nanoquímica: aplicacions en biomedicinadiposit.ub.edu › dspace › bitstream › 2445 › 98211...
TRANSCRIPT
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Department of Pharmacology and Therapeutical Chemistry, Faculty of Pharmacy Institute of Nanoscience and Nanotechnology UB (IN2UB)
University of Barcelona
Nanoqu ímica : aplicacions en Biomedicina
Ma Lluïsa Pérez-García
Seminaris de Recerca- Facultat de Farmàcia (UB)- 6 de ma rç 2012
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Feynman’s Vision
http://www.zyvex.com/nanotech/feynman.html
http://www.photosynthesis.com/RICHARD_F.html
Dec 1959 Talk at APS / CalTech
J. Bonsen (Mmotors-MITTiny)
"There's Plenty of Room at the Bottom, An Invitation to Enter a New Field of Physics"
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Simple molecules<1nm
red blood cell~5 µm (SEM)DNA
proteins nm
diatom30 µm
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10,000 BC
StoneWood
0 18001000 BC 1900 20002000 BC3000 BC
Material: things needed for doing or making something; "writing materials"; "useful teaching materials"
Material, stuff: the tangible substance that goes into the makeup of a physical object; "coal is a hard black material"
Nanomaterials
Materials
“A nanomaterial is a material consisting of a substance or structure which has at least one dimension less than 100 nm”
http://www.zyvex.com/AboutUs/Profiles/Sabbio.html
Pozzolanacement
SteelIron SyntheticPolymers
Nano-materials
Galileo (1638)Science of Materials
BronzeGlassGold
Silicon Chip
Size-dependent properties make the nanometre regime special
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Mixed approaches
e.g.Lithographyand Self-Assembly
0,1 nm 1 nm 10 nm 100 nm 1 µµµµm 10 µµµµm 100 µµµµm 1 mm
“Bottom-up”
Individual atoms and molecules are placed or are driven to preciselywhere they are needed by:Chemical synthesisSelf-assemblySelf-organisationDeposition
“Top-down”
Take a block of material and carve it away until the object that is wanted is reached by:EngravingPhotolithographyMillingDestruction!
Two contrasting approaches to create Nanostructures:
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Take a block of material and
carve it away until the object that is wanted is reached
Top-Down Nanoscience and Technology
Intel® 45nm, six transistor SRAM cell.
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Molecular Molecular chemistrychemistry
• Molecular recognition
• Self-organisation
• Self-assembly
SupramolecularSupramolecular
ChemistryChemistry
NanomaterialsNanomaterials
Non-covalentinteractions
Bottom-up
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Nanoscience
Mat
eria
ls
Biology Chemistry
Phy
sics
NanomedicineNanomedicineNanotechnology
Medicine
Diagnosis
Treatment
(Nanomaterials) Imaging
Tissue
regeneration
InterdisciplinaryInterdisciplinary sciencescience
NanomedicineNanomedicine
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• Direct patient exposure so technologymust be safe
Analytical tools, diagnostics and sensors - for use outside the patient- with surgical access
Imaging molecules and patients
Therapeutics and Drug Delivery Systems
Applications of Nanotechnology in MedicineApplications of Nanotechnology in MedicineApplications of Nanotechnology in Medicine
Technology must be cost effective and convenient to use
Professor Alan Hill-Oxford Biosensors
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" Nanopharmaceuticals can be developed either as drug delivery systems or biologically active drug products”.
" Nanopharmaceuticals"" Nanopharmaceuticals"or "Nanomedicineor "Nanomedicine ss""
……….. nanometre size scale complex systems, consisting of at least two components, one of which being the active ingredient……..
European Science Foundation (Dec 2005) www.esf.org
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nanoparticlesnanoparticles
polymer micelles
Polymer Therapeutics
Liposomes
Polymer-protein conjugates
Myelotarg, Rituximab
antibodies conjugates
vectors for gene therapy
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NanoscienceNanoscience Nanomaterials NanotechnologyNanotechnology
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Gold nanoparticles� Easy to synthesize
� Easy control of their properties (size, morphology, surface functionalization…)
� Biocompatible
� SPR
� ScatteringSensing and deliveryPhotothermal therapy
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A spontaneously organised molecule layer in which a suitable functionalised
molecule assembles through chemisorption on metal or glass surfaces.
•Immobilize (bio)active molecules
• sense important chemical or biological
parameters
•detect pathogens and metabolites
Applications : DIAGNOSTIC TOOLS
Self assembled monolayerSelf assembled monolayer
(BIO)SENSORS (BIO)CHIPS
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Self Assembled Monolayers ( SAMs )
substrate
Receptor: Terminal functional group (binds (bio)molecules)
Alkyl chain: linker and gives stability
Head group (binds to the substrate)
Parts of a SAM
SAM
protein
silicon, silica, gold, glass
�excellent biosensor stability
�easy preparation in the Laboratory
� economical viable
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Sensor Applications
���� Electrochemical biosensors
• Glucose sensor for monitoring blood glucose levels
- Immobilization of GLUCOSE OXIDASE (GOx-FAD)
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Supramolecular chemistry
Self-assembly
Functional Nano-Materials
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Self-assembly : surfactants
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Self-assembly : proteins
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Template based self-assemblyAnion templated-synthesis of
anion receptors
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Template-Directed synthesis
Kind of templates
Cations
Neutral molecules
Anions
����
����
����
nnn
+
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1. Anionic Template-Directed Synthesis of Dicationic [14]Imidazoliophanes
N N
NN+ ++
2X-
Anion
Quantification of the template effect
����
Assessment of the anion control����
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In solid state…In solution…
E. Alcalde, N. Mesquida, L. Pérez-García, Eur. J. Org. Chem. 2006, 3988-3996.
E. Alcalde, C. Alvarez-Rúa, S. García-Granda, E. García-Rodriguez, N. Mesquida, L. Pérez-García, Chem. Commun. 1999, 395-396
N N
N N
2Cl-N N
N N
2PF6-
24
26
23 25
Imidazolium derived macrocycles for anion recognition
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ANIONS
ANIONS
Molecular level …Molecular level …
… Supramolecular level …… Supramolecular level …
… Soft Nanomaterials… Soft Nanomaterials
BisBis--imidazolium amphiphilesimidazolium amphiphiles
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N N
NN+ +
n n2X–
n= 5, 7, 9, 15
N N
NN
OR
OR
2X–
+ +
R= -(CH2)17-CH3; -(CH2)11-S-(CH2)11-CH3
N N
R R
NN+ +
2X–
OMe
Dicationic amphiphiles
sensors
surfactants
Liquid crystals
Self-assembly and self-organization
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Thermotropic LC
N N
N N2Br-
PpC18SIII·2Br
15 15
0 5 10 15 20 25 30 35
2θ / degrees
Inte
nsity
/ A
.U.
25ºC
40ºC
80ºC
XRD
55ºC 60ºC
POM - HT
20 30 40 50 60 70 80 90 100 110 120
Temperature / ºC
End
othe
rmic
DSC
Bis-imidazolium amphiphiles: liquid crystal behaviour
60.9 ºC
(b)
L. Casal-Dujat, O. Penón, C. Rodríguez-Abreu, C. Solans and L. Pérez-García, New. J. Chem., 2012, 36, 558–561
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Bis-imidazolium amphiphiles: liquid crystal behaviourThermotropic LC
N N
O
N N
O
n
n
CpC10SI·2Br : n=7CpC18SI·2X: n=15 (X=Br, BF4, CF3SO3, N(CF3SO2)2
2X-
60
80
100
120
140
160
180
TSC
-LC
tran
sitio
n / º
C (a) CpC10·2Br
(b) CpC18·2BF4
(c) CpC18·2Br
(d) CpC18·2N(CF3SO2)2
(e) CpC18·2CF3SO3
(a)
(b)(c)
(d)(e)
� The increase of carbon atoms in the alkyl chain induce decrease in SC-LC transitiontemperature
� The counter-ion modulates the SC-LC transition temperature in CpC18 and decrease in theorder: BF4 > Br > N(CF3SO2)2 > CF3SO3
Transition temperatures:
SC-LC
Cyclophanes
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Surfactants
At the air-water interface:
Aggregation systems:
In the bulk:
Micelles
I II III
Self-assembly
Monolayer
Self-organisation
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Dicationic amphiphiles Organization
7.0µm121086420
4
3.5
3
2.5
2
1.5
1
0.5
0
X[µm]
Z[n
m]
Tapping mode Topography scan images
5mM en CH2Cl2 / CCl410µm, round negative
On gold surfaces
C. Sporer, L. Casal, D. Caballero, J. Samitier, A. Errachid, L. Pérez-García, Sensor Lett., 2009, 7, 757-764
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Gold nanoparticles for drug delivery
• Synthesis
• Characterisation
• Toxicity studies
• Internalization in cells
• Incorporation of anionic drugs
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Synthesis of gold nanoparticles
Brust-Schiffrin
(AuNP in organic solvent)
Turkevitch
(AuNP in water)
HAuCl4 (aq)
+
tetraoctylammonium (TA)
NaBH4 (reducing agent)
+
dodecanethiol (stabilizer)
HAuCl4
boiling
+
citrate (stabilizer)
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Synthesis of gold nanoparticlessoluble in organic media
+ HAuCl4 (aq)HAuCl4 (dcm)+ NaBH4 (aq)
AuNP-o
+ +
L. Casal-Dujat, M. Rodrigues, A. Yagüe, A. C. Calpena, D. B. Amabilino, J. González-Linares, M. Borràs, and L. Pérez-García, Langmuir, 2012, 28, 2368–2381
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Synthesis of gold nanoparticlessoluble in water
+ HAuCl4 (aq)
AuNP-w
+ NaBH4 (aq)+ +
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Characterization UV-vis – size
(TEM)AuNP-o
AuNP-w
TEM micrographs of NP-a, NP-b, and respective size distribution histograms.
Size/nm
AuNP-o 8.8 ± 2.2
AuNP-w 10.4 ± 4.2
a) b)
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Stability - UV-Vis and DLS
Temperature/°C Size/nm
25 18.28±0.14
37 19.52±0.29
4 19.89±0.09
5nm 8.8nm 5nm
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Toxicity studies
EC50 µg.mL -1 nM
1·2Br 13.18 14600
AuNP-o > 70 -----
AuNP-w ----- 0.96
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Internalization studies
TEM images from Caco-2 cells treated with AuNP-o at 15 (A), 30 (B-C) and 60 (D-F) minutes, and after 4 (G-J) and 24 (K) hours.
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Release of model drug from AuNP
Ibuprofenate
pKa 4.45
Piroxicam
pKa 5.1
pH T/°C
7.4 37
5.5 32
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Release of ibuprofenate from AuNP-a
pH 7.4 pH 5.5
pH KD
7.4
Ib-AuNP 39.98 h-1
Ib-1·2Br 65.47 h-1
Ibuprofenate 106.10 h-1
5.5 Ib-AuNP0.00001265 mmol
h-1
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Biofunctionalization of micronanotools to tag, sense
and actuate in living cells
• Synthesis
• Characterisation
• Cell tagging
1
32
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Micronanotool elements
• (Bio)molecule
• Biocompatible material
• Self assembled monolayer
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Biomolecule
• Wheat Germ Agglutinin (WGA) is used as a biomolecule
• Capacity to recognize specific sugars (N-acetylglucosamine and sialic acid)
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SAM
• Amine bond
CHO-SAM2 WGA-SAM2
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TESUD SAM FORMATION
Hydrophobic
Hydrophilic
Hydrophobic
Contact Angle
Pictures
3. TESUD Deposition
1. H2SO4/H2O22. NH4OH/H2O2/H2O
94º
100º
15 º
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PROTOCOL FOR TESUD SAM FORMATION
3. TESUD Deposition
– Contact Angle Characterization
1 mM, 50 mM, 100mM, 135 mM, 150 mM, 200 mM.
Solution-phase Vapor phase
:
EthanolTolueneWater
60 min120 min180 minovernight
� Concentration � Method
� Type οf solvent � Deposition time
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Atomic Force Microscopy (AFM)
Laser desorption/ionization time of flight mass spectrometry (LDI-TOF MS)
Si
OO O
O
H
SiSi
Si
OO
O
H
Si
Si
OO O
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Fluorescence microscopy
• Silicon wafer
20x
20x
60x
• Barcodes
b)
40x
• Particles
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Cell Tagging: Cell Tagging: Barcodes adhesion
Silicon barcode 10x6um Fluorescence microscopy Optical microscopy
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MICINN TEC2008-06883-C03-02TEC2011-29140-C03-02
Generalitat de Catalunya (2009SGR158)
Supramolecular systems in Nanomedicine
Dra. Susana RamosDra. Lucia Casal-DujatDr. Christian SporerOriol PenónMafalda RodriguesPaula GarcíaAniuska BolívarAlex YagüeDavide SantucciDimitris Siapkas
Dra. Carme Nogués. UABDr. José Antonio Plaza. IMB-CSIC
Dra. Laura Rodriguez-UBDra. Anna Calpena-UBDr. Miquel Borras-CERETOXDr. Jordi Hernández-UBDra. Teresa Montero-UBDra Conxita Solans, IQAC-CSICDr. Carlos Rodriguez-Abreu, INL, PortugalDr. D. Amabilino, ICMAB-CSICDr. Peter Griffiths, University of Cardiff