IEEE MAGNETICS SOCIETY SECTION
Recei ed May 27, 2021, accep ed July 9, 2021, da e o publica ion July 12, 2021, da e o cu en e sion July 20, 2021.
Digi al Objec Iden i ie 10.1109/ACCESS.2021.3096740
Nano lowe s Ve sus Magne osomes: Compa ison
Be ween Two P omising Candida es o Magne ic
Hype he mia The apy
ELIZABETH M. JEFREMOVAS 1, LUCÍA GANDARIAS 2, IRATI RODRIGO3,
LOURDES MARCANO3,4, CORDULA GRÜTTNER5, JOSÉ ÁNGEL GARCÍA6,
ENEKO GARAYO 7, (Membe , IEEE), IÑAKI ORUE8, ANA GARCÍA-PRIETO9,
ALICIA MUELA2, MARÍA LUISA FERNÁNDEZ-GUBIEDA3, JAVIER ALONSO 1,
AND LUIS FERNÁNDEZ BARQUÍN1, (Membe , IEEE)
1Depa amen o CITIMAC, Facul ad de Ciencias, Uni e sidad de Can ab ia, 39005 San ande , Spain
2Depa amen o Inmunología, Mic obiología y Pa asi ología, Uni e sidad del País Vasco (UPV/EHU), 48940 Leioa, Spain
3Depa amen o de Elec icidad y Elec ónica, Uni e sidad del País Vasco (UPV/EHU), 48940 Leioa, Spain
4Helmhol z-Zen um Be lin ü Ma e ialien und Ene gie, 12489 Be lin, Ge many
5Mic omod Pa ikel echnologie GmbH, 18119 Ros ock, Ge many
6Depa amen o de Física, Uni e sidad del País Vasco (UPV/EHU), 48940 Leioa, Spain
7Depa amen o de Física Aplicada, Uni e sidad Pública de Na a a, 31006 Pamplona, Spain
8SGIke Medidas Magné icas, Uni e sidad del País Vasco (UPV/EHU), 48940 Leioa, Spain
9Depa amen o de Física Aplicada I, Escuela de Ingenie ía de Bilbao, 48013 Bilbao, Spain
Co esponding au ho : Elizabe h M. Je emo as ([email p o ec ed])
This wo k was suppo ed in pa by he Spanish ‘‘Minis e io de Ciencia, In es igación y Uni e sidades’’ unde P ojec
MAT2017-83631-C3-R, and in pa by he Nano echnology in T ansla ional Hype he mia (HIPERNANO) unde G an
RED2018–102626–T. The wo k o Elizabe h M. Je emo as was suppo ed by he Beca Concepción A enal h ough he Gobie no de
Can ab ia–Uni e sidad de Can ab ia unde G an BDNS: 406333. The wo k o I a i Rod igo was suppo ed by he P og ama de
Pe eccionamien o de Pe sonal In es igado Doc o (Gobie no Vasco) unde G an POS–2020–1–0028 and G an IT–1005–16. The wo k
o Lou des Ma cano was suppo ed by he Pos doc o al Fellowship om he Basque Go e nmen unde G an POS–2019–2–0017.
ABSTRACT Magne ic Fluid Hype he mia media ed by i on oxide nanopa icles is one o he mos
p omising he apies o cance ea men . Among he di e en candida es, magne i e and maghemi e
nanopa icles ha e e ealed o be some o he mos p omising candida es due o bo h hei pe o mance and
hei biocompa ibili y. None heless, up o da e, he li e a u e compa ing he hea ing e iciency o magne i e
and maghemi e nanopa icles o simila size is sca ce. To ill his gap, he e we p o ide a compa ison
be ween comme cial Synomag Nano lowe s (pu e maghemi e) and bac e ial magne osomes (pu e magne i e)
syn hesized by he magne o ac ic bac e ium Magne ospi illum g yphiswaldense o hDi ≈ 40–45 nm. Bo h
ypes o nanopa icles exhibi a high deg ee o c ys allini y and an excellen deg ee o chemical pu i y and
s abili y. The s uc u al and magne ic p ope ies in bo h nanopa icle ensembles ha e been s udied by means
o X–Ray Di ac ion, T ansmission Elec on Mic oscopy, X–Ray Abso p ion Spec oscopy, and SQUID
magne ome y. The hea ing e iciency has been analyzed in bo h sys ems using AC magne ome y a se e al
ield ampli udes (0–88 mT) and equencies (130, 300, and 530 kHz).
INDEX TERMS Hype he mia, nanopa icles, X– ay di ac ion, magne ic p ope ies.
I. INTRODUCTION
In ecen yea s, he e has been an inc easing numbe o
wo ks on i on oxide based magne ic nanopa icles o di -
e en kinds o biomedical applica ions, such as D ug Deli -
e y, Magne ic Resonance Imaging (MRI), Magne ic Pa icle
Imaging (MPI), and Magne ic Hype he mia [1]–[6]. Among
The associa e edi o coo dina ing he e iew o his manusc ip and
app o ing i o publica ion was Mon se a Ri as.
hese, Magne ic Hype he mia, which is media ed by mag-
ne ic nanopa icles (MNPs), cons i u es a p omising app oach
o cance ea men . The basic idea behind his ea men
consis s on deli e ing he MNPs o he umo a ea so ha ,
unde he applica ion o an ex e nal AC magne ic ield wi h a
equency anging be ween 100 kHz and 1 MHz, he MNPs
elease hea in a localized way, he eby deac i a ing he can-
ce cells wi hou a ec ing he heal hy ones [7], [8]. Phase I
clinical ials on magne ic hype he mia we e pe o med in
99552 This wo k is licensed unde a C ea i e Commons A ibu ion 4.0 License. Fo mo e in o ma ion, see h ps://c ea i ecommons.o g/licenses/by/4.0/ VOLUME 9, 2021
E. M. Je emo as e al.: Nano lowe s Ve sus Magne osomes: Compa ison Be ween Two P omising Candida es
he ea ly 2000s in Ge many (MagFo ce Nano echnologies,
see [9]), and ecen ly new ials ha e been app o ed o
ea men o speci ic ype o cance s (e.g. glioblas oma and
p os a e) in se e al coun ies a ound he wo ld, including
Japan, Ge many, USA, and China [10]–[14].
Al hough di e en ma e ials ha e been in es iga ed as
magne ic hype he mia agen s, i on oxide based MNPs ha e
ecei ed mos o he a en ion due o hei chemical s abil-
i y, high magne iza ion, ela i ely well–known me abolism,
high biocompa ibili y, e c. [7], [15]. On op o ha , some
o he bes hea ing esul s in magne ic hype he mia ha e
been epo ed o i on oxide based MNPs, wi h hea ing
e iciency alues (quan i ied by he Speci ic Abso p ion
Ra e, SAR) up o SAR/ =8 W/gkHz in exchange cou-
pled e i es [16]–[18]. Ne e heless, he e m ‘‘i on oxide’’
is gene ic and can encompass a wide ange o di e en
oxide phases, such as γ-Fe2O3(maghemi e), Fe3O4(mag-
ne i e), α-Fe2O3(hema i e), FeO (wüs i e), e c. [19]. Each
one o hese i on oxide phases p esen s di e en kinds o
magne ic beha io , and he e o e, a e y di e en hea ing
e iciency. As has been p e iously desc ibed [20], he hea -
ing e iciency o he MNPs is di ec ly ela ed o he ‘‘hys-
e esis losses’’ o he MNPs unde an ex e nal AC ield.
These losses a e p opo ional o he hys e esis loop a ea, and
he e o e, a e di ec ly ela ed o he magne ic beha io o
he MNPs. Al hough he e ha e been a ew epo s on he
hea ing e iciency o MNPs made o i on oxide phases such
as FeO [21], –Fe2O3[22] o α–Fe2O3[23], mos o he
cu en a icles a e based on MNPs composed o magne i e
and/o maghemi e, since hese compounds a e he only ones
app o ed by he Uni ed S a es Food and D ug Adminis a-
ion (FDA) and he Eu opean Medicines Agency (EMA) o
clinical use.
Magne i e and maghemi e a e e imagne ic i on oxides
wi h a simila cubic s uc u e [24]. Magne i e p esen s a
ace–cen e ed cubic spinel c ys al s uc u e wi h e ahed al
si es occupied by Fe3+ions while oc ahed al si es a e e enly
illed by Fe2+and Fe3+ions. In s oichiome ic magne i e,
he a io o Fe2+and Fe3+is 1:2. Magne i e phase ends o
oxidize in o maghemi e upon exposu e o oxygen, esul ing
in he con e sion o all Fe2+ions in o Fe3+. Fo he case
o his s oichiome ic magne i e, he e imagne ic momen
a ises om unpai ed Fe2+spins in oc ahed al si es, while in
he case o maghemi e, unpai ed oc ahed al Fe3+spins a e
he ones esponsible o he magne ism [19], [25].
Since maghemi e is a mo e s able i on oxide phase
han magne i e, many o he MNPs de eloped o mag-
ne ic hype he mia, especially comme cial ones, a e made
ei he o maghemi e, o a magne i e co e and an oxi-
dized maghemi e shell [26]–[30]. Fo example, in a ecen
wo k, Bende e al. [31] showed ha comme cial maghemi e
Nano lowe s (hDi ∼ 40 nm), composed o se e al
c ys alli es/co es, p esen ed e y high hea ing e iciency,
SAR (µ0H=8.8 mT, =939 kHz ) =322 W/g,
in compa ison o o he simila i on oxide based nanopa icles.
On he o he hand, pu e magne i e nanopa icles a e also e y
p omising bu gene ally hey need o be coa ed wi h some
kind o capping agen in o de o p e en oxida ion. Se e al
wo ks ha e s udied hei use o magne ic hype he mia [17],
[18], [32]. An in e es ing case is ha o magne osomes,
pu e magne i e MNPs syn hesized by magne o ac ic bac e ia
and in insically coa ed wi h a lipid bilaye . To his espec ,
ecen wo ks ha e epo ed e y high hea ing e iciency
alues in hese cube–oc ahed al magne osomes o hDi ≈
45 nm (SAR/ up o 5 W/gkHz) [33]–[37]. In bo h cases
(NFs and BMs), se e al wo ks ( [38] o [39], espec i ely)
ha e e idenced hei high biocompa ibili y, as hey can be
almos comple ely assimila ed by human cells once hei
he apeu ic unc ion is comple ed, being deg aded a e wa ds.
In addi ion, we mus s ess ha al hough some imes in he
li e a u e magne i e and maghemi e a e p esen ed as ‘‘in e -
changeable’’ ma e ials when e e ing o MNPs, due o hei
simila sa u a ion magne iza ion (Msa Fe3O4 ∼92 Am2/kg
and Msa γ–Fe2O3 ∼76 Am2/kg [25]), his is no en i ely
co ec , gi en ha hese i on oxide phases do ac ually p esen
se e al di e ences in hei magne ic esponse (e.g. magne ic
aniso opy, Ve wey ansi ion...), and his can a ec hei
pe o mance in di e en biomedical applica ions, including
magne ic hype he mia [40]. The e o e, a good cha ac e i-
za ion o he magne ic p ope ies o magne i e/maghemi e
MNPs becomes manda o y [17], [41], [42].
Conside ing all his, in his wo k we ha e compa ed wo o
he mos p omising MNPs o magne ic hype he mia: com-
me cial maghemi e Nano lowe s (NFs) and magne i e bac e-
ial magne osomes om Magne ospi illum g yphiswaldense
(BMs). Bo h samples p esen simila size (hDi ∼ 40–45 nm),
high c ys allini y, and well de ined mo phology (mul ico e
o he NFs and cube–oc ahed al o he BMs). We ha e ana-
lyzed hei mic os uc u e using X–Ray Di ac ion (XRD)
and T ansmission Elec on Mic oscopy (TEM), checked hei
composi ion by using X– ay Abso p ion Nea Edge Spec-
oscopy (XANES) o ensu e he chemical pu i y o each
ensemble, s udied hei magne ic esponse wi h DC magne-
ome y, and inally compa ed hei hea ing e iciency using
AC magne ome y. To his espec , we ha e employed a
no el home–made se up o AC magne ome y measu e-
men s, which has allowed us o measu e he SAR o hese
MNPs a 3 di e en equencies, applying AC ields up o
88 mT. This has allowed us o clea ly depic he di e en
hea ing anges o hese magne i e/maghemi e MNPs, and
also o ob ain a landscape o he ields and equencies ha
maximize hei hea ing e iciency unde ce ain sa e y limi s.
II. MATERIALS AND METHODS
Comme cial Synomag Nano lowe s we e supplied by Mic o-
mod Pa ikel echnologie GmbH (Ge many). Each lowe
consis s on Dex an–coa ed (∼12 nm hickness) maghemi e
γ-Fe2O3mul ico es (∼10 co es/each). The mul ico e
maghemi e s uc u e is o ∼45 nm. These MNPs we e syn-
hesized ollowing a polyol me hod [43], [44].
The magne osomes employed in his s udy a e magne i e
Fe3O4nanopa icles syn hesized by magne o ac ic bac e ia
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E. M. Je emo as e al.: Nano lowe s Ve sus Magne osomes: Compa ison Be ween Two P omising Candida es
om he Magne ospi illum g yphiswaldense s ain MSR-1
(DMSZ 6631). Bac e ia we e cul u ed mic oae obically a
28◦C o 48 hou s in Flask S anda d Medium, as desc ibed
by Heyen and Schüle [45], supplemen ed wi h 100 µM
i on (III)–ci a e o suppo magne osome o ma ion. B ie ly,
cul u e was ca ied ou in h ee 1 L-bo les a 28◦C unde
mic oae obic condi ions (bo les loosely capped and wi hou
shaking). Cells we e collec ed a e 120 h when well– o med
magne osomes we e p esen . BMs ha e been measu ed ei he
in he whole cells (DC–magne ome y, XRD and XANES)
o isola ed om he bac e ia (TEM, AC magne ome y).
Fo he p epa a ion o whole bac e ia samples, he cells
we e ha es ed by cen i uga ion, ixed in 2% glu a alde-
hyde, and washed h ee imes in mQ wa e . The ixed and
washed cells we e eeze-d yed, esul ing in a powde sam-
ple. Complemen a y, magne osomes we e ex ac ed ollow-
ing he p o ocol desc ibed by G ünbe g e al. [46] wi h mino
modi ica ions. The cells we e collec ed by cen i uga ion,
suspended in 20 mM HEPES–4 mM EDTA (pH =7.4),
and dis up ed using a F ench p ess a P =1.4 kba . The
lysa ed cells we e sonica ed, p omo ing he sepa a ion o
magne osomes, and cen i uged a 600 g o 5 min, o emo e
cell deb is. Then, magne osomes we e collec ed om he
supe na an by magne ic sepa a ion and insed 10 imes wi h
10 mM HEPES-200 mM NaCl (pH =7.4). Finally, he iso-
la ed magne osomes we e e–dispe sed in deionized wa e
(pH 7.4), s e ilized in au ocla e (115◦C, 15 min), and s o ed
a 4◦C. The s abili y o he magne i e magne osomes agains
oxida ion is secu ed du ing se e al weeks.
XRD measu emen s we e pe o med a oom empe a u e
on Synomag NFs and eeze-d ied bac e ia using a B uke
D8 Ad ance di ac ome e equipped wi h a high coun a e
Lynxeye de ec o . This de ec o educes he o al coun ing
ime, which cons i u es a g ea ad an age o minimize he
possible de e io a ion o he samples. The di ac ome e
was used wo king on B agg-Ben ano geome y and Cu-Kα
(λ=1.5418 Å) adia ion. Pa e ns we e collec ed wi hin he
ange 20◦≤2θ≤110◦wi h a 0.02◦inc emen .
TEM was pe o med on bo h Synomag NFs and BMs
(ex ac ed om he bac e ia) adso bed on o 300 mesh
ca bon-coa ed coppe g ids. TEM images we e ob ained wi h
a JEOL JEM–14000Plus elec on mic oscope a an accele -
a ing ol age o 120 kV. The pa icle size dis ibu ion was
analyzed using a s anda d so wa e o digi al elec on mic o-
scope image p ocessing, ImageJ [47].
XANES measu emen s we e pe o med on Synomag NFs
and on BMs loca ed wi hin he bac e ia (whole cells). The
main aim o hese measu emen s was o access in o ma ion
conce ning medium– ange o de , which allow us o clea ly
di e en ia e he oxida ion s a e (phase iden i ica ion) in bo h
MNP ensembles, as XRD p o ides long– ange o de in o -
ma ion [48]. Fe K–edge XAS measu emen s o he NFs we e
ca ied ou a he BL22 CLAESS beamline o he ALBA syn-
ch o on (T=77 K) and a he XAFS beamline o he Ele a
synch o on (T ies e, I aly) (Room Tempe a u e, RT). On he
o he hand, he BMs we e measu ed a he XAFS beamline o
he Ele a synch o on a RT. In all cases, measu emen s we e
pe o med in ansmission mode using a double Si c ys al
monoch oma o o ien ed in he (111) di ec ion. A e e ence
Fe–sample was measu ed o de e mining he posi ion o he
bac e ia Fe–K edge (E=7112 eV).
DC magne iza ion (M) measu emen s we e pe o med
on bac e ia (ob ained as desc ibed be o e), encapsula ed
in gela in capsules. Da a we e collec ed using a Quan um
Design QD-MPMS (SQUID) magne ome e in he empe -
a u e ange o T =5–300 K applying magne ic ields µ0H
be ween 0.5 mT and 2.05 T. M s. T cu es we e measu ed
om 10 o 300 K, ollowing he Ze o Field-Cooling/Field-
Cooling p o ocol (ZFC–FC): The samples we e cooled in he
absence o any ex e nal ield om 300 K o 5 K. A 5 K a ixed
magne ic ield o 5 mT was applied and he magne iza ion
was measu ed upon wa ming o 300 K (ZFC). Wi h he ield
s ill on, he sample was cooled o 5 K and he magne iza ion
was measu ed upon wa ming o 300 K (FC). M s. µ0H
loops we e measu ed a 300 K applying ields up o 5 T. The
high-sensi i i y o he SQUID (∼10 −7emu) allowed us o
use small amoun s o he MNPs (m =12.3 mg in he case o
he NFs and m =0.9 mg o eeze-d ied bac e ia). He e again,
we decided o keep he BMs in acellula o a oid oxida ion
p ocess and magne ic in e ac ions among he magne osomes.
AC magne ome y cha ac e iza ion was pe o med on NFs
and BMs ex ac ed om he bac e ia (i.e., isola ed magne-
osomes) using a e sa ile home–made magne ome e ha
gene a es high magne ic ields able o sa u a e he samples.
This de ice is capable o wo king a a wide equency ange
(100 kHz–1 MHz) wi h la ge ield in ensi y: 90 mT a low
equency side and 35 mT a high equency side. Fu he
de ails on he se up can be ound in [49].
III. RESULTS AND DISCUSSION
A. STRUCTURAL CHARACTERIZATION
Figu e 1shows he X–Ray Di ac ion (XRD) pa e ns
oge he wi h he Rie eld e inemen s (aand b) and wo
ep esen a i e T ansmission Elec on Mic oscopy (TEM)
images, wi h he size dis ibu ion on he igh (cand d)
co esponding o he γ–Fe2O3NFs and he Fe3O4BMs
( eeze–d ied bac e ia o XRD and isola ed magne osomes
o TEM).
The Rie eld e inemen s pe o med on he NFs
(see Figu e 1a) a e consis en wi h a single phase o cubic
Fd–3m space g oup, wi h a la ice pa ame e a =8.3451(3) Å,
and a mean nanopa icle size o hDγ−Fe2O3i = 50.0(4) nm o
he whole MNP co e. The calcula ions also p o ide in o ma-
ion on he mic os ain, whe e a minimal η=0.93(1)% has
been ob ained, which is indica i e o hei good c ys allini y.
The achie ed low B agg ac o RB=3.6% gua an ees he
eliabili y o he i ing. Gi en ha all he XRD peaks a e
indexed wi h hose co esponding solely o he γ–Fe2O3
phase [50], he XRD cha ac e iza ion indica es ha NFs a e
mainly composed o maghemi e. The TEM images o hese
NFs (Fig. 1c) e i y he mul ico e s uc u e ( lowe –shape)
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E. M. Je emo as e al.: Nano lowe s Ve sus Magne osomes: Compa ison Be ween Two P omising Candida es
FIGURE 1. a) and b) include he XRD pa e ns oge he wi h he Rie eld e inemen s co esponding o he NFs and he
BMs, espec i ely. The XRD pa e ns o he NFs a e consis en wi h single phase o maghemi e, whe eas he posi ions o
he B agg peaks o he bac e ia a e consis en wi h a single phase o magne i e. In c) and d), wo ep esen a i e TEM
images and size dis ibu ion a e shown o NFs and BMs, espec i ely.
o each lowe , whe e ∼10 g ains/co e o m he maghemi e–
co e. A LogNo mal size dis ibu ion wi h an a e age diame e
hDMNPi = 42.3 nm and a iance σ=3.6 nm has been
ob ained om he analysis o he TEM images. This size is
sligh ly smalle wi h espec o he one ob ained by means o
XRD, as expec ed [51].
On he o he hand, he XRD pa e n and Rie eld e ine-
men s (RB=4.5%) pe o med on eeze–d ied bac e ia a e
shown in Fig. 1b. The esul s a e consis en wi h a single
phase o cubic Fd–3m s uc u e, wi h a =8.3985(2) Å, which
co esponds o magne i e [52]. No ex a peaks apa om
hose co esponding o magne i e show up, which showcases
he good c ys allini y and he high chemical pu i y o he
magne osomes. The cell gi es a con ibu ion o he sca e ing
in ensi y in he o m o a backg ound ise o 2θ < 50◦.
The Rie eld e inemen s poin o a mean nano-c ys alli e
size o magne i e hDFe3O4i = 45.1(3) nm. He e, an e en
lowe mic os ain η=0.384(2)% is ound, which ensu es a
minimal uni cell dis o ion, e ealing he high c ys allini y
o he BMs. Fig. 1dshows a TEM image co esponding
o magne osomes ex ac ed om he bac e ia. The analysis
o he TEM images indica e a Gaussian size dis ibu ion
cen e ed in hDMNPi = 42.8 nm wi h σ=7.3 nm, which is
again sligh ly smalle wi h espec o he XRD one.
Al hough XRD can gi e us c ys allog aphic in o ma ion
abou he di e en i on oxide phases p esen in ou samples,
addi ional s uc u al in o ma ion can be ob ained by XANES.
XANES is a powe ul echnique ha p o ides accu a e da a
conce ning he local en i onmen and he oxida ion s a e o
he abso bing a oms, in ou case, Fe [53]. Figu e 2shows he
Fe K–edge (E0=7112 eV) XANES spec a co esponding
o a) he NFs and b) BMs wi hin he bac e ia, oge he wi h
e e ence pa e ns o γ–Fe2O3[54] and Fe3O4, and Linea
Combina ion Fi s (LCFs). These LCFs allow us o quan i y
he con en o each Fe–phase in he samples, as i has been
shown in p e ious s udies (e.g., [55]).
Acco ding o he XANES spec um plo ed in Figu e 2a),
he edge posi ion o he NFs, de ined as he ene gy alue a
which he no malized abso p ion µ(E) eaches 0.5, is loca ed
a E0≈7124 eV, which is he ypical alue o maghemi e,
γ–Fe2O3[54], [56]. LCFs indica e a pe ec ma ch be ween
he e e ence γ–Fe2O3pa e n and he expe imen al XAS
da a co esponding o he NFs. This allow us o e i y he
chemical pu i y o he NFs ha was poin ed by XRD cha -
ac e iza ion. On he o he hand, he XANES spec um co -
esponding o he BMs (Fig.2b)) is le -shi ed in ene gy
wi h espec o he NFs (edge posi ion E0≈7122 eV,
i.e., 1E0≈2 eV). This indica es a lowe Fe–oxida ion s a e,
which is expec ed, as magne i e combines bo h Fe2+and
Fe3+, whe eas o maghemi e, only Fe3+is p esen [53], [57].
He e, he LCFs con i m he 100% magne i e–composi ion o
he BMs. The e o e, we can unequi ocally conclude ha he
NFs a e ully composed o maghemi e, whe eas he BMs a e
ully composed o magne i e.
B. MAGNETIC CHARACTERIZATION
Figu e 3shows he magne ic cha ac e iza ion (M(T, µ0H))
o bo h MNP ensembles. In Fig. 3a), he ZFC-FC cu es
measu ed a µ0H=5 mT can be inspec ed. Fi s , conce ning
he NFs (blue squa es), he ZFC and FC b anches a e sep-
a a ed in he whole empe a u e ange, showcasing he high
magne ic i e e sibili y o hese Supe pa amagne ic (SPM)
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E. M. Je emo as e al.: Nano lowe s Ve sus Magne osomes: Compa ison Be ween Two P omising Candida es
FIGURE 2. No malized abso p ion µ(E) Fe K–edge XANES spec a co esponding o a) maghemi e NFs and b)
magne i e BMs. LCFs pe o med wi h e e ence XAS spec a co esponding o pu e γ−Fe2O3(blue) and Fe3O4
( ed). The eliabili y o hese LCFs can be checked by he esidual lines (bo om), which a e close o ze o.
FIGURE 3. a) Ze o Field Cooling-Field Cooling (ZFC-FC) M(T) cu es o γ−Fe2O3NFs (blue ci cles) and Fe3O4BMs ( ed
squa es) measu ed a µ0H=5 mT. In b), he e olu ion o he IA pa ame e s he magne ic applied ield µ0His shown. I can
be seen how he BMs achie e hei maximum alue a highe µ0H han he NFs. The inse shows he no malized hys e esis
loops M/Msa measu ed a T=300 K.
MNPs [31]. On he o he hand, he BMs (wi hin he bac e ia)
( ed ci cles), which a e magne ically blocked a T=300 K,
e idence he expec ed Ve wey ansi ion, a ound TV≈106 K,
cha ac e is ic o Fe3O4. This ansi ion is ma ked by a sud-
den d op o he magne iza ion wi h dec easing T. The TV
alue ag ees well wi h hose p e iously epo ed o magne o-
somes [57], [58] and i is ound o be below he TV∼120 K
co esponding o bulk magne i e [59]. Needless o say, his
Ve wey ansi ion is no p esen in he NFs, as expec ed o
a pu e maghemi e sys em [31], [48]. In e es ingly, he alue
o he magne iza ion measu ed a T=300 K in he BMs
(M≈4.2 Am2/kg) is almos hal he alue co esponding
o he NFs (M≈9.8 Am2/kg). This would sugges a highe
aniso opy ba ie (Eba ie ∝K·V) o he o me . As bo h
IONP ensembles a e e y close in size (i.e., e y simila V),
he BMs a e e ealing as an ensemble wi h highe aniso opy
(K) wi h espec o he NFs. As has been epo ed in he
li e a u e, he e ec i e aniso opy (Ke ) is a key pa ame e o
op imize he hea ing e iciency o MNPs in magne ic hype -
he mia ( [25], [60]). Gi en ha he in e ac ions among he
magne ic momen s do a ec his Ke , we ha e analyzed he
dependence o he I e e sibili y A ea pa ame e (IA, de ined
in [61]), wi h espec o he ex e nal applied ield µ0Hin he
s a ic egime. As desc ibed in [61], his pa ame e p o ides
in o ma ion on he obus ness o he magne ic in e ac ions
among he magne ic momen s, as he g ea e he in e ac ions,
he la ge magne ic ields a e needed o o e come he ene gy
ba ie s be ween wo spin s a es. The esul s, ep esen ed
in Fig. 3b, show ha he BMs a ain hei maximum IA =
174 a µ0H=12.5 mT, whe eas o he NFs, hei maximum
IA =127 is achie ed a µ0H=4 mT, i.e. a ield h ee
imes la ge is equi ed o o e come he ene gy ba ie in he
case o he BMs. This esul con i ms he highe e ec i e
aniso opy o he BMs in compa ison o NFs. The enhanced
Ke in he BMs can also be aced in he o m o coe ci i -
i y (µ0HC) in he no malized hys e esis loops measu ed a
T=300 K (see inse in Fig. 3b)). The e, while he NFs
exhibi a negligible alue o µ0HC, he BMs show a alue
o µ0HC≈20 mT. On he o he hand, ano he impo an
pa ame e ha de e mines he hea ing e iciency o he MNPs
is he sa u a ion magne iza ion Msa . In ou case, Msa alues
ob ained o NFs and BMs a e ∼63 and 92 Am2/kg. A highe
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E. M. Je emo as e al.: Nano lowe s Ve sus Magne osomes: Compa ison Be ween Two P omising Candida es
Msa alue o BMs would in p inciple be an ad an age o
hei use as magne ic hype he mia agen s, since i will gi e
ise o highe hys e esis losses [62].
C. MAGNETIC FLUID HYPERTHERMIA
In o de o s udy he hea ing e iciency o he NFs and he
BMs (ex ac ed om he bac e ia), we ha e employed AC
magne ome y measu emen s. AC magne ome y allows us
o di ec ly measu e he AC hys e esis loops desc ibed by he
magne ic momen s o he nanopa icles in o de o calcula e
hei hea ing e iciency o SAR om he hys e esis losses
associa ed. P e ious wo ks ha e demons a ed he hea ing
e iciency o hese MNP ensembles by measu ing he Tem-
pe a u e s ime cu es [62], [63] . The AC hys e esis loops
measu ed o bo h NFs and BMs dispe sed in wa e (con-
cen a ion ∼3.1 mg/ml and ∼1.5 mg/ml espec i ely) a e
p esen ed in Figu e 4. These AC loops we e measu ed a
h ee di e en equencies, =130, 300, and 530 kHz, wi h
AC ield ampli udes up o µ0HAC =88, 62, and 50 mT,
espec i ely.
As depic ed, he shape o he AC loops changes when
inc easing bo h he µ0HAC and he . Bo h samples exhibi
na ow and elonga ed AC loops a low ield ampli udes, i. e.,
he ypical lance shape [64]. This gi es ise o low hys e esis
losses and low hea ing e iciencies. None heless, as he ield
ampli ude inc eases, he AC loops become bigge and mo e
squa ed un il hey each a ce ain sa u a ion a high enough
ields, whe e he di e ences be ween he sa u a ed loops a e
small. In addi ion, we can obse e ha he AC loops end o
become sligh ly wide and mo e squa ed a high enough ield
ampli udes.
I we compa e bo h samples, quan i a i e di e ences a e
al eady seen, especially a high ield ampli udes: he coe ci e
ield alue, µ0HC−AC , is up o ∼85% highe o BMs han
o NFs, and he Msa -AC is up o ∼26% highe . This sugges s
ha he hea ing e iciency o BMs is going o be highe han
NFs, especially in he high ield egion. In o de o check his,
SAR alues ha e been calcula ed o bo h MNPs. These SAR
alues, in W/g, we e di ec ly ob ained om he a ea, A, o he
AC hys e esis loops acco ding o he ollowing equa ion:
SAR =
c·A=
c·Iµ0M dH (1)
whe e M is he ins an aneous magne iza ion a ime ,H he
sinusoidal magne ic ield o equency a ime , and cis
he magne ic ma e ial weigh concen a ion in he dispe sing
medium.
SAR s. µ0HAC cu es a e shown in Figu e 5. Fo bo h
he NFs and he BMs, a ield ampli udes below 5 mT, SAR
alues a e nea ly negligible. I we inc ease he ield ampli-
ude, he SAR s a s inc easing apidly un il a sa u a ion is
eached abo e a ce ain ield, µ0Hsa . As inse ed in Table 1,
he maximum SAR alues ob ained wi h BMs a e app eciably
highe (>100%) han hose ob ained o NFs, independen ly
o he equency. These di e ences can be essen ially ela ed
TABLE 1. Values co esponding o he di e en pa ame e s ob ained
om Figu es 4and 5 o he NFs and BMs measu ed a =130, 300 and
530 kHz. E o s o he alues a e below 5%.
o wo pa ame e s: he magne ic momen and he e ec i e
aniso opy o he MNPs.
Conce ning he emanence and he coe ci e ield, he BMs
display g ea e alues han he NFs. This can be ela ed o
di e ences in he e ec i e aniso opy, Ke , o bo h MNPs,
as was al eady in e ed om DC magne ic measu emen s.
In o de o ge an es ima ion o Ke , we can use he app oach
desc ibed by Mehdaoui e al. [64]. Acco ding o hei model,
an es ima ion o Ke om he coe ci e ield alues, HC, o he
AC hys e esis loops, can be ob ained using he ollowing
equa ion:
µ0HC=0.96 ·µ0Hκ(1 −κ0.8) (2)
whe e Hκ=2Ke /µ0Msa is he aniso opy ield, being κa
pa ame e gi en by:
κ=kBT
Ke Vln kBT
4µ0HmaxMsa V τ0(3)
whe e τ0=10−10 s, µ0Hmax is he maximum applied ield,
and Vis he MNP olume.
Using his exp ession, he magne ic aniso opy, Ke , can
be es ima ed o ou BMs and NFs, as indica ed in Table 1.
The Ke alues ob ained o hese magne osomes lie wi hin
he ange o alues ypically epo ed o o he highly c ys-
alline magne i e nanopa icles o simila size [18], [34].
As obse ed, he highe e ec i e aniso opy o BMs gi es ise
o wide AC loops, and he eby o highe hys e esis losses.
This is alid, as has been explained be o e [65], [66], i he
applied ields a e s ong enough: µ0HAC µ0Hc-hyp, being
µ0Hc-hyp he ield ampli ude eached a he in lec ion poin
o he SAR s ield cu e [65], [66].
The e o e, hese wo ac o s, highe magne ic momen and
highe e ec i e aniso opy, gi e an ad an age o BMs, com-
pa ed o NFs, in e ms o hea ing e iciency.
Finally, o clinical applica ions i is impo an o conside
ce ain sa e y limi s in he alue o he ield ampli ude and
equency in o de o a oid p oducing non-speci ic hea ing in
he body ha can ha m he pa ien . In he li e a u e, di e en
sa e y limi s ha e been p oposed. Acco ding o he so called
A kinson-B ezo ich c i e ion, H· should be lowe han
4.85·108A m−1s−1[67], [68], while ollowing he He g
c i e ion, which has become a mo e accep ed es ima ion, his
limi is en imes highe , ∼5·109A m−1s−1[69]. A his
poin , i is wo h men ioning ha he He g c i e ion does no
ake in o accoun he exposed olume o he magne ic ield.
Thus, in o de o a oid he possible induc ance o damaging
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E. M. Je emo as e al.: Nano lowe s Ve sus Magne osomes: Compa ison Be ween Two P omising Candida es
FIGURE 4. AC hys e esis loops measu ed o he NFs and he BMs (ex ac ed om he bac e ia) a h ee di e en
equencies, =130, 300 and 530 kHz, wi h AC ield ampli udes up o µ0HAC =88, 62, and 50 mT, espec i ely.
FIGURE 5. SAR s. µ0HAC cu es o he NFs (blue squa es) and he BMs ( ed ci cles) measu ed a a) =130, b) =300, and c)
=530 kHz, wi h AC ield ampli udes up o µ0HAC =88, 61.5, and 50 mT, espec i ely. In all o he cases, he SAR co esponding o he
BMs is mo e han wice he one o he NFs a high ields.
eddy cu en s connec ed o he use o high ield ampli udes
and/o equencies, ei he he olume o exposed issue o
he hea ing ime should be educed. Following his He g
c i e ion, he maximum achie able SAR o ou samples can
be calcula ed. As indica ed in Table 1, bo h samples achie e
hei maximum SARlimi a =300 kHz (µ0Hlimi =20.7 mT),
eaching a alue o 455 W/g and 1125 W/g o NFs and
BMs, espec i ely. The la e SARlimi o BMs compa es well
wi h he epo ed ones ound in he li e a u e (e.g. [34]).
A la ge SARlimi o BMs again suppo s he use o magne i e
based NPs o maximizing he hea ing e iciency in magne ic
hype he mia unde clinical condi ions. Ne e heless, a his
s age, i should be eminded ha Synomag NFs ha e been
bla an ly p esen ing a high pe o mance compa ed o o he
mo e con en ional i on oxide nanopa icles syn hesized by
a i icial ou es. Such ou pu is su ely connec ed o he ac
ha he e is some deg ee o spin diso de and exchange
coupling in hei nanome ic scale, which al oge he p omo e
a la ge igu e o me i o biomedical pu poses [31]. The
ac ha hey a e comme cially a ailable demons a es i s
echnological in e es , easonable yield in la ge–scale p o-
duc ion p ocesses and high ep oducibili y. In addi ion, hose
Synomag NFs may also be ele an o cus omized su ace
modi ica ions. All in all, i holds ue ha he magne i e
BMs p esen a highe hype he mia pe o mance compa ed o
maghemi e NFs. Ne e heless, he condi ions o ep oducibil-
i y and la ge–scale p oduc ion o such biological MNPs a e o
be be e de ined, whe eas Synomag NFs cons i u e al eady a
high–a ailable echnological ad anced p oduc .
IV. CONCLUSION
Magne osomes syn hesized by he magne o ac ic bac e ium
M. g yphiswaldense ha e e ealed be e pe o mance o
Magne ic Fluid Hype he mia pu poses wi h espec o
comme cial Synomag Nano lowe s. The highe e ec i e
aniso opy and sa u a ion magne iza ion o BMs gi e ise o
highe hea ing e iciency in compa ison o NFs in all he
ange o ield ampli udes and equencies analyzed. In his
way, i has been shown ha he maximum SAR a ainable
unde clinical condi ions, SARlimi , is nea ly 2.5 highe in
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BMs wi h espec o Synomag NFs, which a e al eady con-
side ed an ou s anding candida e o Magne ic Hype he mia
The apy. In he case o BMs, he p ocess o ge ing comme -
cial amoun s is he nex challenge o be aced, as hey a e
s ill a om he p oduc ion o hese Synomag NFs, whose
ab ica ion p ocess is well–s anda dized. The wo k p esen ed
he e is also opening a esea ch line aiming o compa e Mag-
ne ic Hype he mia The apy pe o mance in p omising can-
dida es by bo h AC magne ome y and calo ime ic me hods.
Finally, he ac ha bo h NFs and BMs can be almos o ally
assimila ed and deg aded by human cells is, indeed, a s ong
poin o hei clinical use and a key ac o o hei long– e m
biocompa ibili y.
ACKNOWLEDGMENT
The au ho s would like o hank he ALBA and Ele a syn-
ch o on adia ion acili ies and s a o he alloca ion o
beam ime and assis ance du ing he expe imen s.
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ELIZABETH M. JEFREMOVAS was bo n in
San ande , Spain, in 1994. She ecei ed he
B.S. deg ee in physics om he Uni e sidad de
Can ab ia, in 2017, and he M.Sc. deg ee in
nanophysics and ad anced ma e ials om he
Uni e sidad Complu ense de Mad id, in 2018.
She is cu en ly pu suing he Ph.D. deg ee
in nanomagne ism unde he supe ision o
P o . Luis Fe nández Ba quín wi h he Uni e -
sidad de Can ab ia g an ed wi h a ‘‘Concepción
A enal’’ Fellowship (Uni e sidad de Can ab ia–Gobie no de Can ab ia).
He cu en esea ch in e es s include s udy o 4 and biocompa ible
Fe–oxides magne ic nanopa icles o basic esea ch and hei po en ial
applica ions.
99560 VOLUME 9, 2021
