what can nanotechnology do to fight cancer

7/30/2019 What Can Nanotechnology Do to Fight Cancer

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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



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 -

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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

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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



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.

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% 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



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



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



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



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 .

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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 .

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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 -

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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

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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

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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 -

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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 ,

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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

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