Nanomateriali in biologia

Report
NANOMEDICINE
A.A. 2011-2012
An expanding field,
Nanomedicine represents an active field of
pharmacological research.
However, only a small part of nanodrugs and
nanosized devices potentially usefull for the
exploitation in humans have reached the
clinical experimental phase; even fewer are
approved for use in humans.
Nanosized drugs: main properties.
1. Enhanced Permeabilization and Retention
(EPR): accumulation in newly forming
endothelia
2. Compartimentalization
3. Accessibility to districts with blood barriers
(e.g. brain, posterior pole of the eye)
Main results: changes of the bioavailability and of
other pharmacological paramenters in comparison
with traditional formulations.
The STHEALTH technology.
The EPR effect, while useful for targeting
newly vascularized tissues, can be
indesirable if it reduces the half life of the
nanodrug.
En efficient way to reduce this effect is to
cover the nanoparticle with a layer of PEG.
This procedure is a technology customized
under the name STHEALTH®.
STHEALTH nAu
Uncoated nAu (on the left ) enters the phagocyte in very
larger amount than PEG-coated nAu (on the right) of similar
size and shape.
Surface functionalization
In addition to the STHEALTH, nanodrugs
can be functionalized through the addition of
layers of antibodies directed to protein
specifically expressed by the targed tissue,
or of the substrate for specificaly bounding
receptors.
Modular molecules are designed, able to
disassemble gradually when approaching their
target.
Clinical advantages
The main clinical advantages of therapy with
nanosized and functionalized drugs are:
• Higher concentrations of the active drug at
the site of action
• Possible targeting to desired cellular type
to be targeted, or even to selected cellular
districts
• Lower general toxicity of the active
principle
Major toxicity hazard
• The toxicity of the nanomaterial itself is mostly
unknown, it is not possible to infer it from the
properties of the equivalent bulk material
• Adequate models for toxicity studies “in vivo”
and in humans are mostly lacking
• The dissolvation of elements from complex
nanomaterials is at the present unpredictable,
especially in complex environment like the fluids
of the body.
Nanoparticles can enter the cell.
Co3O4 nanoparticles form small
aggregates inside the cell.
Courtesy Lab. Cell Biol. University of Insubria
Nanoparticles can be toxic for the
cells
Courtesy Lab. Cell Biol. University of Insubria
Main fields of exploitation in human
clinics
• Cancer, especially if advanced, refractory
or affecting poorly accessible tissues
• Drug-resistant, life-threatening bacterial
and parasite infections
• Diseases affecting the posterior pole of the
eye and the Central Nervous System
(CNS)
Carriers for nanodrugs: lipid-based.
From the left: liposomes and STHEALTH
liposomes (embedded with PEG), liquid and
solid lipid nanoparticles (LLN, SLN).
Cattaneo et al. 2010. J. Appl. Toxicol. 30: 730–744. DOI 10.1002/jat.1609
Liposomes
A multilamellar liposome in equilibrium with planar membrane.
Sucrose
This technology was conceived to get a system similar to the cell membrane
bilayer, possibly integrated with it when used to carry chemicals inside the
cell. Updated, customized technologies use both multi- and monolayered
liposomes.
(Pidgeon & McNeely, 1987, Biochemistry 26:17-29, modified)
TEM image of doxorubicine, an antineoplastic agent, embedded
in bilayered liposomes (Doxil).
(Gabizion et al., Eur. J. Pharm. Sci, 45: 388–398)
Pharmacokinetics
Liposomal doxorubicin is
partially protected from rapid
renal clearance after three
cycles (B), therefore the plasma
levels increase (A).
Data are taken in cancer
experimentally induced in
mice.
(Gabizion et al., Eur. J. Pharm. Sci, 45: 388–398)
Effect on experimental cancer
Doxorubicin in tissues
appears red-orange.
Soluble doxorubicin (A)
does not accumulate in
tumoral nodules.
The nanoformulation of the
drug, embedded in
bilayered liposomes (B),
clearly accumulates.
(Gabizon et al., Eur. J. Pharm. Sci, 45:
388–398)
Some metallic nanodrugs.
1. Nanogold, nAu
2. Nanosilver, nAg
3. UltraSmall Paramagnetic Iron Oxides
(USPIO)
For diagnostics and therapeutics.
USPIO greatly enhance the signal of
(Magnetic Resonance Imaging (MRI)
nAu coated with TNF (Aurimune) in
oncology
Au nanoparticles aggregates inside the tumoral cells
The Combidex: an USPIO for
cancer diagnostics.
Combidex is a customized formulation of dextrancoated USPIO.
The pictures show its 3D structure (the iron oxide
cluster at the center of dextran molecules is in violetblue) and the aspect of particles at TEM.
The particles mean diameter is 21 nm.
USPIO in cancer diagnostics.
Enhanced MRI of metastatic cancer in the brain.
From the left: without contrasting agents, with Gd as
contrast, with USPIO (Combidex).
Control
Contrast: Gd
Contrast: Combidex
Functionalized Iron oxide as a
targeted carrier for drugs
Boyer et al., NPG Asia Materials , 23–30 (2010) | doi:10.1038/asiamat.2010.6
Size-dependent Magnetic properties
of IONPs
A) TEM of differently sized Iron
Oxide NanoParticles
(IONPs)
B) Size-dependent T2-weighted
MR images of IONPs in
aqueous solution at 1.5 T
C) As before, color-coded
D) Graph of T2 value versus
size of water soluble IONPs.
E) Magnetization of water
soluble IONPs measured by
a SQUID magnetometer.
doi:10.1038/asiamat.2010.6;
doi: 10.1021/ja0422155
Carriers for nanodrugs: bioactive
silicon.
Mesoporous silicon, with nanopores, shows
properties useful for:
1. Sustained, localized and prolonged
release of drugs
2. Enhanced reconstruction of tissues
through cell growth stimulation or
promoting accelerated mineralization of
bones.
Carriers for nanodrugs: organic
compounds.
Those exploited for the use in humans are in
the following categories:
1. Polymers (polylactide, polyglycolide)
2. Dendrimers (polyamidoamides)
3. Albumin nanotubes
2
3
J. Appl. Toxicol. 2010, 30:730-744; wileyonlinelibrary.com/journal/pat
Theranostics and “modular”
nanoparticles.
Theranostics: combining diagnosis with therapy.
NPs with high imaging properties and able to kill the cell when activated
(es. light sensitive molecules) are coated to prolonge their half-life,
conjugated at the surface to be targeted to specific cells (e.g. tumoral) and
with molecules improving the uptake into the target cell.
Or:
NPs able to kill the cells (e.g. radioactive isotopes) are coated and
functionalized for targeting, and injected locally in the bloody supply of the
tumor.
Or:
NPs with high imaging properties (e.g. USPIO) are coated and
functionalized for targeting and killing the cell, than directed to the target by
functionalization or by a directional magnetic field.
An hypothetical modular nanocarrier.
Protective coating
NP
Cell permeabilization agent
Sensor
(e.g. Ab to recognize tumor cell)
And a scheme of how it works….
Binding to the target
Degradation
Activation
Cell damage:
THERAPY
Signal for imaging
DIAGNOSIS
A modular nanoparticle for “in situ”
cancer treatment
PEG
Dextran
Iron oxide
Monoclonal antibodies
(ChL6)
Isotope: In111
(with chelator, DOTA)
20 nm
Cai & Chen, 2007, Small, 3: 1840 (modified)
Binding to the target
Degradation
Internalization of IONPs
Internalization of In111
Ionizing radiation:
Cell death
Therapy
Enhanced signal for NMI
Diagnosis
Other nanosized materials
1. Tissues and coating releasing nanometals
(e.g. nAg, with antibacteric properties)
2. Creams eluting active, nanosized compounds
(nAg for antibacteric gels, nTiO2 for solar
creams)
3. Drugs eluting devices (silicon scaffolds for
wluting drugs to the the posterior pole of the
eye, central venous catheter with nAg).
How to test toxicity?
• “in silico”: nano-QSAR and PSAR
(pseudo-structure-activity-relationships)
• “in vitro”: toxicity test on monocellular
organisms, tissues and cells
• “in vivo”: toxicity tests on model organisms
• Metabolomics: newer methodology to get
contemporary informations on a complete
panel of biological parameters

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