Aqueous Ligand-Stabilized Palladium Nanoparticle Catalysts for Parahydrogen-Induced 13C Hyperpolarization

Article abstract of DOI:10.1021/acs.analchem.7b01363

Parahydrogen-induced polarization (PHIP) is a method for enhancing NMR sensitivity. The pairwise addition of parahydrogen in aqueous media by heterogeneous catalysts can lead to applications in chemical and biological systems. Polarization enhancement can be transferred from ¹H to ¹³C for longer lifetimes by using zero field cycling. In this work, water-dispersible N-acetylcysteine- and l-cysteine-stabilized palladium nanoparticles are introduced, and carbon polarizations up to 2 orders of magnitude higher than in previous aqueous heterogeneous PHIP systems are presented. P¹³_C values of 1.2 and 0.2% are achieved for the formation of hydroxyethyl propionate from hydroxyethyl acrylate and ethyl acetate from vinyl acetate, respectively. Both nanoparticle systems are easily synthesized in open air, and TEM indicates an average size of 2.4 ± 0.6 nm for NAC@Pd and 2.5 ± 0.8 nm for LCys@Pd nanoparticles with 40 and 25% ligand coverage determined by thermogravimetric analysis, respectively. As a step toward biological relevance, results are presented for the unprotected amino acid allylglycine upon aqueous hydrogenation of propargylglycine.

Full text of DOI:10.1021/acs.analchem.7b01363

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Article
Aqueous Ligand-Stabilized Palladium Nanoparticle
Catalysts for Parahydrogen Induced 13C Hyperpolarization
Jeffrey McCormick, Alexander M. Grunfeld, Yavuz N. Ertas, Akash Neil Biswas,
Kristofer Lee Marsh, Shawn Wagner, Stefan Gloggler, and Louis-S. Bouchard
Anal. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Jun 2017
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Analytical Chemistry
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Aqueous Ligand-Stabilized Palladium Nanoparticle Catalysts
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for Parahydrogen Induced C Hyperpolarization
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[a.b]
[a]
[b,c]
[a]
Jeffrey McCormick , Alexander M. Grunfeld , Yavuz N. Ertas , Akash N. Biswas , Kristofer
[a]
[d]
[a,e,f]
[a,b,c]
L. Marsh , Shawn Wagner , Stefan Glöggler
, Louis-S. Bouchard*
[
a]
Department of Chemistry and Biochemistry, University of California at Los Angeles, 607 Charles E Young Drive
East, Los Angeles, CA 90095-1569, USA
[
b]
The Molecular Biology Institute, Jonsson Comprehensive Cancer Center, California NanoSystems Institute
(CNSI), University of California Los Angeles, Los Angeles, CA 90095, USA
[c]
Department of Bioengineering, University of California at Los Angeles, 420 Westwood Plaza, Los Angeles, CA
90095, USA
[
d]
Biomedical Imaging Research Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis Building G149E,
Los Angeles, CA 90048, USA
[
e]
Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany
[
f]
Center for Biostructural Imaging of Neurodegeneration, Von-Siebold-Str. 3A, D-37075 Göttingen, Germany
Keywords: parahydrogen induced polarization • palladium nanoparticles • heterogeneous catalysis • polarization
transfer • hyperpolarization
ABSTRACT: Parahydrogen induced polarization (PHIP) is a method for enhancing NMR sensitivity. The pairwise addition
of parahydrogen in aqueous media by heterogeneous catalysts can lead to applications in chemical and biological systems.
1
13
Polarization enhancement can be transferred from H to C for longer lifetimes by use of zero field cycling. In this work,
water-dispersible N-acetylcysteine- and L-cysteine-stabilized palladium nanoparticles are introduced and carbon polari-
zations up to two orders of magnitude higher than previous aqueous heterogeneous PHIP systems are presented. P13C val-
ues of 1.2% and 0.2% are achieved for the formation of hydroxyethyl propionate from hydroxyethyl acrylate and ethyl ace-
tate from vinyl acetate, respectively. Both nanoparticle systems are easily synthesized in open air, and TEM indicates an
average size of 2.4 ± 0.6 nm for NAC@Pd and 2.5 ± 0.8 nm for LCys@Pd nanoparticles with 40% and 25% ligand coverage
determined by thermogravimetric analysis, respectively. As a step toward biological relevance, results are presented for
the
unprotected
amino
acid
allylglycine
upon
aqueous
hydrogenation
of
propargylglycine.
Introduction
polarization times and costly equipment. SABRE and
PHIP techniques utilize the para nuclear spin isomer,
parahydrogen (para-H ). Para-H is generated by passing
Although prevalent in chemical, biological and biomedi-
cal sciences, nuclear magnetic resonance (NMR) suffers
from inherently low sensitivity due to the constraints of
thermal polarization of nuclear spins at liquid water tem-
peratures. The advent of hyperpolarization methods such
as dynamic nuclear polarization (DNP) , parahydrogen-
induced polarization (PHIP) and signal amplification by
reversible exchange (SABRE) has led to enhancements
2
2
hydrogen gas over a catalyst bed at low temperature. At
20 K, the purity of the para-H spin state can be enriched
2
9
to as high as 99.82% , and is stable when pressurized and
stored at room temperature. The subsequent polarization
1,2
enhancement of para-H is then obtained by hydrogena-
2
3
tion of unsaturated precursors during PHIP, or non-
hydrogenative coordination via SABRE.
4–6
of detectable magnetization by several orders of magni-
7
tude .
Current PHIP methods predominantly use homogeneous
+
-
transition metal catalysts such as [Rh(I)(nbd) ] [BF ] and
2
4
10,11
Dissolution DNP, a technique involving the transfer of
polarization from unpaired electrons to nuclear spins at
near absolute zero temperature, has recently been applied
in vivo . While DNP has been demonstrated in biomedical
applications, current DNP methods are limited by long
its derivatives . The homogeneous catalyst cannot be
readily removed from the mixture, which raises toxicity
concerns due to the high metal concentration. To over-
come this clinically limiting challenge, aqueous heteroge-
neous platinum catalysts have recently been demonstrat-
8
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Page 2 of 6
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ed to achieve H polarization values as high as 0.7%
,
aqueous PHIP of an unprotected amino acid by a hetero-
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near the threshold for biological consideration (P
≥
geneous catalyst.
1
H
1
4
1
%) . Phase separation techniques of soluble catalysts
have been demonstrated using 2-propynyl-2-
oxopropanoate hydrogenation into pyruvate before aque-
ous extraction; however, this method resulted in ~40%
reduction of hyperpolarized product as well as additional
1
5
signal loss from relaxation . Unlike homogeneous cata-
lysts, heterogeneous catalysts have the potential to be
immobilized on support material allowing for quick filtra-
tion of the catalyst away from the hyperpolarized mole-
cules in solution, a necessary requirement for potential
clinical utilization.
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In this work, ligand-stabilized palladium nanoparticles
are introduced and characterized as water-soluble cata-
lysts demonstrating the highest heterogeneous carbon
and proton polarizations to date (P13C = 1.2%, P1H = 1.2%) in
water, in nearly identical conditions to previous experi-
ments using a water-optimized homogenous Rh catalyst .
The cost of palladium per gram is significantly lower than
that of platinum, making this type of catalyst attractive.
Comparison of nanoparticle synthesis methods and sur-
face oxidation under inert conditions versus open air
shows that air-synthesized nanoparticles retain equiva-
lent polarization ability, granting higher polarization per-
formance in lower-cost, simple synthesis conditions.
1
1
Figure 1. Synthesis summaries of a) NAC@Pd and b)
LCys@Pd nanoparticles. TEM shows an average particle size
of c) 2.4 ± 0.6 nm for NAC@Pd, and d) 2.5 ± 0.8 nm for
LCys@Pd.
Two particle-capping amino acid ligands are investigated
herein: L-cysteine (LCys), and its analog, N-acetylcysteine
(NAC). Both ligands are biologically compatible small
molecules shown to coordinate strongly to transition
Experimental Section
Figure 1a) and 1b) show the synthesis schemes of
NAC@Pd and LCys@Pd, respectively. For both systems,
the precursor H PdCl was dissolved in water and reduced
1
3
metals and create stable, water-soluble nanoparticles .
1
2
4
Because H relaxation times are short-lived (T of usually ≤
1
by NaBH in the presence of ligand at a molar ratio of 1:1
4
1 s), in vivo applications likely hinge on the preservation of
in open air.
hyperpolarized state by transfer of polarization to nearby
1
3
heteronuclei with longer relaxation times such as C.
Solvent fractionation using isopropanol and hexanes fol-
lowed by centrifugation and repeated washes with etha-
nol yielded nanoparticle products stored after drying.
TEM images of LCys@Pd and NAC@Pd prepared in water
shown in Fig 1c) and d) reveal average particle sizes of 2.5
Heterogeneous PHIP has been demonstrated in gas phase
1
6,17
18
reactions , and has recently been shown in water at
P13C ~0.01%. The present work demonstrates two orders of
magnitude improvement, as well as potential for ligand
optimization rather than bare metal systems. To demon-
strate the potential for biological applications, the acetate
precursor ethyl acetate (EA) is hyperpolarized from vinyl
acetate (VA), a compound previously shown in PHIP side
±
0.8 nm and 2.4 ± 0.6 nm, respectively (see Fig. S3 for
sizing details). UV/Vis and X-ray photoelectron spectros-
copy (XPS) reveal Pd nanoparticle formation and higher
0
Pd-O surface oxidation during air synthesis (see Fig. S6).
PHIP experiments were performed as previously de-
1
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arm hydrogenation (PHIP-SAH) investigations . Acetate
1
2,13
scribed and the resulting spectra are shown in Figure 2.
Nanoparticles and substrate were suspended in degassed
is a relevant metabolite for in vivo hyperpolarization stud-
1
9
ies . Hyperpolarized hydroxyethyl propionate (HEP), a
D O and heated to 80°C before pressurization with para-
2
compound previously demonstrated in in vivo angi-
20
H to 6.5 bar. The sample was shaken in transit to the
2
ography , is also shown by hydrogenation of 2-
hydroxyethyl acrylate (HEA).
1
13
magnet and inserted for H experiments whereas for C a
field cycling step was included before scanning. The data
was acquired after a single 45° ( H) or 90° ( C) pulse, and
x x
the enhancement calculated by comparison to thermal
spectra. Concentration experiments showed optimal po-
larization of P1H = 1.2% at 10 mg/mL for both nanoparticles
1
13
1
3
Transfer of polarization from para-H to adjacent C is
2
achieved by cycling hydrogenation product mixtures in
and out of zero field using a concentric ring μ-metal
chamber. The amino acid propargylglycine (PraH) is par-
ahydrogenated into hyperpolarized allylglycine without
(
see Fig. S7).
1
chemical protection on the amine, and H polarization of
Discussion
P1H = 0.9% is shown. This is the first demonstration of
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Analytical Chemistry
were selected for this work based on biocompatibility,
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convenient thiol and amine groups involved in transition
metal coordination, and previous demonstration of heter-
1
2,13
ogeneous PHIP in platinum nanoparticle systems
.
Previous studies have proposed NAC as a control experi-
ment in which amine coordination is blocked and thus
1
3
limiting surface diffusion . However, coordination of
nitrogen on NAC is not blocked and serves to stabilize Pt
and Pd nanoparticles tightly enough to produce recycla-
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ble particles in this work (see S8 in SI) and elsewhere .
Au nanoparticles have been recently demonstrated as
sensitive colorimetric probes for the detection of NAC
due to strong functional group interaction , supporting
this interpretation.
21
This suggests a strong geometric dependence on ligand
involvement in pairwise hydrogenation as LCys and NAC
are similar in size, yet undergo different binding mecha-
nisms due to amine protection, which may orient NAC in
a more favorable position for pairwise addition on the Pd
surface. Consistent synthesis procedures also showed
NAC@Pd ligand density 1.6x higher than that of
LCys@Pd, despite similar particle size (40%wt versus
25%wt, Table 1). This increase cannot be explained solely
by the difference in molecular weight of NAC compared
to LCys (163.19 versus 121.16 g/mol, respectively). This sug-
gests that NAC is better able to stack on the particle sur-
face, and that this efficient stacking contributes to the
ability of NAC to improve pairwise H addition. Nanopar-
2
ticle fractionation demonstrated higher polarization than
the bulk nanoparticle mixture (data not shown). Previous
Figure 2. a) Reaction mechanism of VA and HEA hydrogena-
1
3
1
tion and transfer of polarization to C. Thermal H spectra of
b) HEP and d) EA, as well as their hyperpolarized spectra (c)
work has reported lower ligand densities for Pt nanoparti-
12,13
13
cle systems without solvent fractionation
.
and e), respectively. C hyperpolarized spectra following zero
field transfer for f) HEA and g) EA products with thermal
13
Due to Pd nanoparticles’ tendency to crystallize in the fcc
spectra overlaid are also shown. Thermal C spectra were
2
2
structure and TEM confirming spherical geometry, a
cubo-octahedral structure can be assumed in turnover
acquired after 256 scans. Spectra shown in magnitude mode.
23
frequency (TOF) calculations . TOF calculations were
In heterogeneous PHIP, pairwise addition of para-H is
2
performed by flowing H into nanoparticle mixtures with
2
thought to be preserved by ligand density, which limits
diffusion across the particle surface. Significant diffusion
HEA under ambient N flow heated to 80° C and conver-
2
sion was monitored by NMR every 15 minutes to compare
catalyst activity. Often, high ligand coverage of a catalytic
surface sacrifices activity due to reduction of available
catalytic sites, yet surprisingly NAC@Pd showed a TOF of
1.97x that of LCys@Pd despite higher ligand density (Ta-
1
2
would otherwise lead to loss of para-H spin order . Thus,
2
ligands are chosen not only for control of particle disper
sity and solubility, but also for their ability to restrict H2
diffusion (and catalytic exchange between hydrogen mol-
ecules) during hydrogenation reactions. LCys and NAC
Table 1. Summary of nanoparticle characteristics.
1
1
13
13
Nanoparticle Diameter Ligand
H Polariza- H Polariza-
C
C
Ligands
(mmol/g) Area
Surface
TOF
(h-
(
nm) Density tion,
HEP tion, PraH
(%P)
Polarization, Polarization,
(
%wt)
40
(%P)
(m2/mg) 1)
HEP (%P)
1.2 ± 0.1
EA (%P)
NAC@Pd
LCys@Pd
2.4 ± 0.6
2.5 ± 0.8
1.2 ± 0.1
0.9 ± 0.2
-
0.20 ± 0.03
2.45
2.06
1.81
42.9
21.7
x 10-10
1.96
25
0.9 ± 0.1
-
-
x 10-10
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ble 1). This work utilizing the catalyst NAC@Pd demon-
strates nanoparticle systems showing 1.71x higher H po-
tigated as a substrate for NAC@Pd to demonstrate the
advantage in using a heterogeneous system. Propargylgly-
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larization and 1.35x higher TOF than was previously
cine (PraH) is a naturally occurring, water-soluble amino
1
3
25
shown with Pt nanoparticles of similar diameter . The
current catalyst NAC@Pd TOF corresponds to production
of 1.1 μmol of HEP product in the 10 s time period follow-
ing parahydrogenation, resulting in 1.1 mM in 1 mL solu-
tion. This conversion is also measured at ambient pres-
acid found in certain fungal systems with an unsaturated
1
triple bond. H PHIP experiments using Boc-protected
PraH
in
methanol-d4
and
homogeneous
Rh(dppb)(COD)BF catalyst yielded polarization values of
4
P1H = 0.4%, comparable to ~1.2% when adjusting from 50%
26
sure H , far lower than PHIP experimental conditions (6.5
para-H enrichment to ~100% . PraH has recently been
2
2
1
4
bar para-H ). Recently, work by Zacharias et al demon-
incorporated into sunflower typsin inhibitor along with
O-propargyl-L-tyrosine in mixed solvent system to yield
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strates metabolic imaging of hyperpolarized aqueous di-
ethyl succinate. Soluble Rh(dppb)(nbd)BF4 catalyst was
dissolved and used to hydrogenate diethyl fumarate
P1H = 0.14% (expected 0.42% with ~100% para-H ) without
2
27
loss of activity , demonstrating PraH’s potential in bio-
logical investigations.
(
20 mM) before injection into live mice using an opti-
mized polarizer and deuterated compounds for spin
preservation. Comparison with our system indicates our
current catalyst is a mere 18-fold concentration and 2-fold
polarization away from current in vivo investigations.
Considering that 1.1 mM is typical for most physiological
conditions, the catalyst systems proposed here may be
sufficient for in vivo use. Since transit time to the magnet
was recorded at 9 seconds from pressurization to spectra
acquisition, it is possible that with a well-optimized polar-
1
Figure 3 shows hyperpolarized H peaks from DL-
allylglycine, yielding a polarization of P1H = 0.9%. Howev-
er, PraH’s triple bond has the potential for two parahy-
1
4
drogenations , allowing further enhancement under
higher conversion regimes, though only characteristic Iz–
S peaks for allylglycine are observed here. Both investiga-
z
28
tions of propyne in gas-phase heterogeneous PHIP and
27
O-propargyl-L-tyrosine in solution PHIP report only
single hydrogenation product enhancement. Magnetic
field cycling experiments were attempted on PraH,
1
3
izer nearly two full T relaxation cycles could be avoided,
1
leading to potential polarizations ≥ 10%.
1
3
though no C enhancement was observed. This can be
explained due to allylglycine’s dense proton environment
on adjacent carbons to the hydrogenation site which like-
ly interfere with the observed magnetization after trans-
fer. The relatively large distance to the ester carbon often
1
3
chosen in C transfer requires zero field draw speeds
longer than para-H relaxation and is unlikely to be ob-
2
served.
In conclusion, this work demonstrates novel water-
soluble palladium nanoparticles as catalysts in aqueous
heterogeneous PHIP, capable of transferring polarization
1
3
13
1
to C on biologically relevant compounds. Both C and H
polarizations are unprecedented in aqueous heterogene-
1
3
ous reactions, C by up to two orders of magnitude com-
pared to the previous state-of-the-art experiments. High
C enhancement on compounds of biological interest
1
3
represents a crucial advancement in heterogeneous PHIP
application. Similarly, robust polarization of unprotected
peptides and other nitrogenous compounds widens the
breadth of potential PHIP labels to meet the future needs
of diagnostic imaging.
Figure 3. a) PHIP mechanism of propargylglycine into al-
1
lylglycine. b) Thermal and c) hyperpolarized H spectra of
allyglycine peaks following hydrogenation. Spectra shown in
magnitude mode.
As advances in PHIP are made towards broader investiga-
tion of biologically relevant substrates, one barrier is that
unprotected functional groups have been shown to hinder
polarization due to unfavorable interactions with PHIP
ASSOCIATED CONTENT
Supporting Information. Materials and Methods, Synthetic
Procedures, Nanoparticle Characterization, PHIP Experi-
ments, Nanoparticle Recovery. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
1,24
catalysts . Because of this problem and widespread in-
terest in hyperpolarized peptides, protecting groups for
amines and carboxylates are often investigated to create
product analogs of varying biological activity and solubili-
ty. Strategies proposed to remove the protecting group by
AUTHOR INFORMATION
Corresponding Author
1
5
cleavage after para-H addition are untenable for a clini-
2
cally relevant technique. In this work, aqueous parahy-
drogenation of unprotected DL-propargylglycine is inves-
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*Professor Louis Bouchard
605–608.
1
louis.bouchard@gmail.com
(14)
15)
Zacharias, N. M.; Chan, H. R.; Sailasuta, N.; Ross, B. D.;
Bhattacharya, P. J. Am. Chem. Soc. 2012, 134, 934–943.
Reineri, F.; Boi, T.; Aime, S. Nat. Commun. 2015, 6, 5858.
Bouchard, L. S.; Kovtunov, K. V.; Burt, S. R.; Anwar, M. S.;
Koptyug, I. V.; Sagdeev, R. Z.; Pines, A. Angew. Chemie - Int.
Ed. 2007, 46 (22), 4064–4068.
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(
Present Addresses
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†If an author’s address is different than the one given in the
affiliation line, this information may be included here.
(17)
Bouchard, L.-S.; Burt, S. R.; Anwar, M. S.; Kovtunov, K. V.;
Koptyug, I. V.; Pines, A. Science (80-. ). 2008, 319 (5862),
Author Contributions
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42–445.
All authors have given approval to the final version of the
manuscript.
(
18)
Kovtunov, K. V.; Barskiy, D. A.; Shchepin, R. V.; Salnikov,
O. G.; Prosvirin, I. P.; Bukhtiyarov, A. V.; Kovtunova, L. M.;
Bukhtiyarov, V. I.; Koptyug, I. V.; Chekmenev, E. Y. Chem. -
A Eur. J. 2016, 22 (46), 16446–16449.
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Bhattacharya, P.; Harris, K.; Lin, A. P.; Mansson, M.;
Norton, V. A.; Perman, W. H.; Weitekamp, D. P.; Ross, B.
D. Magn. Reson. Mater. Physics, Biol. Med. 2005, 18 (5),
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Funding Sources
The authors would like to gratefully acknowledge financial
support from the National Science Foundation (NSF) (re-
search grants CHE-1153159, CHE-1508707, equipment grant
CHE-1048804), the Arnold and Mabel Beckman Foundation,
The Max Planck Society and the Jonsson Comprehensive
Cancer Center Foundation at UCLA.
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45–256.
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30.
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ABBREVIATIONS
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PHIP, parahydrogen-induced polarization; Pd, palladium;
NMR, nuclear magnetic resonance; PraH, propargylglycine;
LCys, L-cysteine; TEM, Transmission Electron Microscopy;
NAC, N-acetylcysteine; .
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Gruppi, F.; Xu, X.; Zhang, B.; Tang, J. A.; Jerschow, A.;
Canary, J. W. Angew. Chemie - Int. Ed. 2012, 51 (47), 11787–
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