Materiales nanoestructurados tubulados con propiedades

Materiales nanoestructurados tubulados con propiedades

Universidad Nacional Educación a Distancia (UNED)
MEDITRANS- Targeted delivery of Nanomedicine
A novel generation of contrast agents for the
imaging of vascular competence by Magnetic
Resonance Methods
(MULTIMAG SBIO/0179/2006)
Prof. P. Ballesteros, UNED
Dr. S. Cerdán, CSIC
Evolution of concepts of disease
Anatomic
Histologic
Molecular
Present and Future
of Non Invasive Imaging:
“From Anatomy to Molecular Biology”
1980´s
1990´s
7.9
2000´s
6,8
A well developed model of Molecular Imaging- The atheroschlerotic plaque
Choudhury et al (2004) Nat Rev drug Disc.3, 913-925
The concept for specific contrast enhanced MRI
Choudhury et al (2004) Nat Rev drug Disc.3, 913-925
MACROMOLECULAR CONTRAST AGENTS
Linear Polymers (Polylysine)
PL-DTPA MW 48700
Gd 60-70 r1 850
Proteins (Human Serum Albumin)
HSA DTPA MW 90000
Gd 90 r1 420
Non Covalent (Hydrophobic)- MS-235
Covalent
Trapping into Liposomes
Dendrimers
2nd generation
1st generation
(MULTIMAG)
Magnetically Labelled Nanotubes
*
Peptidic nanotubes
*
* self-assembly by H-H bonds
* self-assembly by π-π stacking interactions
Carbon nanotubes
* single walled carbon nanotubes (SWNTs)
(MULTIMAG)
Peptidic Nanotubes
H-H bond interactions: Dota derivatives
4
HN
HO2C
HO2C
N
N
Gd3+
N
NH
O
O
N
CO2H
N
H
O
A
HN
H
N
NH
H
N
O
H 2C
S
CO2H
S
CH 2
O
O
N
H
N
N
N
N
Gd3+
HO2C
Ion r1
mol r1
Ion r2
mol r2)
Aa
2,51±0,01
5,01±0,03
3,20±0,04
6,41±0,08
Ab
2,33±0,02
4,67±0,05
3,02±0,06
6,03±0,12
Gd(III)-Complex
*T1(2) measured at 60 MHz. Relaxivities, r1(2), are expresed in s-1mM-1. a1 mM
complexone or Gd-complex, 150 mM NaCl and 100 mM TRIS/HCl at pH 7 and
37ºC. b1 mM complexone or Gd-complex in water at 37ºC.
CO2H
(MULTIMAG)
Peptidic Nanotubes
π−π stacking interactions: Dota derivatives
ButO2C
ButO2C
N
N
N
N
ButO2C
CO2t Bu
C
O
H
N
O
O
O
2
O
O
O
N
H
B
HN
HN
NH
O
O
N
O
O
Gd(III)-B
O
H
N
O
2
C
O
N
N
N
N
CO2t Bu
CO2tBu
(MULTIMAG)
Single Walled Carbon Nanotubes (SW-CNTs)
TEM images
Short SWNTs: produced by CVD method: 10-40 % nanotube (diam. × length 0.7-1.2 nm × 2-20 µm) Aldrich
Commercial SWNTs
Clean SW-CNTs
(using 1M HCl)
Clean SW-CNTs Gd(III)
Transmission electronic microscope
JEOL JEM 1010 (100 KV)
Oxidized SW-CNTs
(using HNO3)
(MULTIMAG)
Single Walled Carbon Nanotubes (SW-CNTs)
12
12
10
10
8
8
% weight
% w eig h t
Total Reflexion X-Ray fluorescence (TXRF)
6
4
2
% weight
SWNTs
4
2
Fe
Co
Ni
Zn
Gd
0,0589
9,1847
3,2234
0,0169
0
0
Fe
12
12
10
10
8
8
6
4
SWNTsCOOH
Ni
Zn
Gd
0,0043 0,1886
6
4
2
2
0
Co
SWNTsGd[III] 0,0391 10,5737 3,692
% weight
0
6
Fe
Co
Ni
Zn
Gd
0,0103
1,8335
0,68
0,0567
0,0201
0
Fe
SWNTsCOOHGd[III] 0,0494
Co
Ni
Zn
Gd
2,2429
0,7926
0,016
9,7648
(MULTIMAG)
Single Walled Carbon Nanotubes (SW-CNTs)
Relaxivity
Gd[III]-complex
C Gd (mM)
SBDS 2%
T1 (ms)
R1 (s-1)
3826,67
0,26
R1d (s-1)
r1 (mM-1 s-1)
SWNTs-Gd[III]
0,25
137,83
7,26
0,26
218,56
SWNTsCOOH-Gd[III]
0,25
1656,00
0,60
0,26
1,37
SWNTs-Gd[III]/TTHA6-
0,25
149,27
6,70
0,26
201,19
SWNTsCOOH-Gd[III]/TTHA6-
0,25
1695,67
0,59
0,26
1,31
*Conditions: suspensions of SWNTs-Gd[III] in solutions of 2%
SBDS at pH 7.22, in the abscence and presence of TTHA6(Triethylenetetraamino-N,N,N’,N’’,N’’’,N’’’-hexaacetic
acid;
TTHA-Gd[III] = gadolinium complex with q = 0).
*T1 were measured using an instrument Bruker Minispect q60
operating at 60MHz (inversion-recovery sequence).
11
10
9
8
7
6
5
4
3
2
1
0
SWNTs
SWNTsGd[III]
SWNTsCOOH
SWNTsCOOHGd[III]
Fe
Co
Ni
Zn
Gd
(MULTIMAG)
Single Walled Carbon Nanotubes (SWNTs)
Anisotropic properties of SWNTs (MRI)
Nº Patente: P200800024
Model solution: SWNTs-COOH containing paramagnetic metals (Weight %: Ni=0.7, Co=1.8) in H2O
A) Image (perpendicular to B0), B) Image (parallel to B0), and C) Intensity histogram of the
water normalized images A y B (collaboration with SIERMAC; Dr. Sebastián Cerdán)
Gd: Efecto de la velocidad sobre un corte
perpendicular a B0
NanoTubos : Efecto de la velocidad sobre un
corte perpendicular a B0
(MULTIMAG)
Single Walled Carbon Nanotubes (SWNTs)
A
Anisotropic properties of SWNTs with DTPA (MRI)
D
B
F
Frecuencia de repetición de Intensidad
Frecuencia de repetición de Intensidad
C
A)
E
Intensidad de la señal
Intensidad de la señal
Image of Gd-DTPA (50 mM) (perpendicular to B0), B) Image of Gd-DTPA (50 mM) (parallel to B0), and
C) Intensity histogram of the water normalized images A y B.
D) Image of SWNTsCOOH-Gd-DTPA (2.5 mM) (perpendicular to B0), E) Image of SWNTsCOOH-Gd-DTPA
(2.5 mM) (parallel to B0), and F) Intensity histogram of the water normalized images A y B
(collaboration with SIERMAC; Dr. Sebastián Cerdán)
(MULTIMAG)
Single Walled Carbon Nanotubes (SWNTs)
Functionalization of SWNTs
O
HNO3 60%
O
OH
rfx
OH
17
COCl2
Cl
62°C, 24 h
Cl
O
O
18
HCl.H
19
H
N
O
O
2N
t-BuO2C
+
2
E) Bourlinos A.B. et al, Small., 2006, 2, 1188-1191
F) Wei Wu et al, Angew. Chem. Int. Ed., 2005, 44, 6358-6362
-OOC
-OOC
-OOC
N
N
N
N
H
N
C
OO
N
N
N
N
C
O
O
N
H
2
N
H
COO-
O
O
2
O
H
N
N
CO2t-Bu
14
N
H
O
O
O
H
N
t-BuO2C
2
O
O 2
H
N
C
OO
C
N
H
20
O
21
CF3COOH
CH2Cl2
N
CO2t-Bu
THF
O
COO-
N
Et3N
rfx
-OOC
C
O
N
t-BuO2C
N
N
N
N
CO2t-Bu
CO2t-Bu
N
N
N
N
CO2t-Bu
CO2t-Bu
(MULTIMAG)
Single Walled Carbon Nanotubes (SW-CNTs)
Magnetic Resonance Imaging (IRM)
Anisotropic properties of SW-CNTs
?
Hipothesis: utilization of anisotropic materials in order to distinguish the flow
type (laminar or turbulent flow) in the normal or atherogenic macro- and
microvasculature.
Bo
Laminar flow
Normal
Turbulent flow
Pathology