Mechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular Cage

Article abstract of DOI:10.1002/anie.202102383

Supramolecular coordination cages show a wide range of useful properties including, but not limited to, complex molecular machine-like operations, confined space catalysis, and rich host–guest chemistries. Here we report the uptake and release of non-covalently encapsulated, pharmaceutically-active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)-decorated bipyridine ligands are used to assemble an octahedral Pd^II₆(TPT)₄ cage. The supramolecular container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aqueous solution entailing complete cargo release upon rupture, as shown by NMR and GPC analyses.

Full text of DOI:10.1002/anie.202102383

Angewandte
Communications
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How to cite:
International Edition: doi.org/10.1002/anie.202102383
German Edition: doi.org/10.1002/ange.202102383
Host–Guest System
Hot Paper
Mechanochemical Release of Non-Covalently Bound Guests from
a Polymer-Decorated Supramolecular Cage
Robin Kꢀng, Tobias Pausch, Dustin Rasch, Robert Gçstl,* and Bernd M. Schmidt*
Abstract: Supramolecular coordination cages show a wide
range of useful properties including, but not limited to,
complex molecular machine-like operations, confined space
catalysis, and rich host–guest chemistries. Here we report the
uptake and release of non-covalently encapsulated, pharma-
ceutically-active cargo from an octahedral Pd cage bearing
polymer chains on each vertex. Six poly(ethylene glycol)-
decorated bipyridine ligands are used to assemble an octahe-
supramolecular rotaxanes bearing poly(methyl acrylate)
(PMA) backbones was achieved by bond scission at the
rotaxane junction,[10a,c,d] while on the other hand, catenanes
are able to effectively distribute tensile deformation in
macrocycles and can thus be considered a mechanical pro-
tecting group.[10b]
The mechanochemical release of cargo molecules from
their respective carrier polymers is intrinsically challenging,
as covalent chain scission generally results in the production
of two shorter, but still polymeric, chain fragments. Methods
cleverly circumventing this limitation led to proton relea-
se,[11a] metal ion release following ferrocene rupture,[11b] furan
derivative release,[11c–e] or release from sophisticated polymer-
based microcapsules.[11f] In most of these systems, inertial
cavitation generated by ultrasound was the method to exert
force on the solutions of the carrier polymers.
The release and activation of drugs by ultrasound was
achieved in micelles, liposomes, or microbubbles,[12] or by
synergistically increasing drug efficacy.[13] Recently, we estab-
lished the ability of ultrasound in the context of polymer
mechanochemistry,[14] to activate force-responsive molecular
moieties (mechanophores)[15] embedded in polymers to
activate and release drugs.[16] However, many of the above
examples compromise their universal applicability by relying
on strong and selective carrier–cargo interactions or even
chemical modification of the cargo molecules.
dral PdII (TPT)4 cage. The supramolecular container encap-
6
sulates progesterone and ibuprofen within its hydrophobic
nanocavity and is activated by shear force produced by
ultrasonication in aqueous solution entailing complete cargo
release upon rupture, as shown by NMR and GPC analyses.
M
etal-mediated self-assembly of organic ligands into dis-
crete nanoscopic structures, such as cages[1] and capsules[2]
(amongst other motifs),[1c,3] has generated a large number of
unique structures over the last decades. Some of these
assemblies were shown to encapsulate guest compounds
with high affinity,[4] can be used as molecular transporters,[5] or
were used to modulate physicochemical properties inside the
confined spaces within the assemblies.[6] A variety of respon-
sive systems have been reported using light[7a–c] or chemical
stimuli as triggers.[7d,e]
Concomitantly, the mechanochemical activation of vari-
ous metal ligand bonds (metallocenes;[8] Zn, Cu, Ni, and Rh
À
complexes;[9a,b] N-heterocyclic carbene complexes with Ag,
Ru,[9c–i] and Cu;[9j–m] as well as Pd phosphanes[9n]) was
successfully carried out. In addition, force activation of
Herein, we report the ultrasound-induced disassembly of
a cargo-loaded self-assembled supramolecular PdII (TPT)4
6
cage with the release of its nanoconfined guests. We
demonstrate examples of several non-covalently bound,
completely unmodified and pharmaceutically active com-
pounds (Figure 1) as cargo.
[*] R. Kꢀng, T. Pausch, Dr. B. M. Schmidt
Institut fꢀr Organische Chemie und Makromolekulare Chemie
Heinrich-Heine-Universitꢁt Dꢀsseldorf
À
To enable the force-induced scission of the Pd N units
within the Pd cage 1a, modified bipyridines were chosen as
cis-blocked, end-capped ligands for the Pd corners. Therefore,
4-bromomethyl-4’-methyl-2,2’-bipyridine was synthesized and
poly(ethylene glycol) methyl ether (PEG, Mn = 10 kDa) was
introduced by nucleophilic substitution, affording PEG-
functionalized bipyridine 9 (see the SI, Figure S2). PEG was
specifically chosen for its water solubility, which is necessary
to utilize the hydrophobic effect of the cage cavity. Over two
steps, the corresponding Pd compound bearing nitrate
counter anions 11 was obtained in 92% yield. Adapting
established procedures,[1d] the PEG-functionalized octahedral
cage 1a was synthesized in aqueous solution by using six
equivalents of the PEG-functionalized Pd complex 11 and
four equivalents of triazine TPT, giving access to the polymer-
embedded star-shaped[17] cage 1a in almost quantitative
yields. 1H NMR of 1a in D2O showed the characteristic
signals for the bipyridine and TPT panels, while the ethylene
Universitꢁtsstrasse 1, 40225 Dꢀsseldorf (Germany)
E-mail: Bernd.Schmidt@hhu.de
D. Rasch, Dr. R. Gçstl
DWI—Leibniz Institute for Interactive Materials
Forckenbeckstrasse 50, 52056 Aachen (Germany)
E-mail: goestl@dwi.rwth-aachen.de
D. Rasch
Institute of Technical and Macromolecular Chemistry
RWTH Aachen University
Worringerweg 1, 52074 Aachen (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102383.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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ures S69–S74, S80–S98). Model
compound shows identical
2
chemical shifts with guest com-
pounds in 1H NMR and clearly
indicates that each cavity encap-
sulates exactly one progesterone
or two ibuprofen guests.
Subsequent sonication experi-
ments of the cargo-loaded cage 1a
were performed using an immer-
sion probe sonicator (20 kHz) in
water. The release was monitored
by 1H NMR and is shown in
Figure 2 for 1a·(ibuprofen)2. The
characteristic upfield guest signals
of the isopropyl and methyl groups
1, 2, and 9 (d = À0.45, 0.35 ppm,
and 0.7 ppm), (Figure 2c, blue
line) completely disappeared
over the course of the sonication
experiment. We hypothesized that
Figure 1. Schematic representation of the PEG-functionalized octahedral cage 1a, bearing on average
220 repetitive ethylene glycol units at each vertex, leading to a total molar mass of 60 kDa. Activation
by ultrasound in aqueous solution leads to fragmentation of the cage, releasing the non-covalently
bound cargo. The preloaded cargo is depicted as the orange dot within the cavity of cage 1a,
representing either precisely one molecule of progesterone or two molecules of ibuprofen per
supramolecular entity.
glycol repeat units and the methyl end groups were in
accordance with the anticipated ratio (48:36:5330:18). Cage
1a was subsequently loaded with progesterone or ibuprofen,
respectively, by adding excess drug to an aqueous solution of
ibuprofen released from the cage precipitated from the
aqueous solution concomitant with signals appearing corre-
sponding to possible cage fragments (d = 8.79–8.60, 8.16,
7.88–7.75 ppm). Hence the release process was unequivocally
connected to cage fragmentation. Yet, the fragmentation
pathway remained unclear in that the guest molecules were
either released from 1) damaged, partially intact cages or
2) the removal of one ligand induced complete disassembly of
the overall cage structure.
Quantitative release was also observed for the sonication
of 1a·(progesterone), where the methyl groups serve as an
excellent probe to follow the release in the upfield 1H NMR,
undisturbed by the broad PEG resonances (Figure S6).
Additionally, the fragmentation of the Pd cage 1a not bearing
cargo was observed on a similar time scale
(Figure S5).
1
the cage. Guest uptake was again confirmed by H NMR in
D2O by observing the distinctive shielding effect of the
triazine panels on the encapsulated guests, leading to
significant upfield shift of the peaks of around d = 1 ppm for
both guests (Figure 2c) and unambiguously confirming
encapsulation within the cavity of cage 1a. Additionally, the
encapsulation of both drugs and several other guests was
carried out with a model compound 2, without PEG units,
thus allowing extensive NMR experiments including
1H DOSY and heteronuclear 2D measurements (see SI Fig-
To examine the cargo release mechanism,
1a·(ibuprofen)2 was sonicated for only 15 min.
Within this short period of time we reasoned
that a considerably smaller fraction of the cage
1a would have the opportunity to fracture by
inertial cavitation, but in principle still might
have been able to release the guests due to an
increased cavity size through ultrasound-
induced uncoiling of the polymers, facilitating
guest “slippage”.[18] As anticipated, cage 1a
showed only minute amounts of fragmenta-
tion product, but at the same time, no cargo
release was observed by 1H NMR (Figure S8).
To unambiguously prove the mechanochem-
ical origin of the observed release, model
compound 2 bearing no polymer chains, and
thus hypothesized not to be susceptible to
force activation, was sonicated under identical
conditions (Figure S11). As expected, cage 2
did not show any changes in the 1H NMR after
sonication experiments. Furthermore, control
sonication experiments using 2·(ibuprofen)2,
Figure 2. 1H NMR (D2O, 298 K) of the encapsulated 1a·(ibuprofen)2 (blue line) and
release of ibuprofen cargo (red line). Sonication time 3 h, a sequence of 1 s on and 1 s
off was chosen, for each experiment only the “on” time is reported. The asterisks in the
insets indicate the cage fragmentation products.
2
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showed neither cargo release nor core fragmentation (Fig-
ure S12).
To probe the force-induced degradation of the star-shaped
polymeric supramolecular assembly in more detail, samples
before and after sonication of each 1a, 1a·(ibuprofen)2, and
1a·(progesterone) were analyzed by gel permeation chroma-
tography (GPC) using CHCl3 as the eluent (Figure 3). The
cages disassembled under most GPC measurement conditions
because of interference from organic solvents and salts. While
the molar mass distributions of the disassembled fragments
before sonication matched those of the pristine PEG-
functionalized bipyridine 9 (Figure S13), a shoulder appeared
at lower molar masses after sonication. This was attributed to
non-specific scission events of individual PEG chains either
before or after the cage structure was already cleaved. Since
the extent of observed non-specific scission was only marginal
compared to the observed quantitative mechanochemical
release of the cargo molecules by NMR, we reasoned that the
mechanochemically weakest link lay within the cage structure
and not within the polymer chains, rendering the force
activation of 1a reasonably selective.
Next, we investigated whether an increase in the degree of
polymerization of the attached PEG chains was also reflected
in an increased tendency to release cargo. Therefore, we
prepared an isostructural cage using PEG with Mn = 20 kDa
at each vertex (Figure 4). Samples of the Pd cage 2 bearing no
PEG chains, cage 1a bearing 220 repeat units at each ligand,
and cage 1b bearing 440 repeat units at each ligand, were
sonicated over the course of 1 h. Judging from 1H NMR
integration, the anticipated molar mass dependency was
observed, corresponding to a roughly 100% increase in
release rate when using 440 (cage 1b) instead of 220 repeat
units (cage 1a, Figure 4).
Figure 3. GPC chromatograms obtained in CHCl3 from the RI detector
of cage 1a with and without guests before and after sonication for 1 h.
In conclusion, we have presented the first example of
a
supramolecular coordination
cage forming a star-shaped, water-
soluble polymer structure which is
responsive to ultrasonication-
induced shear force in solution.
We showcased the mechanochem-
ical release of both ibuprofen and
progesterone from the same parent
cage structure. Since the release of
small molecules from their latent
macromolecular carriers by means
of polymer mechanochemistry gen-
erally requires specifically func-
tionalized cargo molecules, we
anticipate that our combination of
universal supramolecular encapsu-
lation and force as an external
stimulus will contribute to the
development of molecular release
systems and potentially advanced
therapeutics.
Figure 4. 1H NMR (D2O, 298 K) of 2, 1a, and 1b (from top to bottom), after 1 h of total sonication
“on” time. The asterisks indicate the cage fragmentation. Only the aromatic region showing panels
and bipyridine ligands is shown because of the intense and very broad resonances of the PEG
chains.
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nell, C. S. Wood, P. P. Neelakandan, J. R. Nitschke, Chem. Rev.
2015, 115, 7729 – 7793; d) S. M. Jansze, K. Severin, J. Am. Chem.
Soc. 2019, 141, 815 – 819; e) S. M. Jansze, G. Cecot, K. Severin,
Chem. Sci. 2018, 9, 4253 – 4257.
Acknowledgements
We thank the Strategic Research Fund of Heinrich Heine
University (F-2018/1460-4) and the Manchot Foundation for
a fellowship to R.K. Analytical support from Markus
Leutzsch, Mohanad Aian, and Dimitri Wilms is gratefully
acknowledged. D.R. and R.G. are grateful for support by
a Freigeist-Fellowship of the Volkswagen Foundation (No.
92888). Parts of the analytical investigations were performed
at the Center for Chemical Polymer Technology CPT, which
was supported by the European Commission and the federal
state of North Rhine-Westphalia (No. 300088302). Open
access funding enabled and organized by Projekt DEAL.
[8] a) Y. Zhang, Z. Wang, T. B. Kouznetsova, Y. Sha, E. Xu, L.
Shannahan, M. Fermen-Coker, Y. Lin, C. Tang, S. L. Craig, Nat.
Chem. 2021, 13, 56 – 62; b) Y. Sha, Y. Zhang, E. Xu, C. W.
McAlister, T. Zhu, S. L. Craig, C. Tang, Chem. Sci. 2019, 10,
4959 – 4965; c) Y. Sha, Y. Zhang, E. Xu, Z. Wang, T. Zhu, S. L.
Craig, C. Tang, ACS Macro Lett. 2018, 7, 1174 – 1179.
[9] a) X. Zhang, Y. Vidavsky, S. Aharonovich, S. J. Yang, M. R.
Buche, C. E. Diesendruck, M. N. Silberstein, Soft Matter 2020,
16, 8591 – 8601; b) A. Levy, R. Feinstein, C. E. Diesendruck, J.
Am. Chem. Soc. 2019, 141, 7256 – 7260; c) R. T. M. Jakobs, S. Ma,
R. P. Sijbesma, ACS Macro Lett. 2013, 2, 613 – 616; d) R. T. M.
Jakobs, R. P. Sijbesma, Organometallics 2012, 31, 2476 – 2481;
e) R. Groote, L. van Haandel, R. P. Sijbesma, J. Polym. Sci. Part
A J. Polym. Sci. A 2012, 50, 4929 – 4935; f) R. Groote, R. T. M.
Jakobs, R. P. Sijbesma, ACS Macro Lett. 2012, 1, 1012 – 1015;
g) J. Rooze, R. Groote, R. T. M. Jakobs, R. P. Sijbesma, M. M.
van Iersel, E. V. Rebrov, J. C. Schouten, J. T. F. Keurentjes, J.
Phys. Chem. B 2011, 115, 11038 – 11043; h) R. Groote, B. M.
Szyja, E. A. Pidko, E. J. M. Hensen, R. P. Sijbesma, Macro-
molecules 2011, 44, 9187 – 9195; i) A. Piermattei, S. Karthikeyan,
R. P. Sijbesma, Nat. Chem. 2009, 1, 133 – 137; j) H. Rupp, W. H.
Binder, Macromol. Rapid Commun. 2021, 42, 2000450; k) S.
Funtan, A. Funtan, R. Paschke, W. H. Binder, Org. Mater. 2020,
2, 116 – 128; l) P. Michael, S. Mehr, S. Khazraee, W. H. Binder, J.
Polym. Sci. Part A 2017, 55, 3893 – 3907; m) P. Michael, W. H.
Binder, Angew. Chem. Int. Ed. 2015, 54, 13918 – 13922; Angew.
Chem. 2015, 127, 14124 – 14128; n) J. M. J. Paulusse, R. P.
Sijbesma, Angew. Chem. Int. Ed. 2004, 43, 4460 – 4462; Angew.
Chem. 2004, 116, 4560 – 4562.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cage compounds · drug release
host–guest systems · mechanochemistry · polymers
[1] a) S. Saha, I. Regeni, G. H. Clever, Coord. Chem. Rev. 2018, 374,
1 – 14; b) M. Han, D. M. Engelhard, G. H. Clever, Chem. Soc.
Rev. 2014, 43, 1848 – 1860; c) M. M. J. Smulders, I. A. Riddell, C.
Browne, J. R. Nitschke, Chem. Soc. Rev. 2013, 42, 1728 – 1754;
d) M. Yoshizawa, J. K. Klosterman, M. Fujita, Angew. Chem. Int.
Ed. 2009, 48, 3418 – 3438; Angew. Chem. 2009, 121, 3470 – 3490.
[2] a) M. Yamashina, S. Kusaba, M. Akita, T. Kikuchi, M. Yoshizwa,
Nat. Commun. 2018, 9, 4227; b) M. Yoshizawa, L. Catti, Acc.
Chem. Res. 2019, 52, 2392 – 2404; c) M. Yoshizawa, J. K. Kloster-
man, Chem. Soc. Rev. 2014, 43, 1885 – 1898.
[3] a) Y. Sun, C. Chen, J. Liu, P. J. Stang, Chem. Soc. Rev. 2020, 49,
3889 – 3919; b) D. Bardhan, D. K. Chand, Chem. Eur. J. 2019, 25,
12241 – 12269; c) S. Samantray, S. Krishnaswamy, D. K. Chand,
Nat. Commun. 2020, 11, 880; d) B. M. Schmidt, T. Osuga, T.
Sawada, M. Hoshino, M. Fujita, Angew. Chem. Int. Ed. 2016, 55,
1561 – 1564; Angew. Chem. 2016, 128, 1587 – 1590.
[10] a) R. Sandoval-Torrientes, T. Carr, G. De Bo, Macromol. Rapid
Commun. 2021, 42, 2000447; b) M. Zhang, G. De Bo, J. Am.
Chem. Soc. 2020, 142, 5029 – 5033; c) M. Zhang, G. De Bo, J.
Am. Chem. Soc. 2019, 141, 15879 – 15883; d) M. Zhang, G.
De Bo, J. Am. Chem. Soc. 2018, 140, 12724 – 12727.
[11] a) C. E. Diesendruck, B. D. Steinberg, N. Sugai, M. N. Silber-
stein, N. R. Sottos, S. R. White, P. V. Braun, J. S. Moore, J. Am.
Chem. Soc. 2012, 134, 12446 – 12449; b) M. Di Giannantonio,
M. A. Ayer, E. Verde-Sesto, M. Lattuada, C. Weder, K. M.
Fromm, Angew. Chem. Int. Ed. 2018, 57, 11445 – 11450; Angew.
Chem. 2018, 130, 11616 – 11621; c) M. B. Larsen, A. J. Boydston,
J. Am. Chem. Soc. 2014, 136, 1276 – 1279; d) M. B. Larsen, A. J.
Boydston, J. Am. Chem. Soc. 2013, 135, 8189 – 8192; e) X. Hu, T.
Zeng, C. C. Husic, M. J. Robb, J. Am. Chem. Soc. 2019, 141,
15018 – 15023; f) A. P. Esser-Kahn, S. A. Odom, N. R. Sottos,
S. R. White, J. S. Moore, Macromolecules 2011, 44, 5539 – 5553.
[12] a) S. E. Ahmed, A. M. Martins, G. A. Husseini, J. Drug Targeting
2015, 23, 16 – 42; b) F. Kiessling, S. Fokong, P. Koczera, W.
Lederle, T. Lammers, J. Nucl. Med. 2012, 53, 345 – 348.
[13] a) K. R. Lattwein, H. Shekhar, J. J. P. Kouijzer, W. J. B. van Wa-
mel, C. K. Holland, K. Kooiman, Ultrasound Med. Biol. 2020, 46,
193 – 215; b) I. Rosenthal, J. Z. Sostaric, P. Riesz, Ultrason.
Sonochem. 2004, 11, 349 – 363.
[14] For reviews see a) M. Stratigaki, R. Gçstl, ChemPlusChem 2020,
85, 1095 – 1103; b) Y. Chen, G. Mellot, D. van Luijk, C. Creton,
R. P. Sijbesma, Chem. Soc. Rev. 2021, 50, 4100 – 4140; c) E. Izak-
Nau, D. Campagna, C. Baumann, R. Gçstl, Polym. Chem. 2020,
11, 2274 – 2299; d) B. H. Bowser, S. L. Craig, Polym. Chem. 2018,
9, 3583 – 3593; e) P. A. May, J. S. Moore, Chem. Soc. Rev. 2013,
42, 7497 – 7506.
[4] a) F. J. Rizzuto, K. S. von Krbek, J. R. Nitschke, Nat. Rev. Chem.
2019, 3, 204 – 222; b) F. J. Rizzuto, J. P. Carpenter, J. R. Nitschke,
J. Am. Chem. Soc. 2019, 141, 9087 – 9095.
[5] a) L. Ma, C. J. E. Haynes, A. B. Grommet, A. Walczak, C. C.
Parkins, C. M. Doherty, L. Longley, A. Tron, A. R. Stefankie-
wicz, T. D. Bennett, J. R. Nitschke, Nat. Chem. 2020, 12, 270 –
275; b) B.-N. T. Nguyen, A. B. Grommet, A. Tron, M. C. A.
Georges, J. R. Nitschke, Adv. Mater. 2020, 32, 1907241; c) M.
Kieffer, A. M. Garcia, C. J. E. Haynes, S. Kralj, D. Iglesias, J.
Nitschke, S. Marchesan, Angew. Chem. Int. Ed. 2019, 58, 7982 –
7986; Angew. Chem. 2019, 131, 8066 – 8070.
[6] a) J. Gemen, J. Ahrens, L. J. W. Shimon, R. Klajn, J. Am. Chem.
Soc. 2020, 142, 17721 – 17729; b) L. Pesce, C. Perego, A. B.
Grommet, R. Klajn, G. M. Pavan, J. Am. Chem. Soc. 2020, 142,
9792 – 9802; c) A. I. Hanopolskyi, S. De, M. J. Białek, Y. Diskin-
Posner, L. Avram, M. Feller, R. Klajn, Beilstein J. Org. Chem.
2019, 15, 2398 – 2407; d) D. Samanta, D. Galaktionova, J.
Gemen, L. J. W. Shimon, Y. Diskin-Posner, L. Avram, P. Krꢀl,
R. Klajn, Nat. Commun. 2018, 9, 641; for reviews see e) A. B.
Grommet, M. Feller, R. Klajn, Nat. Nanotechnol. 2020, 15, 256 –
271; f) A. B. Grommet, L. M. Lee, R. Klajn, Acc. Chem. Res.
2020, 53, 2600 – 2610; g) C. J. Brown, F. D. Toste, R. G. Bergman,
K. N. Raymond, Chem. Rev. 2015, 115, 3012 – 3035.
[15] For reviews see a) R. T. OꢁNeill, R. Boulatov, Nat. Rev. Chem.
2021, 5, 148 – 167; b) C. L. Brown, S. L. Craig, Chem. Sci. 2015, 6,
2158 – 2165.
[7] a) S. J. Wezenberg, Chem. Lett. 2020, 49, 609 – 615; b) L. Wang,
Q. Lia, Chem. Soc. Rev. 2018, 47, 1044 – 1097; c) A. J. McCon-
4
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[16] a) Z. Shi, Q. Song, R. Gçstl, A. Herrmann, Chem. Sci. 2021, 12,
[18] a) T. Kusukawa, M. Fujita, J. Am. Chem. Soc. 2002, 124, 13576 –
1668 – 1674; b) S. Huo, P. Zhao, Z. Shi, M. Zou, X. Yang, E.
Warszawik, M. Loznik, R. Gçstl, A. Herrmann, Nat. Chem. 2021,
13, 131 – 139; c) Z. Shi, J. Wu, Q. Song, R. Gçstl, A. Herrmann, J.
Am. Chem. Soc. 2020, 142, 14725 – 14732; for a review see d) Y.
Zhang, J. Yu, H. N. Bomba, Y. Zhu, Z. Gu, Chem. Rev. 2016, 116,
12536 – 12563.
13582; b) M. D. Pluth, K. N. Raymond, Chem. Soc. Rev. 2007, 36,
161 – 171.
Manuscript received: February 16, 2021
[17] a) D. C. Church, G. I. Peterson, A. J. Boydston, ACS Macro Lett.
2014, 3, 648 – 651; b) H. Oka, K. Imato, T. Sato, T. Ohishi, R.
Goseki, H. Otsuka, ACS Macro Lett. 2016, 5, 1124 – 1127.
Revised manuscript received: March 8, 2021
Accepted manuscript online: March 17, 2021
Version of record online: && &&, &&&&
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Communications
Host–Guest System
R. Kꢁng, T. Pausch, D. Rasch, R. Gçstl,*
B. M. Schmidt*
&&&& — &&&&
Mechanochemical Release of Non-
Covalently Bound Guests from a Polymer-
Decorated Supramolecular Cage
An octahedral PdII (TPT)4 cage with poly-
mer chains on each vertex is activated by
shear force from ultrasonication in aque-
ous solution. The metal–organic cage
encapsulates progesterone or ibuprofen
within its hydrophobic nanocavity and
shows complete cargo release upon rup-
ture.
6
6
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ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!