h. hofman powder technology laboratory · pdf file(bmbf)referat neue werkstoffe;...
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H.
Hof
ma
nPo
wd
er T
echn
olog
yLa
bor
ato
ry
Inorg
anic
nanopart
icle
s fo
r m
edic
al
applica
tions:
Opport
unitie
s, C
hallenges
and R
isks
Def
initi
on:
Euro
pea
n M
edic
ines
Agen
cy
Na
note
chno
logy
is d
efin
ed a
s th
e p
rod
uctio
n a
nd
ap
plic
atio
n of
str
uctu
res, d
evic
es a
nd s
yste
ms
by
cont
rolli
ng the
sha
pe
and
siz
e of
ma
teri
als
at na
nom
etre
sc
ale
. The
na
nom
etre
sca
le r
ang
es f
rom
the
ato
mic
leve
l a
t a
roun
d 0
.2 n
m (2
Å) up
to
aro
und
10
0 n
m.
Na
nom
edic
ine
is d
efin
ed a
s th
e a
pp
lica
tion
of
nano
tech
nolo
gy
in v
iew
of
ma
king
a m
edic
al d
iag
nosis
or tre
atin
g o
r p
reve
ntin
g d
isea
ses.
It
explo
its
the
impro
ved a
nd o
ften
nove
l phy
sica
l, ch
em
ical and
bio
logic
al
pro
pert
ies
of
mate
rials a
t na
nom
etr
e s
cale
.
2
Def
initi
on:
Euro
pea
n C
omm
ission
20
11
Na
nom
ate
ria
l’ m
eans
a n
atu
ral, inci
denta
l or
manufa
cture
d m
ate
rial co
nta
inin
g p
art
icle
s, in
an
unbound s
tate
or
as
an
aggre
ga
te o
r a
s a
n a
gglo
mera
te a
nd w
here
, for
50 %
or
more
of
the
part
icle
s in
the
num
ber
siz
e d
istr
ibut
ion,
one
or
mor
e ex
tern
al d
imen
sion
s is
in the
siz
e ra
nge 1
nm
-100 n
m.
20
11
/69
6/E
U)
3
Euro
pean M
edic
ines
Agency
(EM
A):
Medic
al
pro
duct
s and M
edic
al
Dev
ices
(2007)
4
“All
dev
ices
inco
rpora
ting
or
cons
isting
of
part
icle
s,
com
pone
nts
or
dev
ices
at
the n
ano
scale
are
in
Cla
ss III
unl
ess
the
y are
enc
apsu
late
d o
r bound
in
such
a m
ann
er
that
they
cann
ot
be r
ele
ase
d t
o t
he p
atient
’s o
rgans
,
tiss
ues, c
ells
or
mole
cule
s”.
Prom
ises
:
Na
nom
edic
ine
–N
ano
pha
rma
ceut
ics
–N
ano
dia
gno
stic
Nano
tech
nolo
gy
is o
ne o
f th
e p
rom
isin
g f
utu
re t
ech
nolo
gie
s w
hich
ena
ble
s ne
w
and
bett
er
dia
gno
stic
and
the
rapeutic
tools f
or
the p
atient
s
Med
ica
l ana
lytic
bec
omes
fa
ster
and
mor
e ef
fici
ent us
ing
sm
alle
r q
uant
ities
of
sa
mp
les
-Pa
tien
t ori
ente
d D
iag
nost
ic [
„lab-o
n-a-c
hip“]
Na
nop
art
icle
s tr
ans
por
t a
ctiv
e a
gen
ts (d
rug
s, g
enes
, etc
.) to
disea
sed
tissu
es
-optim
ised
The
rapy
show
ing
les
s si
de
effe
cts
[„dru
g d
eliv
ery“
]
Na
nop
art
icle
s he
at ca
ncer
tis
sue
and
lea
d to
ap
opto
sis
of c
anc
er c
ells
–ca
ncer
the
rapy
with
out to
xic
sid
e ef
fect
s [„
hyper
ther
mia
“]
Na
nost
ruct
ured
sur
face
s a
nd c
onst
ruct
s se
rve
as
scaff
old
for
new
tis
sue/
orga
ns [
„tis
sue
eng
inee
ring
“]
Na
nop
art
icle
s se
rve
to m
ani
pul
ate
intr
ace
llula
r p
roce
sses
-[„
ther
ag
nost
ic“]
Tod
ay’
s H
ope
in N
ano
med
icin
e6
Na
nom
edic
ine
help
s to
dev
elop
mor
e ef
fect
ive,
sa
fe a
nd c
hea
per
the
rap
ies
for
pa
tient
s
utili
zes
flex
ible
and
mul
tifun
ctio
nal a
pp
roa
ches
, tec
hnol
ogie
s a
nd too
ls a
nd e
xplo
it th
e sp
ecific
pro
per
ties
from
the
na
now
orld
sup
por
ts a
sus
tain
ab
le a
nd e
cono
mic
gro
wth
in E
urop
e d
ue to
the
imp
rove
men
t in
the
hea
lth s
yste
m
and
hel
ps
med
ica
l doc
tors
to
dia
gno
se a
nd tre
at d
isea
ses
on a
m
olec
ula
r le
vel –
whe
re the
disea
se is
cre
ate
d.
Ap
plic
atio
n of
Na
note
chno
logy
7
Fiel
ds
of a
pp
lica
tion
for
nano
tech
nolo
gy
rese
arc
h in
the
nex
t 5
to
10
ye
ars
and
the
ma
rket
unt
il 2
02
0
Que
lle: n
ano
.DE-
Rep
ort 2
01
1, B
und
esm
inis
teri
umfü
rBi
ldun
gun
d F
orsc
hung
(BM
BF)R
efer
atN
eue
Wer
ksto
ffe;
Na
note
chno
log
ie,B
onn
(D)
IuK
= In
form
atio
n &
Com
mun
ica
tion
Ma
jor
Tren
ds
in N
ano
dia
gno
stic
s8
“Cur
rent
ly n
ano
dia
gno
stic
s co
ncep
ts
focu
s a
roun
d u
tiliz
atio
n of
na
nosc
ale
p
rop
ertie
s fo
r:
Ultr
ase
nsiti
ve b
iom
ark
er
dev
elop
men
t/m
easu
rem
ent
Mul
ti-a
ssay
for
rea
l-tim
ein
vitr
o a
sses
smen
t
Clin
ica
l na
no-t
race
rs a
nd
cont
rast
agen
ts f
or e
sta
blis
hing
dis
ease
st
age,
dru
g P
K/P
D a
nd m
onito
ring
th
era
py”*
*Mih
ail
C. R
oco,
Ba
rba
ra H
art
horn
, Da
vid
Gus
ton,
Phi
lip S
hap
ira
, ”In
nova
tive
and
res
pon
sib
le g
over
nanc
e of
na
note
chno
log
y fo
rso
ciet
al d
evel
opm
ent”
, J N
ano
pa
rt R
es, J
une
20
11
( b
ase
line
da
ta a
nd c
omp
ound
ed a
nnua
l gro
wth
ra
tes
asr
e b
ase
d o
n: N
ano
tech
nolo
gy
in m
edic
al a
pp
lica
tions
: The
glo
ba
l ma
rket
. Wel
lesl
ey, M
ass
.: BC
C. R
epor
t C
ode:
HLC
06
9A
)
His
tori
cal a
nd p
roje
cted
ma
rket
s fo
r na
noth
era
peu
tics
(Tx)
and
na
nod
iag
nost
ics
(Dx)
*
Con
clus
ions
I
Rela
tions
hip
s b
etw
een
pa
rtic
le p
rop
ertie
s a
nd
beh
avi
our
in b
iolo
gic
al m
edia
, cel
l, tis
sue,
cir
cula
tion
are
stil
l not
kno
wn
in d
eta
il.
This
lea
ds
to u
nrea
listic
dem
and
for
det
aile
d
pa
rtic
le c
hara
cter
iza
tion
Mor
e b
asi
c kn
owle
dge
regard
ing
the
se
rela
tions
hip
s a
re k
ey f
or the
dev
elop
men
t of
m
etho
ds
for
toxi
city
ass
essm
ent
Today,
in
vitr
o m
easu
rem
ents
ha
ve s
till t
oo m
uch
un
cert
ain
ty.
9
10
Whi
te P
ap
er to
the
Hor
izon
20
20
Fra
mew
ork
Prog
ram
me
for
Rese
arc
h a
nd In
nova
tion
-Re
com
men
da
tions
fro
m the
Na
nom
edic
ine
Com
mun
ity
Na
note
chno
logy
for
bio
med
ica
l ap
plic
atio
ns
Dia
gn
osis
Thera
py
Su
pe
rpa
ram
ag
ne
tic Iro
n O
xid
e
Qu
an
tum
do
ts
Ve
sic
les
Bio
se
nso
rs (
ca
ntile
ve
r)
GM
R-
effe
cts
Ve
ssic
les
SP
ION
Hyp
ert
he
rmia
Qu
an
tum
do
ts
Th
era
go
stic d
evic
es
Aft
er
Rie
hem
an
n e
t al. A
ng
ew
. C
hem
. In
t. E
d. 2009,
48,
872 –
897
Why
Inor
gani
c N
ano
pa
rtic
les?
Org
an
ic (
po
lym
er, lip
oso
m))
syste
mIn
org
anic
/org
anic
Hybrid s
yste
m
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4N
H2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
Dru
g m
ole
cu
le
Hig
h lo
ad
ca
pa
city
Pro
tecte
d lo
ad
De
gra
da
ble
Soft
, flexib
le
Mu
ltifu
nctio
na
l
No
n tra
cta
ble
Le
ss tra
ce
ab
le
Lo
w lo
ad
ca
pa
city
Le
ss p
rote
cte
d lo
ad
No
n d
eg
rad
ab
le
Rig
id
Mu
ltifu
nctio
na
l
Tra
cta
ble
Tra
ce
ab
le
Energ
y tra
nsfe
r
Nanoparticles13
Na
m e
t a
l. A
dva
nced
Dru
g D
eliv
ery
Revi
ews
65
(2
01
3) 6
22
–64
8
Su
perp
ara
mag
neti
c
Iro
n o
xid
e n
an
op
art
icle
Si
O
O
NH
2
Si
O
Si
OO
H
O
NH
2
NH
2
Si
OS
i
Si
OS
i
OS
iHO
Si
O
Si
OS
i
O
OH
OH
O
NH
2
NH
2
NH
2
NH
OH
O
NH
2
NH
2
NH
2
OH
O
NH
N
N+
O-
O
NH
R
Fe
2O
3
= A
vid
in
= B
iotin
TT
TT
TT
TT
+
+
Iron
def
icie
ncy
ane
mia
Pare
nter
al d
rug
s fo
r th
e tr
eatm
ent
of ir
on d
efic
ienc
y a
naem
ia15
S. F
ütte
rer
et a
l. /
Jour
nal o
f Ph
arm
ace
utic
al a
nd B
iom
edic
al A
naly
sis
86
(2
01
3)
151–1
60
Sup
erp
ara
ma
gne
ticIron
Oxi
de
as
MRI
con
trast
agen
t16
Cor
e a
nd S
urfa
ce p
rop
ertie
s17
Nanoeff
ect
s
Ferr
o-to
sup
erp
ara
ma
gne
tism
Band
ga
b c
hang
e (f
luor
esce
nce)
Surf
ace
pla
smon
Sca
ling e
fffe
cts
Incr
ease
d r
eact
ivity
per
ma
ssSo
lub
ility
Col
loid
al s
tab
ility
Pene
tra
tion
thro
ugh
ba
rrie
rs
19
19
19
Str
uct
ure
of
inorg
anic
nanopart
icle
s
for
medic
al applica
tions
Cor
e is
sup
erp
ara
ma
gne
ticiron
ox
ide
1. S
hell:
sili
ca
2. S
hell:
Pol
ymer
with
fun
ctio
nal
gro
ups
Ant
ibod
ies
for
targ
et c
oup
ling
to
cells
Pep
tides
for
cel
l
up-t
ake
Sta
bili
sier
s
AP
S-S
PIO
Ns
(~25-3
5 n
m;
+ 3
3 m
V)
PE
G
-A
PS
-SP
ION
s1
hr
rec
irc
ula
tio
n
(~7
0 n
m &
-2
0 m
V)
FL
-pro
tein
-PE
G
-A
PS
-SP
ION
s
cyste
ine
-pro
tein
-FL
-PE
G
-A
PS
-SP
ION
s(~
80
nm
& -
13
mV
)
AP
S:
am
ino
pro
pylt
rie
tho
xysil
an
e
Si
O
O
NH
2
Si
O
Si
OO
H
O
NH
2
NH
2
Si
OS
i
Si
OS
i
OS
iHO
Si
O
Si
OS
i
O
OH
OH
O
NH
2
NH
2
NH
2
NH
OH
O
NH
2
NH
2
NH
2
OH
O
NH
N
N+
O-
O
NH
R
Fe
2O
3
= A
vid
in
= B
ioti
n
TT
TT
TT
TT
+
+
20
20
20
Key
: Rep
rod
ucib
le m
anu
fact
urin
g o
f fu
nctio
naliz
ed n
ano
pa
rtic
les
CSE
M R
eact
orin
egra
ted
into
the
EPFL
set
-up
•St
and
ard
op
era
tion
pro
toco
ls f
or s
ynth
esis,
coa
ting,
cha
ract
eriz
atio
n ((EU
, Hor
izon
20
20,
CC
MX))
•Pr
epara
tion
for
GM
P (E
U, H
oriz
on 2
020)
•H
igh
pot
entia
l for
tra
nsfe
r to
ind
ustr
ial
pro
duc
tion
Prot
ein
and
org
ane
lle ta
rget
ing
Hsp
70 1
-9
Hsp
90
Hsp
75
Hsp
60
Annexin
1+
2
Inte
grin
Mala
tedehydro
genase
ATP s
ynth
ase
Tubulin
Gly
coly
sis
enzy
mes
(4)
Tra
nsk
eto
lase
+ R
est
48
ou
t o
f 5
8 p
rote
ins c
ou
ld b
e r
ela
ted
to
: U
p-t
ake
me
chanis
m, t
ransport
to m
itochondria, m
itochondria
me
mb
ran
e, in
clu
din
g e
ne
rgy r
ela
ted
pro
ce
sse
s. E
vid
en
ce
vie
w o
f th
e p
rote
in in
tera
ctio
n n
etw
ork
in
ST
RIN
G
Ex
tra
ce
llu
lar
ma
trix
cyto
pla
sm
cR
GD
dye
3-o
xo
acyl-
thio
lase
pre
se
qu
en
ce
mit
och
on
dri
a
SP
ION
wit
h A
LE
XA
an
d
NT
PQ
PS
PS
PT
GC
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4N
H2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
SD
S-P
AG
E
Pro
tein
id
en
tifi
cati
on
nan
oE
SI-
MS
/MS
Mag
sep
ara
tio
n
an
d c
on
cen
trati
on
Sp
ec.
ad
so
rpti
on
at
cell
su
rfaces
org
an
ell
es,
EC
M p
rote
ins
Part
icle
lib
rary
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4N
H2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4
NH
2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4N
H2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4N
H2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
NH
O
O O
S
CG
VK
RK
KK
P-A
LE
XA
CH
3 75
NH
2
CH
4
NH
2
NH
O
OO
SC
H3
NH
2
OH
O
75
NH
O
O
O
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
OO
SA
LE
XA
-PK
KK
RK
VG
C
CH
3
NH
O
O
O
SCG
VK
RK
KK
P-A
LE
XA
CH
3
75
75
75
NH
O
OO
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2
OH
O
NH
O
O
O
S
CH
3
NH
2O
H
O
75
75
75
NH
2
NH
2
NH
2
Pa
rtic
le d
eri
va
tize
d
wit
h s
pecif
ic a
nti
bo
die
s
Qu
an
tita
tive d
ete
cti
on
Mag
neti
c,
EL
ISA
Researc
h
Dia
gn
osis
Su
perp
ara
mag
neti
c I
ron
Oxid
e P
art
icle
s
Ma
gne
tic Im
pla
nt H
yper
ther
mia
Inje
cta
ble
Nan
op
art
icle
/
Mo
no
mer
so
luti
on
CT
sca
n
3-D
CT
sc
an
Imp
lan
t
Imp
lan
t
Dete
ctio
n o
f SPIO
N u
pta
ke in s
ynoviu
mC
lin
ical
3T M
RI a
t cl
inic
ally
rele
van
t d
ose
24
n=1
3
Day
3D
ay
6
SPIO
N o
n D
AY
5
no S
PIO
N
T1 V
IBE
T2 S
TIR
Left
Con
trol
w
ith S
PIO
ND
ay
3D
ay
6
T1 V
IBE
T2 S
TIR
25
His
tolo
gic
al Evid
ence
of
Speci
fic
Macr
opha
ge S
PIO
N L
oadin
g
Pru
ssia
n blu
e st
ain
ed h
isto
log
ical
sect
ions
sho
win
g A
min
o-P
VA
-SPIO
Ns
in the
syn
oviu
m o
f ra
t A
IA k
nees
mim
icki
ng the
dis
trib
utio
n of
SPIO
Ns
seen
in
MR im
ag
es. A
, B(z
oom
) are
Pru
ssia
n blu
e st
ain
ed s
ections
fro
m
met
hyl m
etha
cryl
ate
(M
MA
)
embed
ded
kne
e jo
ints
.
A
SPIO
N M
RI si
gnal is
speci
fic
and c
orr
esp
onds
toPru
ssia
n b
lue
stain
ing (
iron s
tain
ing u
sed f
or
SPIO
N d
ete
ctio
n)
as
confi
rmed
by h
isto
logy
26
Dou
ble
sta
ined
pa
raff
in s
ectio
ns (A
: Pru
ssia
n b
lue
for
SPIO
Ns
and
B:
imm
une
fluo
resc
ence
usi
ng a
nti-
CD
68
1ry
ant
ibod
y a
nd 2
nd F
ITC
a
ntib
ody
for
ma
crop
hages
) p
erfo
rmed
on
syno
via
l disse
ctio
n a
rthr
itic
knee
join
ts. C
sho
ws
an
over
lay
of the
tw
o im
ages
.
His
tolo
gic
al Evid
ence
of
Speci
fic
Macr
opha
ge S
PIO
N L
oadin
g
Prus
sia
n b
lue
CD
68
fu
sion
SPIO
N
Gd
Imagesonday6.SPIONgivenonday5
Diffuse
ironatday6,complete
outlineatreasonableintensity
onlaterdays
Exp
erim
ent:
evol
utio
n w
ith S
PIO
N;
n=1
3 n
o d
exa
, n=
15
dex
a t
rea
ted
+ 2
2 li
pos
ome
exp
erim
ent
27
VIB
E
SP
ION
VIB
E
SPI
ON
+ G
d
28
Ma
ma
eva
et a
l. A
dva
nced
Dru
g D
eliv
ery
Revi
ews
65
(2
01
3) 6
89–7
02
Na
nop
art
icle
s fo
r m
edic
al a
pp
lica
tions
Imp
orta
nt p
ara
met
ers
Mec
hani
stic
inju
ry p
ath
ways
29
Na
nom
ate
ria
l Tox
icity
Tes
ting
in the
21
st C
entu
ry N
elet
al.
Band
ga
p e
nerg
y of
Oxi
des
30
Zha
ng,†
, et a
l. V
OL.
6 ’
NO
. 5 ’
43
49–4
36
8 ’
20
12
AC
Sano
Influe
nce
of p
H a
nd s
ize
on E
c, E
vle
vel
and
Ba
nd g
ap
12
23
22
2
00
00
00
11
1.8
0.1
24
11
24
(4)
0.5
0.0
59(
)
0.5
0.0
59(
)
bu
lk
gap
gap
eh
eh
Cga
p
Vga
p
ee
EE
erm
mm
mr
mm
mm
EE
PZ
CpH
EE
PZ
CpH
Bru
s, L
. E
. J.
Phys
. C
hem
.1986
,9
0,
25
55
-9.0
-8.0
-7.0
-6.0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0
-1.0
1.0
3.0
5.0
7.0
9.0
11
.01
3.0
15
.0
Band energy (eV)
Pa
rtic
le r
ad
ius
(n
m)
pH
1
pH
4
Ph
7.4
pH
8
pH
1
pH
4
Ph
7.4
pH
8
Ass
essm
ent of
tox
icity
of
oxid
e N
P32
Zha
ng e
t a
l. A
CS
Na
no V
OL.
6 ’
NO
. 5 ’
43
49–4
368
’ 2
01
2
Ost
wald
–Fr
eund
lich
law
J8,3
14
462
1(7
5)
mo
lK
R
3
2
mJ
molK
mol
mJ
Km
TiO
2
m
ola
r m
ass
: 79
.86
g/m
ol; d
ensi
ty: 4
.23
g/c
m3; su
rfa
ce e
nerg
y 0
.1 J
/m2
012345 0.E
+00
1.E
-08
2.E
-08
3.E
-08
4.E
-08
5.E
-08
6.E
-08
C/C*
Part
icle
radiu
s (m
)
Ch
rom
ium
oxid
e
90
nm
Alu
min
a, C
R 1
25
,
15
nm
Solu
bili
ty o
f C
hro
miu
m o
xid
e a
nd a
lum
inum
oxid
e
na
nopart
icle
s in
wate
r and c
ell
media
as function o
f tim
e.
Fo
r d
eta
iled
th
eo
ry s
ee
: D
isso
lutio
n k
ine
tics o
f o
xid
ic n
an
op
art
icle
s: T
he
ob
se
rva
tio
n o
f a
n u
nu
su
al b
eh
avio
ur
Wo
lfra
m V
og
els
be
rge
r ,
Jochen
Schm
idt,
Fra
nk R
oelo
fs, C
ollo
ids a
nd S
urf
aces A
: P
hysic
ochem
. E
ng.
Aspects
324 (
2008)
51–
57
Na
nop
art
icle
Sys
tem
Para
met
ers
35
36
020
40
60
80
100
120
0
50
100
150
200
250
300
number weighted mean
size [nm]
tim
e [m
in]
PE
I-S
PIO
N R
=2 R
PM
I
PE
I-S
PIO
N R
=2 R
PM
I +
FC
S
PE
I-S
PIO
N R
=2 D
ME
M
PE
I-S
PIO
N R
=2 D
ME
M +
FC
S
* fo
r lo
nger
tim
es s
izes n
ot dete
rmin
able
* *
020
40
60
80
100
120
0
40
80
120
PV
A-S
PIO
N R
PM
I
PV
A-S
PIO
N R
PM
I +
FC
S
PV
A-S
PIO
N D
ME
M
PV
A-S
PIO
N D
ME
M +
FC
S
number weighted mean
size [nm]tim
e [
min
]
wate
r
Part
icle
s in
bio
log
ica
l med
ia
Co
lloid
al sta
bili
ty =
f(c
oati
ng
an
d o
f p
rote
in a
dso
rptio
n)
Applic
ation o
f D
LV
O theory
is
not possib
le
PE
I-S
PIO
Ns
-25
-20
-15
-10-505
10
15
20
25
02
46
810
12
14
Interaction potential (kBT)
Part
icle
Dis
tance
(nm
)
Infl
uence
of
Siz
eTiO
2, Z
eta
Pote
ntial: 3
0 m
V
150
100 n
m
50 n
m
10 n
m
Dos
imet
ry
Teeg
uard
en
http
://w
ww
.pnl
.gov
/sci
ence
/hig
hlig
hts/
hig
hlig
ht.a
sp?i
d=
1
Stok
e
Stok
e-Ei
nste
in
Lam
ina
r co
nvec
tion-
diffu
sion
Eq
uatio
n
Ma
son
and
Wea
ver
Infl
uenc
e of
pa
rtic
le tra
nsp
ort ra
te o
n ce
llula
r d
ose
in v
itro
Teeg
uard
en, T
OX
ICO
LOG
ICA
L SC
IEN
CES
95
(2),
30
0–3
12 (2
00
7)
NP
(SPI
ON
) tr
ans
por
t in
cel
l med
ia +
/-se
rum
41
0
0.0
5
0.1
0.1
5
0.2
00
.05
0.1
0.1
50.2
measured amount of particles (g/m2)
calc
ula
ted a
mount of
SPIO
N (
g/m
2)
•ci
rcle
s : c
ell m
edia
with
out
seru
m,
•sq
uare
s ce
ll m
edia
with
se
rum
; •
fille
d s
ymb
ol: 1
h in
cub
atio
n tim
e,
•em
pty
sym
bol
3 h
incu
ba
tion
time.
Prot
ein
–Na
nop
art
icle
inte
ract
ion
42
Nanodia
ra,
EP
FL,
Thesis
Sakulk
hu
Usaw
adee, E
PF
L-L
TP
44
.
HeLa
cells
in c
onta
ct w
ith c
oate
d S
PIO
N
un
co
ate
dS
PIO
Ns
(a)
n
eg
ati
ve (
b)
neu
tral
(c.)
po
sit
ive
(d)
In v
ivo
-in
vitr
o co
mp
ariso
n45
mole
cula
r w
eig
hts
Relative amount %PV
A c
oate
d S
PIO
N, p
ositi
ve c
harg
e
Usa
wadee S
akulk
hu, Li
onel M
auri
zi, M
ort
eza
Mahm
oudi, A
zza
Gra
mun, M
ari
e-G
abri
elle
Olliv
ier
Beuzelin, Je
an-P
aul V
allée, F
arh
ad
Rezaee, H
ein
rich
Hofm
ann, N
atu
re N
anote
ch.
Subm
itte
d S
ept 2013
L. M
aur
izi,
EPF
L, 2
013
47
Con
clus
ions
: Pro
s a
nd C
ons
MRI
ap
plic
atio
n fo
r liv
er d
iag
nost
ic
is F
DA
ap
pro
ved
and
in c
linic
al u
seA
pp
lica
tions
in im
ag
ing, d
rug
d
eliv
ery,
hyp
erth
erm
ia a
re in
pre
-cl
inic
al a
nd c
linic
al t
ests
Bioc
ompatib
ility
appro
ved
Mul
tifun
ctio
nal p
art
icle
s allo
win
g
act
ive
dia
gno
sis
and
the
rap
eutic
a
pp
lica
tions
For
cont
rast
agen
t th
e m
etho
ds
for
synt
hesi
s, s
urfa
ce m
odif
ica
tion
esta
blis
hed
in in
dus
tria
l sca
le
Fea
sib
ility
for
mol
ecul
ar
ima
gin
g,
cell
and
org
ane
lle ta
rget
ing
is
show
n
Beha
viou
r of
pa
rtic
les
in the
d
iffe
rent
org
ans
not
kno
wn
in
det
ail;
ta
rget
ing
eff
icie
ncy
<1
00
%M
anu
fact
urin
g o
f co
mp
lex
pa
rtic
les
still
at la
b/p
ilot p
lant
le
vel
Part
icle
-pro
tein
inte
ract
ion
still
un
der
inve
stig
atio
n
Com
bin
atio
n of
dia
gno
sis
and
th
era
py u
sefu
l?A
ccep
tanc
e of
na
note
chno
logy
ba
sed
tre
atm
ents
by
pa
tient
s?
Ad
ded
va
lue?
Ris
k-Be
nefi
t b
ala
nce
not ye
t es
tab
lishe
d.
Econ
omic
s, m
ark
et, h
ealth
a
ssur
anc
es?
48
48
A.
Petr
i-Fi
nk
EPFL
, now
Uni
Frib
ourg
J. S
ala
kla
ngEP
FL n
ow
SCK
•CEN
G. B
euze
linEP
FLU
. Salk
huku
EPFL
V. B
erna
uL.
Ma
uriz
iEP
FLA
. Fin
kaEP
FLC
. P. O
'Nei
lEP
FLM
. Mon
iatte
EPFL
L. J
uille
rat
Uni
vers
ity o
f La
usa
nne
X. M
onte
tU
nive
rsity
Hos
pita
l Gen
eva
S. K
am
au
Uni
vers
ity o
f Zu
rich
B. V
on R
eche
nber
gU
nive
rsity
of
Zuri
chM
. Hof
ma
nnM
atS
earc
hC
onsu
lting
G. A
nder
sen
Ant
ia-T
hea
peu
tics
Ack
now
led
gem
ent
SN
F
SN
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