Gold-Triggered Uncaging Chemistry in Living Systems

Article abstract of DOI:10.1002/anie.201705609

Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and

Full text of DOI:10.1002/anie.201705609

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Accepted Article
Title: Gold-Triggered Uncaging Chemistry in Living Systems
Authors: Ana M. Pérez-López, Belén Rubio-Ruiz, Víctor Sebastián,
Lloyd Hamilton, Catherine Adam, Thomas L. Bray, Silvia
Irusta, Paul M. Brennan, Guy Lloyd-Jones, Dirk Sieger, Jesús
Santamaría, and Asier Unciti-Broceta
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705609
Angew. Chem. 10.1002/ange.201705609
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Gold-Triggered Uncaging Chemistry in Living Systems
Ana M. PérezꢀLópez, Belén RubioꢀRuiz, Víctor Sebastián, Lloyd Hamilton, Catherine Adam, Thomas L.
Bray, Silvia Irusta, Paul M. Brennan, Guy C. LloydꢀJones, Dirk Sieger, Jesús Santamaría* and Asier
UncitiꢀBroceta*
Abstract: Recent advances in bioorthogonal catalysis are increasing
our capacity to manipulate the fate of molecules in complex biological
systems. Herein we report a novel bioorthogonal uncaging strategy
that is triggered by heterogeneous gold catalysis and facilitates the
activation of a structurally-diverse range of therapeutics in cancer cell
culture. Furthermore, this solid supported catalytic system enabled —
for the first time— the locally-controlled release of a fluorescent dye
in the brain of a zebrafish, offering a novel way to modulate the activity
of bioorthogonal reagents in the most fragile and complex organs.
the safety of gold and its remarkable catalytic properties to
mediate oxidative reactions at or even below ambient
temperature. In the chemical biology field, however, the
7
chemistry of gold is dominated by the nearꢀcovalent SꢀAu
8
bonding. This spontaneous bond formation provides the basis for
the bottomꢀup selfꢀassembling of monolayers functionalized with
a multitude of small molecules and biomolecules at the surface of
the metal, a highlyꢀreliable process that has found widespread
application in nanotechnology, biotechnology and theranostics.8
Because of the high affinity of thiols for gold and their ubiquitous
presence in peptides and proteins, the attractive alkynophile
properties of gold nanoparticles (AuꢀNP) pass unnoticed in the
biological milieu. We envisioned that embedding AuꢀNP in a solid
support would serve to protect the metal nanostructures from
large thiolꢀrich biomolecules, while allowing the free entry of
alkyneꢀfunctionalized small molecules to undergo goldꢀmediated
chemistries even in biological systems. Importantly, based on the
high biocompatibility of metallic gold, such a device would be
optimal to catalyze bioorthogonal transformations in vivo. In a
suitable shape and size, this functional device could potentially be
implanted by a surgeon at the anatomical site of a localized
cancer (e.g. brain) and enable the local “manufacture” of different
drugs —in a catalytic fashion— from systemicallyꢀadministered
innocuous starting materials. This unique delivery method would
Since the seminal works that showcased the capabilities of
foreign transition metal catalysts to mediate chemoselective
transformations in cells,1 the emerging field of bioorthogonal
2
catalysis has witnessed a wealth of creativity towards a variety
3
aꢀc
of applications ranging from biomolecule labelling,
detection and intra/subcellular probe release
metabolite
to in situ
3
d
3eꢀh
enzyme3iꢀj and prodrug activation.3kꢀo Substoichiometric activity
and access to a greater diversity of chemical processes and
functionalities are some of the added benefits provided by abiotic
transition metals to the current bioorthogonal toolbox, thus
4
expanding the boundaries of this central field of research. One of
the latest additions to this area was recently reported by Tanaka
and coworkers,5 who developed a novel strategy for in vivo
protein labeling mediated by glycoalbuminꢀbound gold(III)
complexes (Scheme 1). Despite recent advances in the field,
many challenges lie ahead as transition metal catalysts show
limited biocompatibility in living systems both in terms of catalytic
versatility and inherent toxicity.
9
offer the benefits of drug release systems (i.e. focal treatment,
reduced general side effects) with fewer limitations (e.g. extended
lifetime, access to multiple therapies).
Towards this goal, herein we report the first example of bond
cleavage chemistry mediated by heterogeneous gold catalysis in
living systems (Scheme 1), a previouslyꢀoverlooked chemical
reactivity of gold that facilitates the efficient bioorthogonal
uncaging of various clinicallyꢀapproved anticancer drugs in
cancer cell culture and the first intracranial activation of a
bioorthogonal probe in zebrafish.
Gold catalysis has received enormous attention in organic
6
synthesis over the last decades. Among the chemical properties
of gold stand out its preference to coordinate with alkynes in the
6
,7
presence of other functional groups including alkenes. Solid
supported gold nanoparticles have also attracted the interest of
chemists searching for greener catalysts due to their recyclability,
a) Tanaka 2017 ꢀ In vivo protein labelling
ALBUMIN AuIIICl
2
O
O
[
*]Dr A. M. PérezꢀLópez, Dr B. RubioꢀRuiz, Dr C. Adam, T. L. Bray, Dr P. M.
Brennan and Dr A. UncitiꢀBroceta
Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and
Molecular Medicine, University of Edinburgh (UK)
F
F
R
+
2
H N R
O
N
physiological
environs
H
structural
proteins
Imaging agent
LABELLED CELL / ORGAN
Eꢀmail: Asier.UncitiꢀBroceta@igmm.ed.ac.uk
b) This work ꢀ Goldꢀtriggered uncaging chemistry
O
[
*]Dr V. Sebastián, Dr S. Irusta and Prof J. Santamaría
Department of Chemical Engineering and Environmental Technology and
Institute of Nanosciences of Aragon (INA), University of Zaragoza (Spain),
and Networking Research Center on Bioengineering, Biomaterials and
Nanomedicine, CIBERꢀBBN, 28029 Madrid (Spain).
R
[Au]-resins
R
N
O
NH
2
H
O
O
Eꢀmail: jesus.santamaria@unizar.es
N
NH
L. Hamilton and Dr. D. Sieger
Centre for Neurogeneration, The Chancellor's Building, University of
Edinburgh (UK)
physiological
environments
O
O
O
R
O
R
OH
Dr P. M. Brennan
Centre for Clinical Brain Sciences, University of Edinburgh (UK)
N
N
H
H
Prof G. C. LloydꢀJones
Inactive probe / prodrug
FLUORESCENT / BIOACTIVE
School of Chemistry, King’s Buildings, West Mains Road, University of
Edinburgh (UK)
III
Scheme 1. a) Au ꢀmediated bioorthogonal amidation reported by Tanaka and
5
coworkers. b) The solid supported gold catalyzed uncaging strategy developed
Supporting information for this article is given via a link at the end of the
document.
in this work.
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Angewandte Chemie International Edition
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COMMUNICATION
Figure 1. (a) Scanning electron microscopy images of [Au]ꢀresins. (b) HAADFꢀSTEM images of a crossꢀsection of a [Au]ꢀresin at different magnifications and
energyꢀdispersive Xꢀray spectra of highlighted areas. (c) Cleavage of NꢀPocꢀprotected prodye 1 (20 ꢁM) in the presence of [Au]ꢀresins (1 mg/mL) at physiological
conditions (pH= 7.4, 37 °C). Central panel: reaction kinetics in PBS or serum. Right panel: fluorescence analysis at 24 h in different conditions. Negative control:
reagent 1 without [Au]ꢀresins.
Solid supported gold catalysts (Fig. 1a,b) were prepared by in
situ generation of AuꢀNP within a PEGꢀgrafted lowꢀcrosslinked
polystyrene matrix. In short, aminoꢀfunctionalized TentaGel® HL
resins of 75 microns in diameter (Rapp Polymere GmbH) were
treated with tetrachloroauric(III) acid and NaOH in water:THF
followed by reduction with tetrakis(hydroxymethyl)phosphonium
chloride (THPC; see full synthesis in the Supp. Inf.). THPC was
used due to its relatively mild reducing properties to control
particle growth and distribution.10 High angle annular dark field
proteins) in the conversion of 1 into 2 by adding (in excess)
ethylene glycol (3a), 2ꢀmercaptoethanol (3b) and ethanolamine
(3c), respectively. These low molecular weight chemicals were
used to facilitate diffusion throughout the resins, thereby
maximizing their interaction with internal AuꢀNP. All the reactions
were carried out in PBS at 37 °C. Although 3a had a relatively
minor effect on the catalytic capacity of the devices, substantial
variations in activity were observed in the presence of 3b and 3c
(Fig. 1c). Thiol 3b suppressed the reactivity of the resins almost
completely, whereas addition of amine 3c significantly boosted
catalytic activity. The combined presence of an excess of both 3b
and 3c resulted in low levels of fluorescence intensity. This
prompted us to investigate the influence of glutathione in the
(
HAADF) scanning transmission electron microscopy (STEM)
images of ultramicrotome crossꢀsections of the resins showed the
presence of polyhedral nanocrystals of 30 nm (average diameter)
uniformly dispersed across the polymer framework (Fig. 1b and
Supp. Fig. 1). Xꢀray photoelectron spectroscopy analysis (Supp.
Inf.) detected an incremental gradient of gold concentration from
2
reaction, a natural reductant that contains a SH and an NH group
in its structure. Since glutathione is ubiquitously found in the
human plasma and the interstitial fluid at a concentration of 2ꢀ20
0
δ+
the surface to the core of the resins with an Au /Au ratio ranging
from 7 (periphery) to 19 (interior).
ꢁM,11 we studied the reaction of
1 and [Au]ꢀresins at
To investigate the properties of the [Au]ꢀresins in physiological
conditions, the devices were incubated with nonfluorescent
compound 1, which upon Oꢀdepropargylation releases strongly
fluorescent rhodamine 110, 2 (Fig. 1c). Reactions were performed
in PBS (pH= 7.4) at 37 °C either with or without serum and
fluorescence measured with a spectrophotometer. Analysis
revealed the rapid generation of fluorescence under both
conditions, with the presence of serum achieving a much greater
fluorogenic effect (~25% yield), demonstrating the feasibility of
performing AuꢀNPꢀmediated chemistry beyond the SꢀAu bonding
in biocompatible environments. Timeꢀcourse and reusability
studies (Supp. Fig. 3ꢀ4) provided proof of the durability of the
devices and their capacity to activate multiple doses of masked
reagent, although a gradual decay in activity was observed over
time.
concentrations ranging from 10 to 400 ꢁM. As shown in the Suppl.
Fig. 5, increasing glutathione levels up to 50 ꢁM promoted the
reaction, whereas greater concentrations led to a substantial
reduction in fluorescence intensity. Notably, a large regain in
catalytic activity was achieved upon addition of an extra mg of
[Au]ꢀresins to the inhibited reactions. In contrast, if the
concentration of probe 1 was augmented, no significant increment
of fluorescence generation was observed. These results indicate
that SꢀAu bonding of glutathione molecules on the surface of the
AuꢀNP promote the dealkylation reaction until a saturation
threshold is reached (see rationale in Scheme 2a). Over the
saturation limit, goldꢀbound biomolecules will coat most active
sites on the AuꢀNP surface thus hindering goldꢀalkyne
coordination. A series of tests carried out to monitor and analyze
the reaction (see Supp. Fig. 6ꢀ7) corroborated that rhodamine 2
was the main product of the reaction and found intermediates that
could correspond to organogold species. However, no reaction
byproducts could be either isolated or identified, which points to
To better understand the enhanced catalytic activity of the [Au]ꢀ
resins in the presence of serum, we investigated the influence of
OH, SH and NH groups (nucleophilic groups found in serum
2
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Angewandte Chemie International Edition
10.1002/anie.201705609
COMMUNICATION
the production of shortꢀlived compounds. Based on these
experimental observations, we tentatively propose a dealkylation
the surgery, either reagent 1 (activation assay) or just DMSO
(negative control) were added to the medium and embryos
imaged at 24 h (n=5). Due to its lipophilicity, prodye 1 can enter
the zebrafish through the skin and/or by ingestion and distribute
systemically, but will only be converted into fluorescent compound
2 upon reaction with the [Au]ꢀbead. As shown in Fig. 2b, a strong
green fluorescent signal originating from the [Au]ꢀresin was
observed only when incubated with 1, confirming the local
generation of rhodamine 2. Prolongation of the study by three
additional days corroborated previous observations regarding the
sustained functionality of the devices (Suppl. Fig 11). This study,
which represents the first bioorthogonal organometallic reaction
to be locally performed in the brain of a living animal, proves the
capacity of heterogeneous gold catalysts to mediate in vivo
bioorthogonal release of functional reagents in a spatially
controlled manner.
pathway whereby gold acts as
a piꢀacid to activate the
nucleophilic addition of biomolecules onto the terminal alkyne
group, leading to release of the leaving group (e.g. a dye or drug)
and the generation of reactive allenyl byproducts (Scheme 2b)
that isomerise or hydrolyse under the reaction conditions.
a
COOH
physiological [GSH]
[GSH]
H
2
N
O
COOH
Alkynes
H
N
R
Nucleophile
N
H
2
N
H
2
N
H
2 2 2 2 2
H N H N H N H N H N
N/O
O
SH
Au-NP stabiliser
Au
Glutathione (GSH)
Au
0
δ+
b
[Au]= Au , Au
R= O/NꢀR'
In conclusion, we have developed a heterogeneous catalytic
system that enables access to chemical properties of AuꢀNP that
were previously out of our reach in biological environments. Such
devices triggered the bioorthogonal uncaging of a structurallyꢀ
diverse selection of cytotoxic precursors via an unexplored
chemical reactivity of gold, providing a novel and safe method to
Nu= NHꢀR'', etc.
[
Au]
NuꢀH
[Au]
[
Au]ꢀ
Nu
ꢀ
B, +BH
Nu
R
H
+
R
R
ꢀ
BH , +B
Scheme 2. (a) Rationale for the assistingꢀinhibiting roles of glutathione in [Au]ꢀ
catalysed O/Nꢀpropargyl cleavage reactions. (b) Tentative reaction mechanism
for the [Au]ꢀtriggered depropargylation of 1 and 4a-c in the biological milieu.
3kꢀo,13,15
activate therapeutics by nonbiological chemical stimuli.
Furthermore, this solid supported catalyst enabled —for the first
time— the locallyꢀcontrolled release of a fluorescent dye in the
brain of a zebrafish, a notable breakthrough that expands our
capacity to chemically modulate the activity of bioorthogonal
reagents into the most fragile and complex organs.
Prior to testing the catalytic properties of the devices in cell
culture, viability assays (PrestoBlue® reagent) were performed to
determine the tolerability of cells to the presence of solid
supported gold. As anticipated, [Au]ꢀresins were found to be fully
biocompatible at the concentrations tested (Supp. Fig. 8).
Acknowledgements
Next, the bioorthogonal [Au]ꢀtriggered release of a structurallyꢀ
diverse selection of clinicallyꢀused anticancer drugs was
investigated in culture with human lung cancer A549 cells. Three
AMPꢀL, CA, PMB and AUꢀB are grateful to the EPSRC
(EP/N021134/1), the CRUK (Pioneer Award) and the Royal
Society (RG150377) for funding. BRꢀR and TLB thanks the EC
(H2020ꢀMSCAꢀIFꢀ2014ꢀ658833, ChemoBOOM) and the CMVM
of the University of Edinburgh (Principal’s scholarship),
respectively, for financial support. LH was supported by a CRUK
PhD Fellowship. DS thanks CRUK for a Career Establishment
Award. VS, SI and JS thanks CIBERꢀBBN for financial support.
CIBERꢀBBN is an initiative funded by the VI National R&D&i Plan
2008ꢀ2011 financed by the Instituto de Salud Carlos III with
assistance from the European Regional Development Fund. VS
and JS are grateful to the University of Zaragoza (Project JIUZꢀ
1
2a
different drug precursors were tested (see Fig. 2a): ProꢀFUdR,
1
2b
4
a, POBꢀSAHA, 4b, and NꢀPocꢀDOX, 4c (novel drug precursor
inspired on prior designs3m,13). Cells were treated with 4a-c and
Au]ꢀresins separately (negative controls) or in combination
activation assay), and unmodified drugs 5a-c used as the
[
(
positive controls. Remarkably, while prodrugs 4a-c did not elicit
any effect on their own, potent anticancer activity was displayed
in combination with [Au]ꢀresins (Fig. 2a), unequivocal evidence
that the active drugs are released in situ by heterogenous gold
chemistry. Reuse of the [Au]ꢀresins in three consecutive prodrug
activation cycles confirmed the capacity of the devices to activate
multiple drug doses (Suppl. Fig. 9). The synthesis of drugs 5a-c
was also verified in vitro (Suppl. Fig. 10), confirming the capability
of gold to cleave both Oꢀ and Nꢀpropargyl groups from a range of
molecules based on structurallyꢀdifferent scaffolds. These studies
support a potential application scenario where goldꢀfunctionalized
implants could be used in situ to modulate the spatiotemporal
generation of chemotherapeutics from inactive precursors in the
treatment of localized malignancies such as brain or prostate
cancer.
2
016ꢀTECꢀ13). The research leading to these results has
received funding from the ERC under the EU's FP7/2007ꢀ2013
ERC grant agreement n° [340163]).
(
Keywords: Gold • Heterogeneous Catalysis • Bioorthogonal •
Prodrugs • Fluorescent Probes
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Angewandte Chemie International Edition
10.1002/anie.201705609
COMMUNICATION
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COMMUNICATION
Ana M. Pérez-López, Belén Rubio-Ruiz,
Víctor Sebastián, Lloyd Hamilton,
Catherine Adam, Thomas L. Bray, Silvia
Irusta, Paul M. Brennan, Guy C. Lloyd-
Jones, Dirk Sieger, Jesús Santamaría*
and Asier Unciti-Broceta*
Hidden in the glorious wildness like unmined gold! A novel bioorthogonal
uncaging strategy triggered by heterogeneous gold catalysis mediates the
activation of probes and therapeutics both in vitro and in vivo.
Page No. – Page No.
Gold-Triggered Uncaging Chemistry
in Living Systems
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