenes are a class of unique
35 macrocycles with π-electron-rich hydrophobic cavities and easily
modifiable outer rims.11 Hence, the host–guest interactions
between pillar[n]arenes and various guests are dynamically
responsive to diverse external physical and chemical stimuli
70
including light, temperature, pH, redox agents, enzymes, etc.12
Scheme 1. Chemical structures of compound WP6 and drug tamoxifen
40 With all those distinctive and smart properties, pillar[n]arenes can
and cartoon representation of formation of the inclusion complex between
be used to construct stimuli-responsive amphiphilic assemblies,13 them.
nanostructures,14 supramolecular polymers15 and many other
systems with various applications in bioactive fields such as
75 First, when it comes to the ability and capacity of WP6 in
artificial transmembrane channels, cell agglutination, bioimaging,
solubilizing tamoxifen, the intrinsic solubility of WP6 is a
45 targeting drug delivery and controlled release.16 With all these
critical parameter. In this case, 1H NMR was used for
abundant studies that have solidly proven that pillar[n]arenes
measurement owing to the integration in spectra could be
have immeasurable and valuable potential in biomedical and
applied to quantify the content of WP6 in saturated solution

This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1
 ChemComm Page 2 of 4

by using a suitable reference. Sodium benzene-1,3,5-

tricarboxylate6f,6i was chosen to be the internal reference
owing to its excellent water-solubility and single 1H NMR
View Article Online
DOI: 10.1039/C7CC05305C
signal in low field which is separately located with signals of
5 WP6. Excessive WP6 was stirred in D 2O for 24 hours to
reach equilibrium. A saturated solution was obtained after
filtration with a LABMAX 0.22 µm inorganic membrane filter
and the content of WP6 in the saturated solution was
calculated according to the integration of the aromatic proton
10 signal on the 1H NMR spectrum. The experiments were
repeated 3 times (Figs. S2-S4) and the solubility of WP6 was
measured to be 56.6 ± 0.9 mM. This good solubility of WP6
in water was the crucial fundation for solubilizing poor-
soluble drugs.
15 Next, we investigated the host–guest interactions between
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WP6 and tamoxifen. In order to confirm the existence of

ChemComm Accepted Manuscript

host−guest complexation, 1H NMR was firstly used for
investigation (Fig. 1). After a 5.00 mM solution of WP6 in
D 2O was made, excess amount of tamoxifen was added. Then
20 the resultant suspension was magnetically stirred at room
temperature for 24 hours. The excessive undissolved
tamoxifen was removed by a LABMAX 0.22 µm inorganic
membrane filter to obtain the sample. Due to the poor water-
solubility of tamoxifen, we could not detect the nuclear
25 magnetic resonance signals of tamoxifen in D 2O. However,
the proton signals of tamoxifen obviouly appeared in the
solution of WP6 (Fig. 1, spectrum a), indicating that a certain
amount of tamoxifen was dissolved in the solvent under the
existence of WP6. Moreover, the signals of aromatic protons
30 H a of tamoxifen were separately located from the signal of
aromatic protons H 1 of WP6 on the spectrum. This chemical
shift difference is very important since this means that we can
use 1H NMR to deterimine the concentration of tamoxifen in
the following water-solubility enhancement studies on
35 tamoxifen. Besides, compared with the spectrum (Fig. 1,
spectrum b) of WP6 at the same concentration, all of the
proton signals of WP6 became broad and the signals of
protons H 1 and H 3 shifted to downfield slightly. It could be
concluded preliminarily as a sign of the existence of
40 host−guest interactions between WP6 and tamoxifen.
Futhermore, 2D NOESY NMR experiment was performed to
investigate the relative positions of the two components in
D 2O. As shown in Fig. S5, NOE correlative signals were
observed between protons of WP6 and protons of tamoxifen.
45 These phenomena suggested that tamoxifen was encapsulated
into the cavity of WP6 to form a host−guest complex WP6-T
(Scheme 1). Electrospray ionization mass spectrometry
(ESIMS) of a solution of WP6 (5.00 mM) and tamoxifen
exhibited a peak at m/z = 1798.7 corresponding to [WP6-T –
50 12NH 4 + 12H – e]+, which confirmed the formation of a 1:1
complex between WP6 and tamoxifen, as shown in Fig. S6.
Fig. 1 1 H NMR spectra (400 MHz, 298 K): (a) tamoxifen dissolved in
55 a solution of WP6 (5.00 mM); (b) WP6 (5.00 mM) in D 2 O.
In addition, UV-vis absorption spectra and fluorescent
spectra were recorded to give the reliable evidence of the
host–guest complex. As displayed in UV-vis absorption
60 spectra, the saturated solution of tamoxifen in water exhibited
almost no absorption owing to its very low water-solubility
while the solution of WP6 exhibited an absorption band at
291 nm. After dissolving tamoxifen in the solution of WP6,
the absorption band slightly increased and bathochromic shift
65 to 292 nm. Similarly, when the samples were excited at 291
nm the fluorescent emission spectrum of WP6 exhibited an
intensity decrease at 327 nm and appearance of three new
peaks at 372 nm, 388 nm and 411 nm (Fig. 2). All these
results clearly indicated the existence of the host−guest
70 interactions between WP6 and tamoxifen.
Fig. 2 (a) UV-vis spectra and (b) fluorescent emission spectra of saturated
solution of tamoxifen (black line), WP6 (5 × 10–5 M, red line), and
75 tamoxifen dissolved in a solution of WP6 (5.00 mM) then diluted to 5 ×
10–5 M (blue line).
After the confirmation of the host−guest interactions
between WP6 and tamoxifen, we further investigated the
80 water-solubility enhancement of tamoxifen on this basis by
using 1H NMR with the similar method of content
measurement as mentioned above. Excessive amount of
tamoxifen was added into the solutions of WP6 with known
concentrations and the resultant suspensions were stirred for
85 24 hours. As shown in Figs. S7-S14, the contents of
tamoxifen were obtained by the integration calculation
compared to the internal reference sodium benzene-1,3,5-
tricarboxylate. As shown in Fig. 3, with the increase of the
concentration of WP6, the content of drug tamoxifen also
90 increased, demonstrating remarkably good solubilizing effect

2 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 Page 3 of 4 ChemComm
of WP6 to tamoxifen. At the maximum concentration of WP6,
751-fold amount of solute tamoxifen was achieved compared
to the intrinsic water-solubility of tamoxifen in water (1.60 ×
10–2 mM). Furthermore, WP6 displayed superior ability to
5 enhance the water-solubility of tamoxifen compared to the
previously reported acyclic cucurbituril-type containers and
hydroxypropyl β-cyclodextrin. For previously reported acyclic
cucurbituril-type containers and hydroxypropyl β-cyclodextrin,
less than 1.50 mM tamoxifen was dissolved in the presence of
10 10 mM molecular container6f,6i while here 4.76 mM was
dissolved under the existence of 10.0 mM WP6. In addition,
the binding constant between WP6 and tamoxifen was
determined to be 5.10 × 104 M –1 according to the method of
Connors using equation S1 (Fig. S15). Therefore, host-guest
15 interactions between WP6 and tamoxifen can be used to
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enhance the water-solubility of poorly water-soluble
tamoxifen (Scheme 1).
20 Fig. 3 Phase solubility diagram for tamoxifen in the presence of WP6.
Drug activity and toxicity are very important properties of drug
molecules. Cell viability (MTT) assay was carried out to evaluate
the toxicity of uncomplexed WP6 and the in vitro anticancer
25 effect of solubility-enhanced drug tamoxifen in two cell lines:
MCF-7 and Hela. Both the cell lines were treated with the
solutions of WP6 at concentrations from 0.500 to 20.0 µM and
the incubation time was 4 hours (Fig. 4). As minimal changes of
cell viability and even cell proliferation occurred in the testing
30 range, WP6 showed nearly no harm to both the two cancer cell
lines. By contrast, the cell viability incubated with the inclusion
complex decreased with the increasing concentration of WP6-T.
Here tamoxifen has not revealed the killing impact on the cancer
cells in 4 hours in our experiment. Compared with the MTT assay
35 treated with longer time (12 hours, Fig S16) and the reported
results,17 this could be attributed to that the incubation time was
too short to function. These results demonstrated the host–guest
complexation between WP6 and tamoxifen did not interfere the
bioactivity of the anticancer drug and even expedite the killing
40 process compared to the free drug. Therefore, the host–guest
complex WP6-T between WP6 and tamoxifen was a new
supramolecular drug with good water-solubility and excellent
anticancer effect.
This journal is © The Royal Society of Chemistry [year]
View Article Online
DOI: 10.1039/C7CC05305C
45
Fig. 4 Cell viability of (a) MCF-7 and (b) Hela cells after treatment with
different concentrations of WP6, WP6-T and free drug tamoxifen for 4
hours calculated from MTT assay. Statistically significant differences
were determined (*p < 0.05, **0.001 < p < 0.005, ***p < 0.001).
50
In conclusion, water-soluble pillararene WP6 was applied to
enhance the water-solubility and bioactivity of the anticancer
drug tamoxifen. WP6 not only had good aqueous solubility itself
but also increased the water-solubility of tamoxifen as much as
ChemComm Accepted Manuscript
55 751 times of the intrinsic water-solubility according to the phase
solubility diagram. The inclusion complexation between WP6 as
the host and tamoxifen as the guest was confirmed to have a 1:1
stoichiometry by 1H NMR, 2D NOESY, mass spectrometry, UV-
vis absorption spectroscopy and fluorescent emission
60 spectroscopy. In addition, we further investigated the in vitro
bioactivity in anticancer efficiency towards two cells lines: MCF-
7 and Hela. The result showed that WP6 is a type of harmless
molecular container and the supramolecular drug complex WP6-
T displays higher efficiency in killing both the cancer cells than
65 the free drug. Therefore, pillar[n]arenes can be a new type of
macrocyclic hosts to enhance the water-solubility and bioactivity
of poorly water-soluble drugs.
This work was supported by the National Basic Research
70 Program of China (2013CB834502), NSFC/China (21434005,
91527301) and the Fundamental Research Funds for the
Central Universities.
Notes and references
State Key Laboratory of Chemical Engineering, Center for Chemistry of
75 High-Performance & Novel Materials, Department of Chemistry,
Zhejiang University, Hangzhou 310027, P. R. China; Fax: +86-571-
8795-3189; Tel: +86-571-8795-3189; E-mail: fhuang@zju.edu.cn
†Electronic Supplementary Information (ESI) available: Synthetic
procedures, characterizations, NOESY NMR, and other materials. See
80 DOI: 10.1039/c0xx00000x.
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125 A water-soluble pillar[6]arene functions as a solubilizing agent to
enhance the solubility and bioactivity of poorly water-soluble anticancer
drug tamoxifen.
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