2. Premises
• Since the human body is basically an extremely complex
system of interacting molecules (i.e., a molecular machine),
the technology required to truly understand and repair the
body is the molecular machine technology :
NANOTECHNOLOGY
• A natural consequence of this level of technology will be the
ability to analyze and repair the human body as completely
and effectively as we can repair any conventional machine
today.
4. NANOTECHNOLOGY
Feynman: "There is plenty of room at the bottom"
• Seminal speech on December
1959 at CalTech
• " Why can’t be compressed 24
volumes of Encyclopedia
Britannica on a pin head ?“
• " The biological example of writing
information on a small scale has
inspired me to think of something
that should be possible "
• In 1990, IBM scientists wrote the
logo IBM using 35 xenon atoms on
nickel.
7. E.C.-ETP
“Nanomedicine, is defined as the application of
nanotechnology to achieve breakthroughs in
healthcare. It exploits the improved and often novel
physical, chemical and biological properties of
materials at the nanometer scale. Nanomedicine
has the potential to enable early detection and
prevention, and to essentially improve diagnosis,
treatment and follow-up of diseases.
……………………….
8. Nanomedicine:
European Science Foundation (ESF)
“The field of Nanomedicine is an
offshot of biotechnology aiming at
diagnosing, treating and
preventing disease and traumatic
injury, of relieving pain, and of
preserving and improving human
health, using molecular tools and
molecular knowledge of the
human body. It embraces sub-
disciplines which are in many ways
overlapping and are underpinned
by common technical issues.”
9. The numbers of nanomedicine
The global nanomedicine market reached USD
78.54 billion in 2012.
The “Nanomedicine Market Global Industry
Analysis, Size, Share, Growth, Trends and
Forecast, 2013 - 2019" predicts that the market
globally will be worth USD 177.60 billion by
2019.
According to the report, technological advancement in the field is the
primary growth driver. Rising support from various governments in
terms of funds and increasing collaborations between enterprises for
research and development in nanomedicine is also expected to boost
growth of this market. On the other hand, the lack of a well-organized
regulatory framework and the high costs associated with these drugs and
devices are slowing the nanomedicine market’s growth
10. The largest market segment within the nanomedicine market is
that of oncology, and the fastest growing segment is the
cardiovascular market. Growth in this segment has been fuelled
by the presence of a sizeable patient population, and a
simultaneous growth in the demand for device and drugs that are
based on nanomedicine. These factors are collectively anticipated
to further fuel the growth of the cardiovascular segment within
the nanomedicine market.
11. 0
5000
10000
15000
20000
25000
1 2 3 4 5 6 7 8 9 10
Number of publications related to “nanomedicine” in Medline
1996 1998 2000 2002 2004 2006 2008 2010 2012 2014
14. Topics in nanomedicine
• Therapy:
Drug Delivery: Use nanodevices specifically
targeted to cells, to guide delivery of drugs,
proteins and genes
Drug targeting : Whole body, cellular ,
subcellular delivery
Drug discovery : Novel bioactives and
delivery systems
15. Topics in nanomedicine
• Diagnosis:
Prevention and Early Detection of diseases: Use
nanodevices to detect specific changes in diseased
cells and organism.
17. Why Nanoparticles
1) Drugs, contrast agents, paramagnetic or
radiolabeled probes can be vehiculated by
NPs
2) NPs can be multi-functionalized to confer
differents features on them
2) These features of NP will be transferred to
transported drug
18. • Targeting: nanoparticles control the drug delivery.
The drug follows the NP
• Drugs are concentrated to target. Less systemic
toxicity.
• Less drug is necessary
• Drugs are protected inside NPs and are not degraded.
Longer drug halflife (if NP have long halflife).
• Biologicals (proteins, genes, Antibodies) are most
favourable candidates for NP
1) Drugs, contrast agents, paramagnetic or
radiolabeled probes can be vehiculated by NPs
19. • Multi-functionalization: Controls drug targeting,
drug dosage, and drug release characteristics
2) NPs can be multi-functionalized to confer
differents features on them
20. An ideal Multi-functional nanoparticle vector
Anticorpo
Indirizza la NP verso un
antigene specifico sulla
cellula da colpire
Polietilenglicol
(PEG)
Evita che la NP venga
rimossa dal circolo
Evita che NP venga
digerita nei lisosomi
Tat peptide
Determina Fusione e
ingresso della NP nella
cellula
Probe magnetico
Permette imaging
tramite MRI
Farmaco
24. What are Carbon Nanotubes?
Carbon nanotubes are
hexagonally shaped
arrangements of carbon
atoms that have been
rolled into tubes.
25.
26. Human hair fragment
(the purplish thing) on
top of a network of
single-walled carbon
nanotubes
Nanotubes are members of the
fullerene structural family, which
also includes the spherical
buckyballs. Their name is derived
from their size, since the diameter
of a nanotube is on the order of a
few nanometers, while they can be
up to tenths of centimeters in
length
Nanotubes are categorized as
single-walled nanotubes (SWNTs)
and multi-walled nanotubes
(MWNTs)
28. Armchair (n,n)
• Single-walled nanotubes
are an important variety
of carbon nanotube
because they exhibit
electric properties that
are not shared by the
multi-walled carbon
nanotube (MWNT)
variants.One useful
application of SWNTs is
in the development of the
first intramolecular field
effect transistors (FET).
• (Used for
nanobiosensors).
29. Multi-walled• Multi-walled nanotubes (MWNT)
consist of multiple rolled layers
(concentric tubes) of graphite.
• In the Russian Doll model, sheets
of graphite are arranged in
concentric cylinders, e.g. a (0,8)
single-walled nanotube (SWNT)
within a larger (0,10) single-walled
nanotube.
• In the Parchment model, a single
sheet of graphite is rolled in
around itself, resembling a scroll
of parchment or a rolled
newspaper. The interlayer
distance in multi-walled
nanotubes is close to the distance
between graphene layers in
graphite, approximately 3.4 Å.
30. Properties of Carbon
Nanotubes
Nanotubes have a very broad range of electronic,
thermal, and structural properties that change
depending on diameter, length. They exhibit
extraordinary strength and unique electrical
properties, and are efficient conductors of heat.
31. Strength
• Carbon nanotubes are the strongest
and stiffest materials yet discovered in
terms of tensile strength and elastic
modulus respectively. This strength
results from the covalent sp2 bonds
formed between the individual carbon
atoms. In 2000, a multi-walled carbon
nanotube was tested to have a tensile
strength of 63 gigapascals (GPa).
(This, for illustration, translates into the
ability to endure tension of a weight
equivalent to 6422 kg on a cable with
cross-section of 1 mm2.) Since carbon
nanotubes have a low density for a
solid of 1.3 to 1.4 g·cm−3, its specific
strength of up to 48,000 kN·m·kg−1 is
the best of known materials, compared
to high-carbon steel's 154 kN·m·kg−1.
32. Electrical properties
• Depending how the graphene sheet
is rolled up, the nanotube can be
metallic; semiconducting or moderate
semiconductor.
33. Thermal property
• All nanotubes are expected to be very good
thermal conductors along the tube,
exhibiting a property known as "ballistic
conduction," but good insulators laterally to
the tube axis.
34. Defects
• As with any material, the existence of a
crystallographic defect affects the material
properties. Defects can occur in the form of
atomic vacancies. High levels of such defects can
lower the tensile strength by up to 85%.
Crystallographic defects also affect the tube's
electrical properties. A common result is lowered
conductivity through the defective region of the
tube.
35. Natural, incidental, and
controlled flame environments
• Fullerenes and carbon nanotubes are not
necessarily products of high-tech laboratories;
they are commonly formed in such places as
ordinary flames,produced by burning
methane,ethylene,and benzene, and they have
been found in soot from both indoor and outdoor
air. However, these naturally occurring varieties
can be highly irregular in size and quality
because the environment in which they are
produced is often highly uncontrolled.
37. In electrical circuits
• Nanotube based transistors
have been made that operate
at room temperature and that
are capable of digital switching
using a single electron.The first
nanotube integrated memory
circuit was made in 2004.
Nanotube Transistor
38. Proposed as a vessel for transporting drugs
into the body. The ends of a nanotube might be capped with a
hemisphere of the buckyball structureThe drug can be attached to
the side or trailed behind, or the drug can actually be placed inside
the nanotube.
.
Nanotube
Nanocap
41. Toxicity
Their final usage, however, may be limited by
their potential toxicity.
Results of rodent studies show that CNTs produce
inflammation, epithelioid granulomas (microscopic
nodules), fibrosis, and biochemical/toxicological
changes in the lungs. Comparative toxicity studies
in which mice were given equal weights of test
materials showed that SWCNTs were more toxic
than quartz, which is considered a serious
occupational health hazard when chronically
inhaled. The needle-like fiber shape of CNTs is
similar to asbestos fibers. This raises the idea that
widespread use of carbon nanotubes may lead to
pleural mesothelioma, a cancer of the lungs, or
peritoneal mesothelioma (both caused by exposure
to asbestos). Available data suggest that under
certain conditions, especially those involving
chronic exposure, carbon nanotubes can pose a
serious risk to human health.
45. gold nanoparticles (1-20 nm) are produced by reduction
of chloroauric acid (HAuCl4)
To the rapidly-stirred boiling HAuCl4 solution,
quickly add 2 mL of a 1% solution of trisodium
citrate dihydrate, Na3C6H5O7
.2H2O. The gold
sol gradually forms as the citrate reduces the
gold(III). Remove from heat when the solution
has turned deep red or 10 minutes has elapsed.
46.
47.
48. In cancer research, colloidal gold can be used to target
tumors and provide detection using SERS (Surface
Enhanced Raman Spectroscopy) in vivo.
They are being investigated as photothermal converters
of near infrared light for in-vivo applications, as ablation
components for cancer, and other targets since near
infrared light transmits readily through human skin and
tissue
57. HYDROGELS
Co-polymers (e.g. acrylamide and acrylic acid) create water-
impregnated nanoparticles with pores of well-defined size.
Water flows freely into these particles, carrying proteins and other small
molecules into the polymer matrix.
By controlling the pore size, huge proteins such as albumin and
immunoglobulin are excluded while smaller peptides and other
molecules are allowed.
The polymeric component acts as a negatively
charged "bait" that attracts positively
charged proteins, improving the particles'
performance.
59. Mesoporous silica particles: nano-sized spheres filled with a regular
arrangement of pores with controllable pore size from 3 to 15nm and outer
diameter from 20nm to 1000 nm .
The large surface area of the pores allows the particles to be filled with a
drug or with a fluorescent dye that would normally be unable to pass
through cell walls. The MSN material is then capped off with a molecule that
is compatible with the target cells. When are added to a cell culture, they
carry the drug across the cell membrane.
These particles are optically transparent,
so a dye can be seen through the silica walls.
The types of molecules that
are grafted to the outside will control what
kinds of biomolecules are allowed inside
the particles to interact with the dye.
EM
60. Quantum dots
3 nm
Dots are crystalline fluorophores made of binary compounds such as
lead sulfide PbS, lead selenide PbSe, cadmium selenide CdSe,
cadmium sulfide CdS, indium arsenide InAs, and indium InP.
Dots may also be made from ternary compounds such as cadmium
selenide sulfide. These quantum dots can contain as few as 100 to
100,000 atoms within the quantum dot volume, with a diameter of 10 to
50 atoms. This corresponds to about 2 to 10 nanometers.
A quantum dot is a semiconductor whose excitons are confined in all
three spatial dimensions.
An immediate optical feature of colloidal quantum dots is their
coloration
61.
62. 62
High quantum yield compared to common fluorescent dyes
Broadband absorption: light that has a shorter wavelength than
the emission maximum wavelength can be absorbed, peak
emission wavelength is independent of excitation source
Tunable and narrow emission, dependent on composition and
size
High resistance to photo bleaching: inorganic particles are more
photostable than organic molecules and can survive longer
irradiation times
Long fluorescence lifetime: fluorescent of quantum dots are 15
to 20 ns, which is higher than typical organic dye lifetimes.
Improved detection sensitivity: inorganic semiconductor
nanoparticles can be characterized with electron microscopes
Quantum Dot Properties
63. Quantum Dots
• Raw quantum dots are toxic
• But they fluoresce brilliantly, better than dyes
(imaging agents)
• Only way of clearance of protected QDs from the body
is by slow filtration and excretion through the kidney
64. Quantum Dots
• QD technology helps cancer researchers to observe fundamental
molecular events occurring in the tumor cells by tracking QDs of
different sizes and thus different colors, tagged to multiple
different biomoleules, in vitro by fluorescent microscopy.
• QD technology holds a great potential for applications in
nanobiotechnology and medical diagnostics where QDs could be
used as labels.
First attempts have been made to use quantum dots for tumor
targeting under in vivo conditions.
Generically toxic
65. 65
Figure 2. Phase contrast images (top row) and
fluorescence image NIH-3T3 cells incubated with QDs2;
(c) SKOV3 cells were incubated with QDs2
FPP-QDs specifically bind to tumor cells via the membrane expression of
FA receptors on cell surface
Quantum Dots for Imaging of Tumor Cells
Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50.
66. 66
Quantum dots conjugated with folate–PEG–PMAM
for targeting tumor cells
Folate–poly(ethylene glycol)–polyamidoamine ligands encapsulate and solubilize
CdSe/ZnS quantum dots and target folate receptors in tumor cells.
Dendrimer ligands with multivalent amino groups can react with Zn2+ on the surface
of CdSe/ZnS QDs based on direct ligand-exchange reactions with ODA ligands
Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50.
67. QD nanocrystals are highly toxic to cultured cells under UV
illumination. The energy of UV irradiation is close to that of the
covalent chemical bond energy of CdSe nanocrystals. As a result,
semiconductor particles can be dissolved, in a process known as
photolysis, to release toxic Metal ions into the culture medium. In
the absence of UV irradiation, however, quantum dots with a stable
polymer coating have been found to be essentially nontoxic. NP
encapsulation of quantum dots allows for quantum dots to be
introduced into a stable aqueous solution, reducing the possibility of
Metal leakage.Then again, only little is known about the excretion
process of quantum dots from living organisms..
These and other questions must be carefully examined before
quantum dot applications can be approved for human clinical use.
68.
69.
70. Brand name Description
Emend
(Merck & Co. Inc.)
Nanocrystal (antiemetic) in a capsule
Rapamune
(Wyeth-Ayerst Laboratories)
Nanocrystallized Rapamycin (immunosuppressant) in a
tablet
Abraxane
(American Biosciences, Inc.)
Paclitaxel (anticancer drug)- bound albumin particles
Rexin-G
(Epeius Biotechnology
corporation)
A retroviral vector carrying cytotoxic gene
Olay Moisturizers
(Procter and Gamble)
Contains added transparent, better protecting nano zinc
oxide particles
Trimetaspheres (Luna Nanoworks) MRI images
Silcryst
(Nucryst Pharmaceuticals)
Enhance the solubility and sustained release of silver
nanocrystals
Nano-balls
(Univ. of South Florida)
Nano-sized plastic spheres with drugs (active against
methicillin-resistant staph (MRSA) bacteria) chemically
bonded to their surface that allow the drug to be dissolved
in water.
Nano-particulate pharmaceuticals
71. Company Product
• CytImmune Gold nanoparticles for targeted delivery of drugs to tumors
• Nucryst Antimicrobial wound dressings using silver nanocrystals
• NanobiotixNanoparticles that target tumor cells, when irradiated by xrays the
nanoparticles generate electrons which cause localized destruction of the tumor
cells.
• Oxonica Disease identification using gold nanoparticles (biomarkers)
• Nanotherapeutics Nanoparticles for improving the performance of drug delivery
by oral, inhaled or nasal methods
• NanoBio Nanoemulsions for nasal delivery to fight viruses (such as the flu
and colds) and bacteria
• BioDelivery Sciences Oral drug delivery of drugs encapuslated in a
nanocrystalline structure called a cochleate
• NanoBioMagnetics Magnetically responsive nanoparticles for targeted drug
delivery and other applications
• Z-Medica Medical gauze containing aluminosilicate nanoparticles which help bood
clot faster in open wounds
73. Open Problems
Manufacturing NPs for medical use:
Putting the drug on the particle
Assessment of NPs:
Dynamic structural
features in vivo
Kinetics of drug
release
Triggered drug release
Maintaining the drug in the particle
Making the drug come off the
particle once application is done
Purity and homogeneity of
nanoparticles
74. Open Problems
Toxicity:
short term - no toxicity in animals
long term- not known
Toxicity for both the host and the environment should be addressed
75. Open Problems
Delivery:
Ensuring Delivery to target
organ/cell
SOLUTION:
detection of NPs
at target, organs ,
cells , subcellular
location et al.
Tissue
distribution
Removal of nanoparticles
from the body
77. NPs
The blood-brain barrier
(BBB)
Brain micro-vessel endothelial cells build
up the blood brain barrier (BBB)
The BBB hinders water soluble molecules
and those with MW > 500 from getting
into the brain
78. Open Problems
GMP Challenges
• No standards for:
Purity and homogeneity of nanoparticles
Manufacturing Methods
Testing and Validation
Good manufacturing practices (GMP) are the practices required in order to
conform to guidelines recommended by agencies that control authorization
and licensing for manufacture and sale of food, drug products, and active
pharmaceutical products. These guidelines provide minimum requirements
that a pharmaceutical or a food product manufacturer must meet to assure that
the products are of high quality and do not pose any risk to the consumer or
public.
Good manufacturing practices, along with good laboratory practices and
good clinical practices, are overseen by regulatory agencies in the United
States, Canada, Europe, China, and other countries.
79. • Toxicities of nanomaterials are unknown
• To best target the nanomaterials so that systemic
administration can be used
• To uncage the drug so it gets out at the desired
location
• Removal of nanoparticles from the body
• Mathematical modeling of nanostructures
• Barrier crossing (BBB, G.I., et al.)
• GMP production
Summary
