what can nanotechnology do to fight cancer
TRANSCRIPT
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 1/8
E D U C A T I O N A L S E RI ES B ed se1 es*
W h a t c a n n a n o t e c h n o l o g y d o to f ig ht c an c er ?Oscar Ga l l ego a and Vic tor Pun tes b
aDepartament d'O:neologia. Hospital de Sant Pau. Barcelona. Spain.blnstitut Catali~ d'Estud is i tlecerea Avan~at and Institut Catalfi de Nanotecnologia. Bellaten-a, Barcelona. Spain.
The marr iage of physics, chemist ry an d biology at
the namome t t~c scale , nano technol ogy, i s a power-
ful technology which is predicted to have a large
impacto on l i Ib sciences and par t icular ly cancer
t reatment . In the fol lowing we wi l l show some ex-amples of appl icat ions which h a s al ready reached
cl inical t reatme nts as new ideas which m ay posi -
l ively inf luence the understanding, d iagnosis and
therapy of cancer .
Key words: nanoparticles, drug delivel~~, photo-abla-
tion, in vivo imaging.
Gallego O, Puntes I~ fkhat can nanot eehnology do to f@h tcancer? Clin 7)'ansl Oncol. 2~6;8(11): 788-95.
I N T R O D U C T I O N
There is an accepted ge nera l idea of lack of break-
throughs in elinical treat ment of Cancer. An exami-
nation of the a nnu al statist ical data compiled by the
American Cancer Society quickly reveals that the rate
of mortali ty f l 'om cancer has changed very l i tt le over
the past 50 years. Yet despite progress in understand-
ing cancer, it s diagnosis anti treatment have re-
maine d essentially unch ange d for decades, and death
rates f 'rom the disease are about what they were in
1950 I. In part, it is beca use targeted can cer therapies,
cancer biomarkers, and genomic medicine are st i l l inthe transi tion from basic resea rch to etinical reality.
In addition, although cancer is o[ten portrayed as a
monolithic i l lness, i t is anything but complex. There
are more than 200 types of cancers, each with ma ny
variant s and in every case, diagnosis, treatm ent an d
monito ring is some how diiferent. A report on the state
*Supported by an unrestricted educational grant ['rom
A straZene ca.
C o r r e s p o r i d e l n e : V . P t H l t es .
lnstitut Gatal~ld'Estudis i Recerca Awm~ata n d I n s t i t u t C a t a l f i d e N a n o t e c n o l o g i a .
0 8 1 9 5 B e l l a t e r r a , B a r c e l o n a . S p a i n .] ~ - m a i l : v i e t o r .p t m t e s @ i e r e a . e s
of the art on c anc er re searc h can be fimnd in the 26 m of
May 2006 Science issue: Frontiers in Canc er Research 2.
Besides, nowadays, nanotec hnology' s abil i ty to shape
matter on the scale of molecules is openin g the door
to a new generation of diagnostics, imaging agents,and drugs for detecting and treating cancer at its ear-
liest stages. But perhaps more important, as we will
show, i t is enabli ng researchers to combine a series
of advances, creating thus nanosized particles (fig. 1)
that may contain drugs designed to kil l tmnours to-
gether with targeting compounds designed to home-
in on maligna ncies, and imagin g agents designed to
light up even the earliest stage cancers. In fact, a de-
scription of cancer in mo leeular terms s eem s increas-
ingly likely to improve 1/he ways in whi ch hu ma n
cancers are detected, classified, monitored, and (espe-
cially) treated, and na noparticles, which are small
and therefore allows to address single molecules in
an uni que ma nn er (fig, 2) may be specially uset 'ul ibr
Fig. 1. Nanoscale objects, often have unique biological,
chemical, optical, electronic, magnetic or mechanical proper-
ties when compared to bulk material. These properties can
be employed to improve diagnosis and therapy, specially incancer treatment. In this image we show a 2D self assembly
of 9 nm diameter monodisperse Cobalt nanoparticles. The
unique chemical and physical properties of nanoparticles
can be tailored to give smart biomaterials with great poten-
tial for targeting, imaging, and treating cancer i n v i v o .
788 C Ibz Transl Onc oL 2006;8(11):788-95
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 2/8
GALLEGO O, PUNTES V. WHAT CAN NA NOTECHN OLOGY DO TO FIGHT CANCER?
Fig. 2. ( L e f t ) 40.000 bases DNA chains dispersed onto a Mica substrate image obtained with a atomic force microscopy
an d ( R i g h t ) T r a n s m i s s i o n Electron Microscopy of 14 nm cobalt ferromagnetic nanoparticles, here, the intrinsic magnet-
ic moment of the particles force the to make such nose-to-tail (north-to-south) arrangements. Both images are taken at
the same magnifications, the striking structural similarity suggest the potentiality for hibridation of biological macro-
molecules and inorganic nanoparticles.
t h e s e t a s k s . , ,T h e f u tu r e o f o n c o l o g y - a n d t h e o p p o r t u -
n i t y t o e l i m i n a t e t h e s u f f e r i n g a n d d e a t h d u e t o c a n -
c e r - w i l l h i n g e o n o u r a b i l i t y t o c o n f r o n t c a n c e r a t i ts
m o l e c u l a r le v e l~ , s a y s A n d r e w y o n E s c h e n b a c h , f o r-
m e r d i r e c t o r o f t h e U .S . N a t i o n a l C a n c e r I n s t i t u te
( N C I) in B e t h e s d a , M a r y l a n d . I n 2 0 0 4 , t h e n a t i o n a l
c a n c e r i n s t i t u t e N C I l a u n c h e d a $ 14 4 m i l l i o n c a n c e r
n a n o t e c h n o l o g T i n i t i a t iv e 5. A s t h e f o u n d a t i o n o f t h i s
e f fo r t , l a s t m o n t h N C I a n n o u n c e d $ 2 6 .5 m i l l i o n fo r
t h e f i r st y e a r o f f u n d i n g f o r s e v e n c e n t e r s o f c a n c e r
n a n o t e c h n o l o g y e x c e l l e n c e d e s i g n e d t o f i~ st er i n t e r -
d i s c i p l i n a ry w o r k a m o n g c h e m i s t s, m a t e r i a l s s c i e n -
t i st s , a n d b i o l o g i st s . E u r o p e a n d J a p a n a r e a l s o i n -
v e s t i n g h e a v i l y i n n a n o a p p r o a c h e s t o f ig t h c a n c e r ,
a l t h o u g h n a n o t e c h n o l o g y t h n d i n g a g e n c i e s h e r e d o n 't
b r e a k o u t s p e c i fi c p r o g r a m s f o r c a n c e r . I n th c t, m o -
l e c u l a r n a n o t e c h n o l o g y w i l l i m p a c t m a n y f ie l ds * , a l -
t h o u g h t h e d e v e l o p m e n t o f t h e s e t e c h n i q u e s i s s t il l i n
i ts in f a n c y . C u r r e n t l y , m o r e t h a n a h a l f - d o z e n n a n o -p a r t i c l e - b a s e d i m a g i n g a g e n t s a n d t h e r a p e u t i c s a r e
e i t h e r o n t h e m a r k e t , i n c l i n i c a l t r i al s , o r a w a i t i n g
c l i n i c a l t r i a l s 5. S i m i l a r l y , th e u s e o f s u p e r p a r a m a g -
n e ti c n a n o p a r t i c l e s f o r p h o t o - a b la t i o n ( h y p e r t h e m l i a )
o f b r a i n t u m o u r s i s a p p l i e d a s c o m p a s s i v e t h e r a p y i n
a G e r m a n U n i v e r s i t y H o s p i t a l .
C U R R E N T A P P L I C A T I O N S
O F N A N O T E C H N O I ~ O G Y O N C A N C E R
D I A G N O S I S A N D T R E A T M E N T
C h e m o t h e r a p y , r a d i a ti o n , a nd s u r g e r y - t h e b i g t h r e e
o f t r e a t m e n t s - a l l w r e a k h a v o c o n h e a l t h y c e ll s a n d
t i s s u e s a s w e l l a s c a n c e r o u s o n e s . T h e r e f o r e t e c h -
n o l o g i e s t o t a r g e t t h e d r u g d e l i v e r y , a s s i s t s u r g e r y
- v i a i m a g i n g - o r fa c il i ta t e r e m o t e t u m o u r a b l a ti o n ,
a r e b e i n g e x p l o r e d w i t h t h e u s e o f n a n o t e c h n o l o g y .
N a n o t e c h n o l o g y , a n d m a i n l y n a n o p a r t i c l e s , c a n b e
u s e d a s : a) u l t r a s e n s i t i v e a n d ~ l s t d i a g n o s i s t o o l s , b)
a d v a n c e d i m a g i n g a g e n t s , c) t a r g e t e d a n d i m p r o v e d
d r u g d e l i v e r y s y s t e m s a n d d) h y p e r t e r m i a a g e n t s . I n
t h e t b l lo w i n g w e w i l l s h o w s o m e e x a m p l e s o f p r o -
p o s e d n a n o t e c h n o l o g y s o l u t i o n s i n th e m e n t i o n e d
c a s e s. T h e e x a m p l e s a r e b y fa r e x h a u s t i v e o r c o m p r e -
h e n s i v e , h o w e v e r w e h o p e t h a t t h e y i l l u s t ra t e p r o p e r -
l y t h e w i d e r a n g e o f p o t e n t i a l i t i e s t b r c a n c e r t r e a t -
m e n t b r o u g h t b y n a n o t e c h n o lo g i e s .
D i a g n o s i s
I s w e l l k n o w n t h a t e a r l i e r d e t e c t i o n o f d i s e a s e f h c i li -
t a t e s a n d e n a b l e s c u r e . In 2 0 00 C h e m l a a n d c o pl e a g u e s p r o p o s e d t o u s e t h e m a g n e t i c r e l a x a t i o n o f
m a g n e t i c n a n o p a r t i c l e s a t t a c h e d o r n o t t o a t a r g e t t o
d e v i s e a t h st a n d v e r y se n s i t i v e i m m u n o a s s a y w h e r e ,
i n a d d i t i o n , n o p u r i f i c a t i o n s t e p s w h e r e n e e d e d 6. I n
s u c h s e t - u p , t h e d e t e c t i o n t h r e s h o l d w a s a b o u t 5 0 0
t a r g e t s a n d i t c o u ld b e i m p r o v e d t o p u s h i t f u r t h e r
d o w n t o 50 t a r g e t s . M o r e r e c e n t l y , t h e a b i l i t i e s f o r m i -
n a t u r i z a t i o n l e a r n e d f r o m m i c t r o e l e c t r o n i c s , a n d
p u s h e d f u r t h e r b y n a n o t e c h n o l o g % a n d t h e f in e c o n -
t r o l o f t h e i n t e r a c t i o n o f m o l e c u l e s w i t h e l e c t r o d e s ,
a l l o w e d b o t h , s i m u l k a n e o u s a n d u l t r a - s e n s i t i v e d e t e c -
t i o n o f m o l e c u l e s ( s p e c if i c p r o t e i n s , a n t i b o d i e s , e n -
z y m e s . . . ) . T h u s , i n t h e O c t o b e r 2 0 0 5 i s s u e o f Nature
Cthz Transl Oncol. 2006;8(l l):788-95 789
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 3/8
G A L L E G O O , P UNT E S V. W HA T CA N N A NO T E CHNO L O G Y DO T O F I G HT G A NG ER?
B i o t e c h n o l o g y , r e s e a r c h e r s l e d by C h a r l e s L i e b e r o f
H a r v a r d U n i v e r s i t y d e s c r i b e d t h e u s e o f a r r a y s o f s i li -
c o n - b a s e d n a n o w i r e d e v i c e s t o e l e c t r i c a l l y d e t e c t
m i n u t e l e v e ls o f m a r k e r p r o t e i n s o v e r - e x p r e s s e d i n
c a n c e r c e i l s p r e s e n t i n b l o o d s e r u m 7. T h e s e n s o r s
w e r e n a n o w i r e - b a s e d f i e ld e f l' ec t t r a n s i s t o r s s : i m i ]a r
t o t h o s e i n c o m p u t e r c h i p s . T h e y c h a r g e d t h e si l i c o n
n a n o w i r e s w i th . m o n o c l o n a l a n t i b o d i e s s p e c i f ic f o r
t h e c a n c e r p r o t e i n s . W h e n t h e p r o t e i n s l i n k e d u P
w i t h t h e a n t i b o d i e s , th e e l e c t r i c a l c h a r g e s o f t h e p r o -
t e i n s c h a n g e d t h e c o n d u c t a n c e o f t h e s i ~ c o n n a n o -
w i r e s . T h e se d e v i c e s d e t ec t e d m e r e f e m t o m o l a r c o n -
c e n t r a t i o n s o f t h e t a r g e t p r o t e i n s w i t h o u t t h e
f l u o r e s c e n t l a b e l s o r c o m p l i c a t e d D N A - a m p l i f i c a t i o n
p r o c e d u r e s m o s t o f te n u s e d t o d e t e c t m i n u t e c o n c e n -
t r a t i o n s o f b i o l o g ic a l c o m p o u n d s . F u r t h e r m o r e , t h e
n o v e l a r r a y s c o n t a i n e d 2 00 t r a n s i s t o r s t h a t c o u l d b e
a d d r e s s e d i n d i v i d u a ll y , p o t e n ti a l l y o p e n i n g t h e d o o r
t o n m l t i p l e s i m u l t a n e o u s d e t e c t i o n b y t e s t i n g a s i n g l ed r o p o f b l o o d.
A n o t h e r b o l d e x a m p l e o f t h e u s e o f n a n o t e c h n o l o g y
% r c a n c e r d i a g n o s i s a r e m e t a s t a t i c p o t e n t i a l s t u d i e s
b a s e d o n c e ll m o t i l i t y a n d s e m i c o n d u c t o r n a n o p a r t i -
d e s v i a i m a g i n g o f p h a g o k i n e t i c t r a c k s 8. M o t i l i t y a n d
m i g r a t i o n o f c a n c e r o u s c e ll s a r e e x t r e m e l y d e t r i m e n -
t a l p r o p e r t i e s t h a t l e a d t o m e t a s t a s e s a n d % r m a t i o n o f
s e c o n d a r y t u i n o u r s . M i g r a t io n o f c e l ls a n d t h e i r
m e t a s t a t i c p o t e n t i a l a r e w e l l k n o w n t o be c o r r e l a t e d ,
s o t h a t m e t a s t a t i c p o t e n t i a l c o u l d b e r a p i d l y a s s a y e d
b y s i m p l y m e a s u r i n g m o b i l it y . P r e s e n t m e t h o d s % r
o b s e r v i n g c e ll m o t i l i t y su f l' er f r o m a n u m b e r , o f p r a c -
t i c a l l i m i t a t i o n s . T w e n t y - f i v e y e a r s a g o , A l b r e c h t
B u e h l e r p r o p o s e d a m e t h o d % r s tu d y in g " c e l l m o t i l i t y
b a s e d u p o n o b s e r v a t i o n o f , < p h a g o k i n e t i c t r a c k s, , 9. I n
t h e m o s t g e n e r a l w a y , w e c a n s a y t h at a p h a g o k i n e t i c
t r a c k i s g e n e r a t e d w h e n a c e ll p a s s e s o v e r a l a y e r o f
, ,m a r k e r s, ,, a n d i n g e s t s t h e m , l e a v i n g b e h i n d a b l a n k
s p o t e q u a l t o t h e a r e a t h e c e l l h a s t r a v e r s e d . I n th a t
c a s e g o l d m i c r o p a r t i c l e s w e r e u s e d . I n p r i n c i p l e t h e
m e t h o d i s v e r y p o w e r f u l , a s it p r o v i d e s a r a p i d a n d
a u t o m a t i c m e t h o d fiqr i n t e g r a t i n g c e ll m o t i l i t y w h i l e
p r e s e r v i n g t h e h i s t o r y o f i n d i v i d u a l p a t h s . U n t i l n o w ,
t h e m e t h o d h a s o n l y b e e n u s e d i n a l i m i t e d w a y d u e
t o p r o b l e m s w i t h t h e av a i l a b l e m a r k e r s . L m n i n i s c e n -c e c o u l d n o t b e u s e d fi~ r p h a g o k i n e t i c t r a c k i n g , b e -
c a u s e o r g a n i c d y e s b l e a c h t o o q u i c k l y . I n s t e a d , t i le
o n l y m a r k e r t h a t h a s b e e n u s e d : is s u b - m i c r o m e t e r
;ku p a r t i c l e s , w h i c h c a n b e i m a g e d o p t i c a l l y :in t r a n s -
m i s s i o n , a n d t h e s e i m p o s e m a n y l i m i t a ti o n s , s o th a t
t h e t e c h n i q u e h a s n o t r e c e i v e d w i d e s p r e a d a c c e p t -
a n c e s i n c e t h e A u p a r t i c l e s m u s t b e l a r g e ( 0 .1 5 p r o ) i n
o r d e r t o b e o b s e r v a b l e o p t i c a l ly . S u c h l a r g e p a r t i c l e s
d o n o t s t i ck w e l l t o t h e s u b s t r a t e , a n d t h e r e f o r e h a v e
t o b e g r o w n d i r e c t l y o n to t h e s u b s t r a t e i n a p r o c e s s
t h a t y i el d s h i g h l y i n h o m o g e n e o u s p a r t i c l e d i s t r i b u -
t i o ns . S i n c e t h e p a r t i c l e s a r e g r o w n d i r e c t l y o n t h e
s u b s t r a t e s b y p o u r i n g a h o t ( n e a r b o i l i n g ) g o l d a q u e -
o u s s o l u t i o n , t h e r a n g e o f u s a b l e s u b s t r a t e s i s l i m i t e d .
F u r t h e r , d u e t o t h e l a r g e s i z e o f t h e A u m i c r o c r y s t a l s ,
w h e n a c el l m o v e s o n e d i a m e t e r , :it i n g e s t a v o l u m e o f
A u c o r r e s p o n d i n g t o 1% o f t h e t o t a l c e l l v o l u m e , a n d
t h e r e i s a s t r o n g p o s s i b i l i t y t h a t t h i s p e r t u r b s t h e c e l l
m o t i l i ty . T h i s i s p a r t i c u l a r l y t r u e f o r s m a l l s c e l l s,
s u c h a s e p i t h e l i a l ce l l s , w h i c h a r e o f p a r t i c u l a r i m -
p o r t a n c e i n s t u d i e s o f m e t a s t a s i s , a n d i n n e u r o n s . I n
a d d i t i o n t h e f ih n h o m o g e n e i t y i s p o o r , a n d t h e i n t e r -
p a r t i c l e d i s t a n c e i s l a r g e , l i m i t i n g t h e r e s o l u t i o n . I n
r e g 8, a u t h o r s d e m o n s t r a t e t h e fi r st u s e o f n a n o m e t e r -
s iz e co l l o id a l q u a n t u m d o t s ( s e m i c o n d u c t o r n a n o p a r -
t i t l e s) a s m a r k e r s f o r p h a g o M n e t i c t r a c k s . T h e p r e -
l i m i n a r y w o r k s h o w s t h a t th e u s e o f s e m i c o n d u c t o r
n a n o p a r l i c ] e s h a s t h e p o t e n t i a l t o c i r c u m v e n t a l l t h e
l i m i t a t io n s m e n t i o n e d a b o v e.
A d v a n c e d i m a g i n g
N a n o p a r t i c l e s c a n b e d e s i g n e d t o h a v e o u t s t a n d i n g
i m a g i n g p r o p e r t i e s , ti r os t h e y c a n b e p h o t o e m i t e r s
( s e m i c o n d u c t o r ) , h a v e h i g h e l e c t r o n d e n s i t y to be d e -
t e c t e d i n 6 p i c a l o r e l e c t r o n m i c r o s c o p e s ( m e t a l s ) o r
b e m a g n e t i c c o n t r a s t a g e n t s ( m e t a l l ic o r m a g n e t i c o x -
i d e n a n o p a r t i c l e s ) . T a r g e t i n g t h e b i n d i n g o f a n y
n a n o p a r t i c l e s t o s p e c if i c t i s s u e s c a n i m p r o v e t h e d i s -
c e r n i b l e s i g n a l t o d e t e c t a n d l o c a t e t u m o r s . F o r e x a m -
p i e , m a g n e t i c r e s o n a n c e i m a g i n g ( M R I ) o f c o a t e d s u -
p e r p a r a m a g n e t i c n a n o p a r t i c l e s h a s b e e n s h o w n i n
v i v o f o r f u n c t i o n al i m a g i n g e n h a n c e m e n t a n d f or th e
i m a g i n g o f g e n e e x p r e s s i o n . S i m i l a r l y H I V - I t a t p e p -
t i de c o n j u g a t e d t o s u p e r p a r a m a g n e t i c n a n o p a r t i c l e s
c a n b e i n t e r n a l i z e d b y s p e c i f i c t i s s u e t y p e s a n d p o t e n -
t i a ll y u s e d t b r i n v i v o g e n e - e x p r e s s i o n a n a l ys i s .
X i a o h u G a o a n d c o l l e a g u e s u s e d s e m i c o n d u c t o r
q u a n t u m d o t s (Q D s ) to ta r g e t a n d i m a g e t u m o u r s i n
m i c e l ~
T h e Q D s a r e e n c a p s u l a t e d b y a p r o t e c t i v e c o a t c o n -
s i s t i n g o f a c o o r d i n a t i n g l i g a n d a n d a n a m p h i p h i l i c
p o l y m e r to p r e v e n t p a rt i c l e d e g r a d a t i o n u n d e r c o m -
p l e x i n v iv o c o n d i t i o n s . T u m o u r - t a r g e t i n g a n t i b o d i e s
a n d p o l y ( e t h y l e n e g l y c o l ) ( P E G ) m o l e c u l e s a r e t h e n
a t t a c h e d t o g i v e a n m l t i f u n c t i o n a l n a n o p a r t i c l e p r o b e .
Q D p r o b e s c a r r y i n g a n a n t i b o d y f or a h u m a n p r o s t a tec a n c e r m a r k e r w e r e i n j e c t e d in t o m i c e b e a r i n g t h e s e
t u m o r s . W a v e l e n g t h - r e s o l v e d s p e c t r a l i m a g i n g a l l o w s
t h e o r a n g e - r e d Q D f l u o r e s c e n c e t o b e d e t e c t e d o v e r
t h e g r e e n a u t o f l u o r e s c e n c e o f m o u s e s k in . T h e i m a g -
i n g r e v e a l s t h a t Q D s a r e s u c c e s s f u l l y d e h v e r e d t o t h e
t u m o r s b y , t h e r e s e a r c h e r s s u g g e s t , t w o d i f f e r e n t t a r -
g e t in g m e c h a n i s m s . T h e a n t i b o d y - c o n j u g a t e d Q D s
, ,a c ti v el y ~ r e c o g n i z e t h e t u m o r c e l l s, b u t t h e n a n o p a >
t i d e s p a s s i v e l y a c c u m u l a t e i n t u m o r s a s w e ll b e c a u s e
t h e b l o o d v e s se l s a r e m o r e d e a k y , t h a n i n o r d i n a r y
t i ss u e s d u e to th e r a p i d g r o w o f t u m o u r s (v ide i roera) .
I n o th e r e x a m p l e , N a n o s i z ed o n i o n - l i k e s t r u c tu r e s
c o m p o s e d o f a n i n n e r c a d m i u m - t e l l u r i u m c o r e s ur -
' i '9 0 Clin Transl OncoL 2006; 8(11): 788-95
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 4/8
GALLEGO O, PUNTES V. WHAT CAN NA NOTECHNO LOGY DO TO FIGHT CANCER?
r o u n d e d b y a c a d n l i u m - s e l e n i u m l a y e r a n d t h e n c a p -
p e d w i th a n o r g a n i c c o m p o u n d m a k e t h e s e n a n o p a r ti -
c l es w a t e r - s o l u b l e a n d b i o e o m p a t i b l e . T h e s e p a r t i c l e s
a r e s t r o n g a b s o r b e r s a n d e m i t t e r s o f i n f i 'a r e d l ig h t.
W h e n t h e r e s e a r c h e r s i n j e c t e d a n i m a l s w i t h t i n y
a m o u n t s o f t h e s e q u a n t u m d o t s, l y m p h a t i c c e l ls
q u i c k l y c l e a r e d t h e d o t s a n d r o u t e d t h e m t o t h e
l y m p h n o d e s I I . T h e n , t h e y c o u l d l i gh t u p t h e l y m p h
n o d e s e v e n t h r o u g h e e n t i m e t r e s o f s k i n s i m p l y b y
s h i n i n g n e a r - i n f l ' a r e d l i g h t f l 'o m a h a l o g e n l a m p . O f f
c o u r s e , th e n o t i o n of u s i n g c a d m i u m b a s e d q u a n t u m
d o t s i n l a u m a n s h a s l o n g b e i n g c o n t r o v e r s i a l , b e c a u s e
t h e h e a v y m e t a l i s t o x ic . T h e r e f o r e a s a n a l t e r n a t i v e ,
t h e s a m e r e s e a r c h e r s r e p o r t e d c r e a t i n g i n d i u m - b a s e d
s e m i c o n d u c t i n g d o t s t h a t a l s o w o r k e d f o r m a p p i n g
s e n t i n e l l y m p h n o d e s . T h e s e d o t s c o n t a i n e d a r s e n i c ,
a n o t h e r t o x in , b u t th e a u t h o r s s a y t h e c lo s e r e q u i r e d
t o l i gh t u p l y m p h n o d e s m a y b e s m a l l e n o u g h t o k e e p
t h e t o x i c i b ' l o w . I n a n y c a s e , i n f i ' a r e d l i g h t - e m i t t i n gn a n o p a r t i c l e s a r e l i k e l y t o p r o v e m o s t u s e f i f l i n s p o t-
t i n g t u m o r s n e a r t h e s k i n s u r f a c e . F o r t i s s u e s d e e p
w i t h i n t h e b o d y , m a n y g r o u p s a r e t u r n i n g t o m a g n e t -
i c n a n o p a r t i c l e s t h a t c a n b e u s e d a s c o n t r a s t a g e n t s
f o r m a g n e t i c r e s o n a n c e i m a g i n g ( M B . I ) m a c h i n e s . F o r
e x a m p l e , C a r o l a L e u s c h n e r 12, a b i o c h e m i s t a t t h e
P e n n i n g t o n B i o m e d i c a l R e s e a r c h C e n t e r i n B a t o n
R o u g e , L o u i s i a n a , h a s d e v e l o p e d i r o n o x i d e n a n o p a r -
t ic l e s c a p a b l e o f r e v e a l i n g th e p r e s e n c e o f b re a s t c a n -
c e r c e l l s i n m i c e . L e u s c h n e r ' s t e a m t a r g e t e d t h e i r i r o n
o x i d e p a r t i c l e s t o t u m o r c e l l s b y c o v a l e n t l y l i n k i n g
t h e m t o c o p i e s o f a s h o r t p e p t i d e c a l l e d L H R H , w h i c h
s e e k s o u t a n d b i n d s t o r e c e p t o r s o v e r e x p r e s s e d o n a
w i d e v a r i e t y o f t u r n o u t c e l ls .
S i m i l a r l y , t h e o p t i c a l p r o p e r t i e s o f n a n o p a r t i c l e s a n d
t h e i r m o d i f i c a t i o n , c a n b e u s e d t o s e n s i t i v e b i o c h e m i -
c a l a n a l y s i s e x - s i t u . T h u s , G o l d n a n o p a r t i c l e s c a n b e
u s e d e f f i c i e n t l y a s q u e n c h e r s t h a t h a v e g r e a t e r e f fi -
c i e n c y t h a n c o n v e n t i o n a l q u e n c h e r g r o u p s ( a q u e n -
c h e r s u p p r e s s e s f l u o r e s c e n t e m i s s i o n f l ' om a n e a r b y
f l u o r o p h o r e b y a b s o r b i n g o r d i s s i p a t i n g e n e r g y ; a
p r o p e r t y t h a t c a n b e e x p l o i t e d t o m e a s u r e i n t e r a c -
t i o n s a t d i s t a n c e s i n t h e o r d e r o f 5 n m ) . F o r e x a m p l e ,
i t u s e d i n D N A - b a s e d m o l e c u l a r b e a c o n s d e v e l o p e d
t o f l u o r e s c e o n b i n d i n g t o a c o m p l e m e n t a r y R N A s e -q u e n c e . S i m i l a r l y, t h e s p a c i n g - d e p e n d e n t w a v e l e n g t h
s h i ft o f D N A c o n j u g a t e d g o l d n a n o p a r t i c l e s c o u l d b e
e x p l o i t e d t o e v a l u a t e b i n d i n g a n d s i n g l e m i s m a t c h
de t e c t i on 15.
D r u g d e l i v e r y
O f c o u r s e , f i n d i n g c a n c e r c e l l s is o n l y t h e f i r s t s t e p .
N a n o t e c h n o l o g i s t s a r e a l s o d e v e l o p i n g a n u m b e r o f
p a r t i c l e s d e s i g n e d t o w i p e o u t t u m o r s a s w e l l .
T a r g e t e d u p t a k e o f t h e r a p e u t i c n a n o p a r t i c l e s i n a
c e ll -, t i s su e - , o r d i s e a s e - s p e c if i c m a n n e r r e p r e s e n t s a
p o t e n t i a l ly p o w e r f u l t e c h n o l o g y . T h e r e a r e t w o t y p e s
ANCER CE
Fig. 3. There are conceptu ally two different types of nano-
parUcels: a) Hollow organic nanoparticles which are de-
signed for carrying drugs efficiently, and b) inorganic core
nanoparticles which are able to be remotedly activated to
deliver toxic amounts of heat and display outstanding
marking properties what allows tumor imaging in addition
to be able to carry drugs attached to its surface and there-
fore modify the biodistribuUon of the drug.
of nan opa r t i c l es fo r t h i s app roa ch ( fi g . 3 ) , e i t he r 11ol-l o w o r g a n i c n a n o p a r t i c l e s w h i c h c a r r y t h e d r u g i n i t -
s e lf , o r s o l id i n o r g a n i c n a n o p a r t i c l e s w h i c h h a v e t i l e
d r u g b o n d t o it s s u r f a c e t o g e t h e r w i t h t a r g e t i n g
a g e n t s . M a n y u s e t a r g e t i n g a g e n t s s u c h a s L H R H t o
d i r e c t to x i c c o m p o u n d s t o t u m o r c e l l s , o t h e r s a r e
l i n k i n g t h e c h e m o t h e r a p e u t i c c o n t a i n i n g n a n o p a r t i -
c l e s t o a n a n t i b o d y c a l l e d 2C 5 , w h i c h h o m e s - i n o n
t h e s u r f a c e o f h u m a n c a n c e r c e l ls . T h e y h a v e s h o w n
t h a t th e a p p r o a c h s l o w s t h e g r o w t h o f a v a r i e t y o f t u -
m o u r s , i n p a r t b e c a u s e t h e n a n o p a r t i c l e s c a n f e r r y
l a r ge a m o u n t s o f t h e c h e m o t h e r a p e u t i c d r u g s t o t h e
tu inou r .
T h e e n c a p s u l a t i o n o f d r u g s i n d e g r a d a b l e p o l y m e r
m i c r o p a r t i c l e s t h a t a r e i n j e c t a b l e c a n o f f e r p r e c i s e
c o n t r o l o v e r d r u g - r e l e a s e p r o f i l e s , s o l u b i l i s e l o w s o l -
u b l e d r u g s a n d p r o t e c t t h e m f l ' o m m e t a b o l i z a t i o n .
T h e f i r s t m i c r o p a r t i c l e e x t e n d e d - r e l e a s e f o r m u l a t i o n
o f a p e p t i d e t o b e a p p r o v e d b y t he U n i t e d S t a t e s F o o d
a n d D r u g A d m i n i s t r a t i o n ( F D A ) c o n s i s t s o f p o l y ( l a c -
t i c - c o - g l y c o l ic ) a c i d ( P L G A ) m i c r o p a r t i c l e s t h a t e n -
c a p s u l a t e th e l e u t e i n i z i n g - h o r m o n e - r e l e a s i n g h o r -
mon e (LHRH) agon i s t , l eu p ro re l i n ac e t a t e 14. Th i s
l b r m u l a t i o n it i s u s e d f o r d i s e a s e s s u c h a s e n -
d o m e t r i o s i s a n d p r o s t a t e c a n c e r . C o r r e s p o n d i n g l y ,
t h e f i r s t m i e r o p a r t i e l e e x t e n d e d - r e l e a s e f o r m u l a t i o nt b r a p r o t e i n t o b e a p p r o v e d b y t h e F D A u s e d P L G A
m i c r o p a r t i c l e s to e n c a p s u l a t e r e c o m b i n a n t h u m a n
g r o w t h h o r m o n e , f or t h e t r e a t m e n t o f g ro w t h h o r -
m o n e d i s o r d e r s . S i nc e t h e n , t h e r e h a s b e e n m u c h r e -
s e a r c h i n to t h e u s e o f p o l y m e r i c n a n o p a r t i c l e s f o r
d r u g d e l i v e r y ; f o r e x a m p l e , p o l y ( e t h y l e n e g l y c o l ) d e -
r i v a t i v e s h a v e b e e n s h o w n t o e n t r a p u p t o 4 5% b y
w e i g h t o f a d r u g w i t h i n n a n o p a r t i c l e s t h a t h a v e e x -
t e n d e d c i r c u l a t i o n t i m e s c l u e t o d e c r e a s e d u p t a k e b y
t h e m o n o n u c l e a r p h a g o c y t e s y s t e m . S u c h s y s t e m s
c o u l d b e u s e f u l f o r a l t e r i n g d r u g b i o - d i s t r i b u t i o n t o
d e l i v e r, fo r e x a m p l e , m o l e c u l e s , p r o t e i n s a n d g e n e s
t h r o u g h m u c o s a l b a r r i e r s .
Clht Transl Oncol. 2006;8(I I ): 788-95 79 1
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 5/8
G A L L E G O O , P UNT E S V . W HA T CA N N A NO T E CHNO L O G Y DO T O F I G HT G A NG ER?
New applications of micro- and nanoparticles have
created new possibilities %r dru g delivery. Not all
drug candidates are wa ter soluble, which is problem-
atic for oral delivery. One approach to making drug
particles fi 'om poorly soluble compounds is to form
nanopartieles by mechanically milling the substance
and then stabilize these nanoparticles with a coatingto form an aqueous suspension. The first FDA-ap-
proved drug produced by this technique, the im-
munosupp ressant Rapamune (sirolimus), was re-
leased in 2000. The diamete rs of these nan ocrystals
are in the order of 100-/,000 nm. In general, smaller
partic les offer t~lster releas e, and large r particle s offer
longer, uni%rm dosing. With respect to alternative
delivery routes, puhn onary drug delivery provides
another possibility. Particle size and density can be
optimized to greatly enhance the aerosolization effi-
ciency (by minimizing aerosol aggregation) and drug
longevity (by reducing phagocytosis). A typical appli-cation would be low density, porous structm~s with a
diamete r of 5-50 pm and an aero dyna mic diameter
up to 1-5 pm %r the deli very of drug s to deep lung tis-
sue. Another appro ach to puh non ary d rug deliver y is
the use of inhaled, mucoadhe sive nano particul ate
sy ste ms 15.
A recent case ap peare d fills year us ed prostate ca ncer
as a model. Docetaxel (Dtxl)-encapsulated nanoparti-
cles %rmulated with biocompatible and biodegrad -
able poly(D,L-lactic-co-glycolic ac id) -b lock-poly (e th-
ylene glycol) (PLGA-b-PEG) copolymer and surthce
t~mctionalized with the AI0 2-flu orop yrimi dine RNA
aptam ers that recognize the extrac ellular domain of
the prostate-specific memb ran e antigen (PSMA), a
well characterized antigen expressed on the surface
of prostate cancer cells, were prep ared I6. These Dtxl-
encapsulated nanopartiele aptamer bioeon)ugates
(Dtxl-NP-Apt) bind to the PSMA protein expressed on
the surface of LNCaP prostate epithelial cells and get
taken up by these cells by endocitosis resulting in sig-
nificantly enhance d in vilro cellular toxicity as com-
pared with nontarg eted nanopa rtieles that lack the
PSMA aptamer (Dtxl-NP) (p < 0.0004). After a single
intratumoral injection of Dtxl-NP-Apt b:ioconjugates,
complete tumor reduction was observed in five ofseven LNCaP xenograft nude mice (initial tum or vol-
rune of 500 ramS), and 100% of these a nim als sur-
vived the 109-day study. In contrast, two of seven
mice in the Dtxl-NP group had complete tumor re-
duction with 109-day surviva bilit y of only 57%. Dtxl
alone had a smwiva bility of only 14%. Saline and
nanopartic les without drug were similarly non-eft?ca-
cious.
An interesting strategy %r multiple targeting the tu-
mour with a special time control, has re cently p~)ven
efficacy and opens a way tbr nanoparticle controlled
nmlti-dru g release ~7 combin ing traditional chemo-
therap y which kills tumour cells directly with some
newer drugs which work instead by cutting the tu-
mour's blood supply. In fact, in 1971, Judah Folkman
already proposed that the :progression of cancer
might be halted by preventing tulnours fl:om recruit-
ing new blood vessels (a process called angiogenesis)
which :provide them wi th oxyg en and nu trients. It is
well known traditional chemotherapeutic agents Mllall rapidly growing cells in the body~both cancer
cells and other cells that divide quickly (for example,
blood, hair and cells lining the intestine). This leads
to the distressing side etfects of chemotherapy, and
limits the practic al dose and fi 'equeney of application
of the drugs. One tactic to avoid these efl'eets is to tar-
get the drug sp ecifically to the tumo ur. A second issue,
however, is that the drug may escape the tumour, or
some tumours develop resistance to a particular
drug, so efforts to identify- targets that are not pro ne to
developing resistance continue. Endothelial cells,
which line blood vessels, may provide an attractivetarget, as they are thought to be genetically nlore stable
than cance r cells and so less likely to develop muta-
lions that might promote resistance. Therefore, si-
multaneous delivery of chemotherapeutic and anti-
angiogenic drugs is clearly beneficial, but because
chemotherapy is blood-borne, shutting down the tu-
mour's blood supply with anti-angio genie drugs ma y
decrease the deliveD~ of drugs desig ned to kill the tu-
rnout cells. Sengupta et a117 hypot hesiz ed that a mor e
elfeclive strategy would be to use a delivery vehicle
that became concentrated in tmnours betbre the vas-
eulature shuts down, and allowed the staged release
of the two d rugs. More s pecifically, the de liver y of the
anti-angiogenic tYctor could lead to a collapse of the
vascular network and imprison the vehicle -st i l l
bearing its second payload of chemotherapeutic
dr ug- :in the tumour. The subseq uent rele ase of the
latter drug within the tmnour would Mll the cancer
cells. These auth ors also expl oited, again, the fiaet that
the blood vessels of tumour s are ,leaky% so tumour
lissue can take up larger particles than can normal
lissues, promoting selectivity. They created eomposite
vehicle particles of 80-120 nm, consisting of a solid
biodegr adable polyme r core surr ound ed by a lipid
membra ne. The anti-angiog enic drug combretastatinwas dissolved in the lipid layer, fi'om which it rapidly
escaped. This drug attacks the internal skeleton of
cells, and quickly disrupts blood vessels. The chemo-
therapeutic drug doxorubiein was bound chemically
to the inner core of the particle, and so was rele ased
more slowly as the bond holding the d rug to the poly-
mer broke down. Doxorubiein is a common chemo-
therapeutic agent, and its structure consists of chemi-
cal groups that are amenable to attachment to
polymer s. Sengupta et al exa min ed the e[~Eets of the
drugs on two types of tumour in mice, and showed
that, unsurprisingly, either drug alone slowed tumour
growth, and that when the drugs were delivered si-
7 92 Clin Transt OncoL 2006; 8(1 l): 788-95
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 6/8
G A L L E G O O , P UNT E S V . W HA T CA N N A NO T E CHN O L O G Y DO T O F I G HT G ANG E R?
m u l t a n e o u s l y t h e r e w a s a n a d d i t i v e e ll i~ ct . T h e g e n e r -
a l c o n c e p t o f t i m i n g t h e a v a i l a bi l i t y o f d r u g s a i m e d a t
s p e c i fi c s t a g e s o r t a r g e t s i n c a n c e r :is w i d e l y a p p l i c a -
b l e, a n d i t i s c o n s i s t e n t w i t h s i m i l a r e f f o r ts to p r o m o t e
b l o o d - v e s s e l % r m a t i o n i n d i s e a s e s i n v o l v i n g i n s u ff i -
c i e n t b l o o d f lo w . I t m a y a l s o b e n e c e s s a r y t o t a r g e t
m u l t i p l e a s p e c t s o f a n g i o g e n e s i s , e i t h e r b y u s i n g s e v -
e r a l d r u g s o r b y u s i n g a d r u g t h a t i n t e r f e r e s w i t h s e v e r -
a l p a t h w a y s , t o p r e v e n t t u m o u r s f r o m s w i t c h i n g o n
a l t e r n at i v e a n g i o g e n e s i s p a t h w a y s . R e g a r d i n g a n -
g i o n g e n e si s , a m u c h m o r e s i m p l e a p p r o a c h h a s b e e n
p r o p o s e d w h i c h i n v o l v e s m a g n e t i c n a n o p a r t i e l e s : a
d i s p e r s i on o f n o n - ag g l o m e r a t e d s u p e r p a r a m a g n e t i c
n a n o p a r t i c l e s c a n b e d i s p e r s e d i n t h e b i o l o g i c a l m e -
d i a a n d o n e c a n i n d u c e t h e i r l o c a l a g g l o m e r a t i o n
w i t h m a g n e t i c f i e ld s i n t h e a r e a o f t h e t u m o r . I n f a st
g r o w i n g t u i n o u r s , t h e b l o o d v e s s e l s i n a d d i t i o n o f b e -
i n g l e a k y t h e y al s o s h o w n a r r o w d i a m e t e r s , t h er e f o r e
a n e m b o l i z a t i o n c a n b e i n d u c e d t o s t o p b l o o d s u p p l yt o t h e t u m o u r .
H y p e r t h e r m i a . D e l iv eh w o f t o x i c a m o u n t s o f h e a t
T h i s t ar g e t e d , m i n i m a l l y i n v a s i v e t h e r a p y i s s i m p l e t o
p e r f o r m a n d c o u l d b e u s e d in v i ta l r e g i o n s w h e r e
s u r g e r y i s n o t f ea s i b le . I r r a d i a t i o n a s a m e a n o f r e -
m o t e l y h e a t i n g b i o l o gi c a l U s s u es m e d i a t e d b y i n o r -
g a n i c n a n o p a r t i c l e s h a s b e e n e x t e n s iv e l y ' e x p l o r e d i n
a c e l l u l a r s c a l e a s c a n c e r t r e a t m e n t 18 a n d i t w a s p r o_
p o s e d t o b e u s e f u l a t a m o l e c u l a r s c a l e t o d e h y b r i d i z e
D N A w i t h o u t a n y b u l k h e a t in g a n d w i t h o u t d i s t u r b -
i n g s u r r o u n d i n g m o l e c u l e s . I n t h i s ea s e , t h e D N A r e -
s p o n d e d a s m a c r o s c o p i c a l l y h e a t e d a t a b o u t 40 ~
T h i s p r i n c i p l e w a s a l s o a p p l i e d t o r e m o v e t o x i c a m y -
l o d d e p o s i t s w h e n g o l d n a n o p a r t i c l e s w e r e i r r a d i a t e d
w i t h w e a k i n n o c u o u s m i c r o w a v e f i el d s :in w h a t a u -
t h o r s c a l l ed m o l e c u l a r s u r g e r y ~ .
H y p e r t h e r m i a i s b a s e d in t h e p h e n o m e n o n t h a t
n a n o p a r t i c l e s a c t a s a n t e n n a s t h a t a b s o rb e l e c t r o m a g -
n e t i c w a v e s a n d l o c a l l y d e l i v e r to x i c a m o u n t s o f h e a t .
T h e s e a n t e n n a s c a n b e m e t a l l i c (A u n a n o p a r t i c l e s o r
A u n a n o s h e l l s ) , o x i d e ( s u p e r p a r a m a g n e t i c n a n o p a r -
t i t l e s ) o r o r g a n i c ( c a r b o n n a n o t u b e s ) . T h e l i g h t - a b -
s o r p t i o n p h e n o m e n a i s d i f fe r e nt fo r e v e r y m a t e r i a lb u t t h e e f f ec t i s t h e s a m e : a l o c a l t e m p e r a t u r e i n -
c r e a s e i n t he s u r r o u n d i n g s o f t h e p a r t i c l e .
T h u s , m a g n e t i c n a n o p a r t i c l e s a c t a s m i n i a t u r e t he ~~
r e a l s c a lp e l s f o r k i ll i n g t u m o r s a s w e l l a s i m a g i n g
t h e m . T h e n a n o p a r t i c l e s , c a n b e m o d i f i e d t o a t t a c h
t u m o u r - t a r g e t i n g m o l e c u l es . T h e e x a c t c o m p o s i t i o n
o f t h e n a n o p a r t i c l e s c a n a l s o b e v a r i e d i n o r d e r t o
c o n t r o l th e a m o u n t o f h e a t i n g t h a t w o u l d r e s u l t u p o n
s t i m u l a t i o n b y a n a l t e r n a t i n g m a g n e t i c f i e l d ( e l e c t r o -
m a g n e t i c w a v e ) . T h i s a b i l i t y c o u l d p r o v e u s e f u l in d e -
s i g n i n g n a n o p a r t i c l e h e a t e r s t h a t w o u l d o n l y ge t s o
h o t b e f o r e l o s i n g t h e i r m a g n e t i c p r o p e r t i e s - i n e s -
s e n c e , t h e s e n a n o p a r t i e l e s w o u l d h a v e a b u i l t - i n
o n / o f f s w i t c h t h a t w o u l d p r e v e n t o v e r h e a t i n g t h a t
c o u l d d a m a g e h e a l t h y t is s u e .
M e t a l l ic n a n o p a r t i e l e s c a n al s o be ~ m o t e l y h e a t e d
b y c o m b i n a t i o n o f F o u e o u l t a n d J o u l e ef fe c t w h e n i r -
r a d i a t e d w i t h a t im e v a r y i n g e l e c t r o m a g n e t i c f i e l d ,
t h i s a l l o w s t h e u s e o f t h e h i g h l y b i o e o m p a t i b l e g o l d
t o d e l i v e r t h e h e a t 1'~}. A m o r e r e f i n e d g o l d b a s e d n a -
n o p a r t i c l e , a s i l i ca o r i r o n o x i d e g o l d c o a t e d n a n o p a r ~
l i el e , w a s r e e e n t l y s y n t h e s i z e d a n d u s e d f o r r e m o t e
a n d l o c a l h e a l i n g b y N a o m i H a l a s a n d c o - w o r k e r s 2~
T h e y h a v e p i o n e e r e d a d a m a g e - c o n t r o l s t r at e g y i n
w h i c h t h e y t a r g e t t u m o u r s w i t h t h e i r g o l d - c o a te d
n a n o p a r t i c l e s , w h i c h t h e n b e c o m e t i n y h e a t e rs t h a t
c o o k t u m o u r c e l l s t o d e a th . A u - s i l i e a n a n o s h e l l s ,
w h i c h s t r o n g l y a b s o r b n e a r - i n f r a r e d (N il:{) li g h t, m e -
d i at e l o c a l iz e d , i r r e v e r s i b l e p h o t o t h e r m a l a b l a t i o n o f
c a n c e r o u s t u m o u r s in viro u n d e r m a g n e t i c re s o -
n a n c e g u i d a n c e . T o t u r n o n t h e h e a t , t h e y h i t t h e
n a n o p a r t i e l e s i n s i d e t u r n o u t s w i t h i n f l ' a r e d li g ht . T h el ig h t p a s s e s h a r m l e s s l y t h r o u g h n o r m a l t i s su e , b ut
t h e n a n o p a r t i e l e s r e a d i l y a b s o r b it a n d w a r m u p t o
m o r e t h a n 4 0 ~ T h e y r e p o r t e d t h a t t h e i r n a n o s c a l e
h e a t e r s w i p e d o u t t u m o u r s i n b o t h c el l cu l t u r e a n d
a n i m a l s t u d i es . T h e n a n o s h e l l s a r e l a y e r e d c o l lo i d s
w i t h a n o n - c o n d u c t i n g n a n o p a r t i c l e c o r e c o v e r e d b y
a t h i n m e t a l s h el l , w h o s e t h i c k n e s s c a n b e c h a n g e d t o
p r e c i s e l y t u n e t h e p h o t o - r e s p o n s e . P r o t e i n s t h at b i n d
o n l y w i t h t u m o u r c e l l s c a n b e a t t a c h e d t o t h e s u r f a c e ,
c r e a t i n g t u m o r - s e e k i n g n a n o p a r t i c l es . B y t u n i n g t h e
s h e l l s t o s t r o n g l y a b s o r b 8 20 n m N IR ~ g h t , w h e r e o p -
t i ca l t r a n s m i s s i o n t h r o u g h b o d y t i s su e i s o p t i m a l a n d
h a r m l e s s , l o w - p o w e r e x t r a - c o r p o r e a l l y a p p li e d la s e r
l i g h t s h o n e a t t h e p a t i e n t i n d u c e s a r e s p o n s e s i g n a l
f l 'o m i n j e c t e d n a n o s h e l l s c l u s t e r e d a r o u n d a tu r n o u r .
I n c r e a s i n g t h e l a s e r p o w e r t o a s t il l m o d e r a t e l y l o w
e x p o s u r e h e a t s t he n a n o s h e l l s j u s t e n o u g h t o d e s t r o y
t h e t u m o r w i t h o u t h a r m i n g h e a l t h y ti s su e . O n e xp o -
s m ~ t o 5 5 W / c m 2 N llq li g h t, h u m a n b r e a s t c a r c i n o m a
c e ll s i n c u b a t e d w i t h n a n o s h e l l s in i,,itro u n d e r g o p h o -
t o t h e r m a l l y i n d u c e d m o r b i d i t y . C e ll s w i t h o u t
n a n o s h e l l s d i s p l a y n o l o s s i n v ia b i li t y -. L i k e w i s e , i n,
v iv o s t u d i e s u n d e r m a g n e t i c r e s o n a n c e g u i d a n c e r e -
v e a l t h a t e x p o s u r e t o l o w - d o s e ( 4 W / e r a ~ ) NI R l i g h t i n
s o li d t u m o u r s t r e at e d w i t h n a n o s h e l l s i n c u r a t em -p e r a t u r e i n c r e a s e o f 57 .4 + 6 .6 ~ w i t h i n 4 -6 m i n u t e s .
T h e t i s s u e d i s p l a y s c o a g u l a t i o n , c e l l s h r i n k a g e , a n d
l o s s o f n u c l e a r s t a i n i n g , i n d i c a t i n g i r r e v e r s i b l e t h e r -
m a l d a m a g e . C o n t r o ls t r e a te d w i t h o u t n a n o s h e l l s
d e m o n s t r a t e d s ig n if ic an t ly - l o w e r t e m p e r a t u r e s a n d
a p p e a r e d u n d a m a g e d . T h e r e s e a r c h e r s u s ed t h is
n a n o s h e l l - a s s i s t e d p h o t o t h e r m a l t h e r a p y o n m i c e i n
w h i c h t u r n o u t s h a d b e e n g r o w n . A l l t r e a t e d t u m o u r s
a b a t e d , a n d t h e m i c e r e m a i n e d f r ee o f t u m o u r s % r
o v e r 9 0 d a y s .
A n o t h e r a p p r o a c h f or t h e r e m o t e a n d l o c a l h e a ti n g o f
m m o u r s i s t h e u s e o f c a r b o n n a n o t u b e s ( C N T ).
C a r b o n n a n o t u b e s a l so s t r o n g l y a b s o r b N i l{ li g h t a n d
Clin Transt Oncot. 2006;8(l l):788-95 7 93
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 7/8
GALLEGO O, PUNTES V. WHAT CAN N ANOTECHN OLOGY DO TO FIGHT CANCER?
Fig. 4. Au nanoparticles inside vesicels of HeLa cells. Work
done in collaboration with Pr. Ernest Giralt and Silvia
Pujals from the Peptides Design, Synthesis and Structure
Laboratory at the Parc Cientific de Barcelona. Arrows indi-
cate the nanoparticles.
g e t h e a t e d . I f i n s i d e a c e l l , t h e y c a n h e a t i t u p s u f f i -
c i e n t l y t o i n d u c e c e l l n e c r o s i s , w h i l e s u r r o u n d i n g
c e l l s w i t h o u t C N T a r e n o t a f f e c t e d 21. C N T h a v e a d i -
a m e t e r h a l f t h e D N A m o l e c u l e a n d c u s t o m i z e d
l e n g t h , a n d a b s o r b s t r o n g l y th e N I R l i g h t w h i c h i s
n o n a b s o r b e d b y l i v i n g t i s s u e , t h u s t h e y c o u l d h e a t
t h e C N T t o 7 0 ~ i n 2 m i n u t e s d e s t r o y i n g c a n c e r c e l l s
w i t h o u t a f f e c t in g s u r r o u n d i n g t i ss u e . T o a d d r e s s t h e
C N T to th e t u m o u r c e l ls , t h e n a n o t u b e s w e r e c o a t e d
w i t h K ~ l a t e ( a o v e r e x p r e s s e d p r o t e i n i n t u m o u r c e l l s )r e c e p t o r s .
A n a d v a n c e d d e s i g n c o u l d b e t o c o m b i n e d r u g a n d
h e a t d e l i v e r y n a n o p a r t i c l e s w i t h c a n c e r c e l l v e c t or s .
A n e x a m p l e o f s u c h a m i x e d n a n o p a r t i e l e w a s r e c e n t -
l y p r o p o s e d b y L a b h a s e t w a r e t a l ga. T h e y d e v e l o p e d a
m u l t i - c o m p o n e n t c o a t i n g s y s t e m f o r i r o n o x i d e
n a n o p a r t i c l e s t h a t d o e s n o t d i m i n i s h t h e m a g n e t i z a -
t i o n o f t h e c o r e p a r t i c l e . T h e c o a t i n g i s f o r m e d b y l a y -
e r i n g o l e i c a cr id o n t o t h e c o r e n a n o p a r t i c l e a n d t h e n
a d d i n g a p o l y m e r k n o w n a s P l ur o n i e T , c o n s i s t i n g o f
a l t e r n a t i n g s e g m e n t s o f p o l y e t h y l e n e o x i d e a n d
p o l y p r o p y l e n e o x i d e . T h e o l e i c a c i d l a y e r s o l u b i l i z e s
a n d h o l d s w a t e r - i n s o l u b l e d r u g s , w h i l e t h e p o l y m e r
l a y e r a c t s a s a s u r f a c t a n t t h a t e n a b l e s t h e n a n o p a r t i -
e l e s t o d i s p e r s e i n w a t e r . T o m o d e l t h e p a r t i c l e s d r u g -
c a r r y i n g a n d d r u g - r e l e a s i n g c h a r a c t e r i s t i c s , t h e i n -
v e s t i g a t o r s l o a d e d t h e n a n o p a r t i e l e s w i t h t h e p o o r l y
s o l u b l e d r u g d o x o r u b i c i n . T h e y m e a s u r e d u p t a k e o f
t h e d r u g b y s e v e r a l c u l t u r e d c a n c e r c e l l li n e s i n a d d i -
t i o n to c y t o t o x i c i t y t b l l o w i n g d r u g a d m i n i s t r a t i o n .
A p p r o x i m a t e l y 2 8 p e r c e n t o f t h e d r u g w a s r e l e a s e do v e r t w o d a y s , a n d a b o u t 6 8 p e r c e n t w a s r e l e a s e d
o v e r o n e w e e k . T h e r e s e a r c h e r s o b s e r v e d h o w t h e
d r u g - lo a d e d n a n o p a r t i e l e s c a u s e d d o s e - d e p e n d e n t e y -
t o t ox i c i t y .
C O N C L U S I O N S
N a n o p a r t i c l e s a r e s m a l l e n t i ti e s w h i c h a r e a b l e to
c a r r y d r u g s o r h e a t o r i m a g i n g c o n t r a s t a g e n t s o r a l l
o f t h r e e t o l oc a l p l a c e s . T h e f u t u r e d e s i g n o f n a n o p a r -
i t e l e s h a v e t o t a k e i n t o a c c o u n t t h e s p e c i a l e n v i r o n -
m e n t o f a t u m o u r , c o n s e q u e n c e o f t h e m o d i f i e d c e l l
a c t i v i t y a n d i n c r e a s e d c e l l u l a r d i v i s i o n r a t e c l ue to
D N A m o d i f i c a t i o n , s u c h c o n d i t i o n s l e a d s t o p o o r e r
o x y g e n e n v i r o n m e n t s , l o w e r p H a n d h i g h e r t h e r m a l
s e n s i t i v it y , T h e s e f e a t u r e s c a n b e d e t e c t e d b y- c h e m i -
c a l l y s e n s i t i v e n a n o p a r t i e l e s ( f i g. 4 ). T h e a d v e n t a g e s
o f n a n o p a r t i e l e s i s t h a t c a n b e d e s i g n e d f o r m u l t i p l e -
t a s k , a n d t h a t w h e n a p r o p e l ' v e h i c l e i s t b u n d , i t m a y
b e a p p l i e d t o a w i d e v a r i e t y o f t u r n o u t s . H o w e v e r , w e
c a n n o t a s s u m e a q u ic k t r a n s l a t i o n o f t h e s e r e s u l t s to
t h e r a p y f o r h u m a n s . T h e b i o l o g ic a l d if f e r e n c e s b e -
t w e en m i c e a n d h u m a n s p r e v e n t d i r e ct c o m p a r i s o n
b e t w e e n t h e s y s t e m s , a n d i t w i l l a ls o b e i m p o r t a n t t oe x t e n d t h e s e s t u d i e s t o l o n g e r t i m e p e r i o d s . I n a d d i -
t io n , r e s e a r c h e r s m u s t f i n d w a y s t o p r e v e n t i m m u n e
c e ll s f r o m c l e a r i n g n a n o p a r t i c l e s b e f o r e t h e y r e a c h
t h e i r t a r g e t s a n d m u s t a l s o o v e r c o m e t u m o u r s ' a c -
q u i r e d a b i l i t y t o s p i t o u t c a n c e r d r u g s t h a t g e t i n s i d e
c e l ls . F i n a l l y , t h e t o x i c i t y o f n a n o p a r t i c l e s r e m a i n s
u n c l e a r . H o w e v e r , d u e t o t h e s e v e r i t y o f c a n c e r , i t i s
l i ke l y a fi e ld w h e r e t h e s o c a l l e d n a n o m e d i c i n e w i l l
h a v e a n e a r l i e r d e v e l o p m e n t a n d l i k el y a la r g e i m -
p a c t . T h e r e f o r e P h a s e I / I I a s s a y s b a s e d o n t h e s e i d e a s
w i l l b e s o o n n e c e s s a r y t o e v a l u a t e t h e p o s s i b il i ty - o f
t r a n s l a t e t h e f i n di n g s f r o m b a s i c r e s e a r c h i n to c l i n i c a l
t r e a t m e n t .
R e f e ~ n c e s
1. Kiberst is PA, Tra vis J, Celebr a tion a Glass
Half-Full. Seienee. 2006;312:1157.
2. Special numl:)er dedicate to canc er re-
search: Front iers in Cancer Research,
Science; 2006. p. 512.
5. hllp://n a no.can eer.go v/
4. Alivisatos AP. Less is more in medicine -
Sophislieated forms of nanoteehnologT~
will find so me of their first real-worl d ap-
pl ications in biomedical research, disease
diagnosis and, possiMy, therapy. Scien-tific A mer ica n. 2001 ;285:66-75.
5. Service. R. Nanotechnol~)gy Takes Aim
at Cancer, Science,2005;510:11 52-4.6. Chemla Y, Grossman HL, Pooh Y, et al.
Ul t rasensil ive magnet ic biosensor %r ho-
mogeneous immunoassay. PNAS. 2000;
97:/4268-72.
7. Zhen g G, Patols ky F, Gui Y, "Wang WU,
Lieber GM. Multiplexed eleclrical detec-
lioll of cancer lllarkers with nanowire
sensor an!ays. Nat Bioleehnol. 2005;25:
1294-301,
8. Parak W, Boudreau R, Le Gros M, et ak
Cell Molilily and Metaslatie PotentialStudies Based on Quantum Dot hnaging
of Phagokinetie Tracks Adv. Mater. 2002;
14:882-5,
9. Albrecht-Buelaler G, Phagokinetie traeks
o[ 5"1'5 ceils: pa rallels bel wee n the orien-
tat ion of h 'ack segments and of cel lular
sl ruetures which contain aet in or mbul in.
Gell. 1977;I2:555-9.
10. Gao X, Cui Y, Levenson R, Chung L, Nie
S. In vfi,o cancer target ing and imaging
with semiconductor quantmn dots Nat .
Biotech, 2004~2:969-76,
11. Zi mm er JP, Kim S-W, C)hnishi S, Tanak a
E, terangioni JV, Bawendi MG. Size Serieso[ Smal l Indium Arsenide-Zine Selenide
79 4 el i, Transl OncoL 2006;8(11): 788-9.5
7/30/2019 What Can Nanotechnology Do to Fight Cancer
http://slidepdf.com/reader/full/what-can-nanotechnology-do-to-fight-cancer 8/8
G A L L E G O O , P UNT E S V . W HA T CA N NA NO T E C HNO L O G Y DO T O F I G HT CA NCE R?
C o r e -S h e ll N a n o c r y s t a l s a n d T h e i r A p p l i -
c a t i o n t o I n V i v o l m a g i n g . J, A m e , C h e m ,
S o e . 2 0 0 6 ; 1 2 8 : 2 5 2 6 - 7 .
1 2 . L e u s c h n e r C , H a n s e l W . T a r g e t i n g b r e a s t
a n d p r o s l a t e c a n c e r s t h r o u g h [ h e ir h o r -
m o n e r e c e p t o r s B i o lo g 'y o f R e p r o d u c t i o n .
2 0 0 5 ; 7 5 : 8 6 0 -5 .
1 3 . D u b e r t r e t B , C a l a m e M , I A b c h a b e r A J .
N n g l e - m i s m a t c h d e t e c t i o n u s i n g g x ) l d -
q u e n c h e d f l u o r e s c e n l o l i g m m c l e o t i d e s ,
N a t u r e B i o t e c h n o l o g y . 2 0 0 1 ; 1 9 " 5 6 5 - 7 0 ,
1 4 . O k a d a H . O n e - a n d t b r e e - m o n t h r e l e a se
i n i ec t a b le m i c r o s p h e r e s o f th e L H - R H s u -
p e r a g o n i s t l e u p r o r e l i n a c e t a t e , A d v . in
D r u g D e l i v R e v . 1 9 9 7 ; 2 8 :7 1 - 8 4 .
1 5 . L a V a n D A , L y n n D M , L a n g e r t L M o v i n g
S m a l l e r i n l ) r u g D i s c o v e r y a n d D e l i v e r y .
N a t u r e R e v i e w s D r u g D i s c o v e r y . 2 0 02 ; 1:
7 7 - 8 4 .
1 0 . F a r o k h z a d O C , C h e n g J , T e p l y B A , e t aL
T a r g e t e d n a n o p a r t i c l e - a p l a m e r b i o c o n ju -
g a t e s f o r c a n c e r c h e m o t h e r a p y in viroP N A S . 2 0 0 6 ; 1 0 5 : 6 5 1 5 - 2 0 .
1 7 . S e n g u p t a S , E a w n ~ o n e D , C a p i l a I , e t a l .
T e m p o r a l t a r g e t in g o f t u r n o u t c e ll s a n d
n e o v a s c l d a t u r e w i t h a n a n o s c a l e d e l i v e ry
s y s t e m N a t u r e . 2 0 0 5 ; 4 5 6 : 5 6 8 - 7 2 .
1 8 . A l e x i o u C , A r n o l d W , K l e i n R J , e t a l . L o -
c o r e g i o n al C a n c e r T r e a t m e n t w i t h M a g n e -
t ic D r u g T a r g e t i n g . C a n c e r R e s . 2 0 0 0 ;6 0 :
6 6 4 1 - 4 8 .
1 9 . K o g a n M , B a s t u s N , A m i g o R , e t a l. L o c a l
a n d R e m o t e M a n i p u l a t i o n o f P r o t e in A g
g r e g a t i o n , N a n o l e t t e r s . 2 0 0 6 ; 6 : 1 1 1 - 6 .
2 0 . O ' N e a l D P , H i r s c h l , R , H a l a s N , e t a l .
P h o t o - t h e r m a l t m n o r a b l a t i o n i n m i c e u s -
i n g n e a r i n f l ' a r e d - a b s o r b i n g n a n o p a r l i c l e s
C a n c e r L e t l. 2 0 0 4 ; 2 0 9 :1 7 1 - 6 .
2 1 . K a m N W S , O ' C o n n e l l M , W i s d o m J A , D a i
H . Se l e c ti v e c a n c e r c e l l d e s t r u ( t i o n : C a r -
b o n n a n o t u b e s a s m u l t if l m c t io n a l b i o l o g i-
c a l I r a n s p o r l e rs a n d n e a r - i n f r a r e d a g e n t s
P N A S . 2 0 0 5 ; 1 0 2 ; 1 1 6 0 0 - 5 ,
2 2 . J a i n T K , M o r a l e s M A , S a h o o S K , L e s l i e -
P e l e e k y D L , I , a b h a s e l w a r V . I r o n O x i d e
N a n o p a r t i c l e s l b r S u s t a i n e d D e l i v e r y o f
A n t i c a n e e r A g e n ts , M o l e c u l a r P h a r m a -
c e u t i c s . 2 0 0 5 ; 2 : 1 9 4 - 2 0 5 .
Clin Transl Oncol. 2006;8 (l l): 788-95 7 9 5