Ferumoxytol nanoparticles are being used clinically for the treatment of anemia and molecular imaging in patients. It is well documented that while most patients tolerate ferumoxytol well, a small percentage of patients (i.e., 0.01%) develop severe allergic reactions. The purpose of our proof-of-concept study was to determine whether patients with or without hypersensitivity reactions have specific protein corona profiles around ferumoxytol nanoparticles. In a retrospective, institutional review board approved pilot study, we enrolled 13 pediatric patients (5 girls, 8 boys, mean age 16.9 ± 8.2 years) who received a ferumoxytol-enhanced magnetic resonance imaging and who did (group 1, n = 5) or did not (group 2, n = 8) develop an allergic reaction. Blood samples of these patients were incubated with ferumoxytol, and the formation of a hard protein corona around ferumoxytol nanoparticles was measured by dynamic light scattering, zeta potential, and liquid chromatography–mass spectrometry. We also performed in vitro immune response analyses to randomly selected coronas from each group. Our results provide preliminary evidence that ex vivo analysis of the biomolecular corona may provide useful and predictive information on the possibility of severe allergic reactions to ferumoxytol nanoparticles. In the future, patients with predisposition of an allergic reaction to ferumoxytol may be diagnosed based on the proteomic patterns of the corona around ferumoxytol in their blood sample.

1.
M.
Lu
,
M. H.
Cohen
,
D.
Rieves
, and
R.
Pazdur
,
Am. J. Hematol.
85
,
315
(
2010
).
2.
V. S.
Balakrishnan
 et al,
Eur. J. Clin. Invest.
39
,
489
(
2009
).
3.
M. H.
Schwenk
,
Pharmacotherapy
30
,
70
(
2010
).
4.
A.
Khurana
 et al,
Nanomedicine
8
,
1969
(
2013
).
5.
A.
Khurana
 et al,
Radiology
264
,
803
(
2012
).
6.
E. A.
Neuwelt
 et al,
Neurosurgery
60
,
601
(
2007
); discussion 611-612.
7.
8.
K. L.
Stabi
and
L. M.
Bendz
,
Ann. Pharm.
45
,
1571
(
2011
).
9.
A.
Singh
,
T.
Patel
,
J.
Hertel
,
M.
Bernardo
,
A.
Kausz
, and
L.
Brenner
,
Am. J. Kidney Dis.
52
,
907
(
2008
).
10.
B. S.
Spinowitz
 et al,
J. Am. Soc. Nephrol.
19
,
1599
(
2008
).
11.
B. S.
Spinowitz
 et al,
Kidney Int.
68
,
1801
(
2005
).
13.
R.
Provenzano
,
B.
Schiller
,
M.
Rao
,
D.
Coyne
,
L.
Brenner
, and
B. J.
Pereira
,
Clin. J. Am. Soc. Nephrol.
4
,
386
(
2009
).
14.
D.
Rampton
 et al,
Haematologica
99
,
1671
(
2014
).
15.
M. P.
Monopoli
,
C.
Aberg
,
A.
Salvati
, and
K. A.
Dawson
,
Nat. Nanotechnol.
7
,
779
(
2012
).
16.
M.
Mahmoudi
,
I.
Lynch
,
M. R.
Ejtehadi
,
M. P.
Monopoli
,
F. B.
Bombelli
, and
S.
Laurent
,
Chem. Rev.
111
,
5610
(
2011
).
17.
S.
Sheibani
 et al, “
Nanoscale characterization of the biomolecular corona by cryo-electron microscopy, cryo-electron tomography, and image simulation
,”
Nat. Commun.
12
,
573
(
2021
).
18.
19.
H.
Nejadnik
 et al,
Radiology
286
,
938
(
2018
).
20.
D.
Walczyk
,
F. B.
Bombelli
,
M. P.
Monopoli
,
I.
Lynch
, and
K. A.
Dawson
,
J. Am. Chem. Soc.
132
,
5761
(
2010
).
21.
T.
Cedervall
 et al,
Proc. Natl. Acad. Sci. U.S.A.
104
,
2050
(
2007
).
22.
S.
Tenzer
 et al,
Nat. Nanotechnol.
8
,
772
(
2013
).
23.
Z. J.
Deng
,
M.
Liang
,
M.
Monteiro
,
I.
Toth
, and
R. F.
Minchin
,
Nat. Nanotechnol.
6
,
39
(
2011
).
24.
F.
Giulimondi
 et al,
Nat. Commun.
10
,
3686
(
2019
).
25.
M. P.
Monopoli
 et al,
J. Am. Chem. Soc.
133
,
2525
(
2011
).
26.
E. F.
Knol
,
F. P.
Mul
,
H.
Jansen
,
J.
Calafat
, and
D.
Roos
,
J. Allergy Clin. Immunol.
88
,
328
(
1991
).
27.
28.
V.
Mirshafiee
,
R.
Kim
,
S.
Park
,
M.
Mahmoudi
, and
M. L.
Kraft
,
Biomaterials
75
,
295
(
2016
).
29.
K.
Mukai
 et al,
J. Allergy Clin. Immunol.
139
,
889
(
2017
).e811
30.
J. F.
Ryan
 et al,
Proc. Natl. Acad. Sci. U.S.A.
113
,
E1286
(
2016
).
31.
K. D.
Nguyen
,
A.
Fohner
,
J. D.
Booker
,
C.
Dong
,
A. M.
Krensky
, and
K. C.
Nadeau
,
J. Immunol.
181
,
5386
(
2008
).
32.
J. M.
Rosenholm
,
V.
Mamaeva
,
C.
Sahlgren
, and
M.
Linden
,
Nanomedicine
7
,
111
(
2012
).
33.
V.
Kodali
 et al,
ACS Nano
7
,
6997
(
2013
).
34.
H.
Liu
 et al,
J. Hazard. Mater.
248-249
,
478
(
2013
).
35.
36.
J. K.
Hsiao
 et al,
NMR Biomed.
21
,
820
(
2008
).
37.
A.
Sindrilaru
 et al,
J. Clin. Invest.
121
,
985
(
2011
).
38.
R.
Weissleder
,
M.
Nahrendorf
, and
M. J.
Pittet
,
Nat. Mater.
13
,
125
(
2014
).
40.
S.
Futterer
,
I.
Andrusenko
,
U.
Kolb
,
W.
Hofmeister
, and
P.
Langguth
,
J. Pharm. Biomed. Anal.
86
,
151
(
2013
).
41.
A. S.
Thakor
and
S. S.
Gambhir
,
CA Cancer J. Clin.
63
,
395
(
2013
).
42.
S. C.
Gad
,
K. L.
Sharp
,
C.
Montgomery
,
J. D.
Payne
, and
G. P.
Goodrich
,
Int. J. Toxicol.
31
,
584
(
2012
).
43.
X.
Wang
,
S. P.
Reece
, and
J. M.
Brown
,
Toxicol. Mech. Methods
23
,
168
(
2013
).
44.
J.
Szebeni
 et al,
Br. J. Pharmacol.
172
,
5025
(
2015
).
45.
S.
Sivagnanam
and
D.
Deleu
,
Crit. Care
7
,
119
(
2003
).
46.
A. L.
Zanen
,
H. J.
Adriaansen
,
E. F.
van Bommel
,
R.
Posthuma
, and
G. M. Th
de Jong
,
Nephrol. Dial. Transplant.
11
,
820
(
1996
).
47.
G.
Caracciolo
 et al,
Nanoscale Horiz.
4
,
1063
(
2019
).
48.
L.
Digiacomo
 et al,
Nanoscale
12
,
16697
(
2020
).
49.
M. J.
Hajipour
 et al,
J. Alzheimers Dis.
59
,
1187
(
2017
).
50.
M. J.
Hajipour
,
S.
Laurent
,
A.
Aghaie
,
F.
Rezaee
, and
M.
Mahmoudi
,
Biomater. Sci.
2
,
1210
(
2014
).
51.
H. E.
Daldrup-Link
,
T.
Henning
, and
T. M.
Link
,
Eur. Radiol.
17
,
743
(
2007
).
52.
53.
See supplementary material at https://doi.org/10.1116/6.0000755 for LC MS/MS outcomes and additional proteomics analysis of the protein corona at the surface of ferumoxytol nanoparticles.

Supplementary Material

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