1. Nanomedicine

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.

3. MAJOR BIOLOGICAL STRUCTURES
IN SCALE

4. Feynman: "There is plenty of room at the
bottom"
•
Seminal speech on December
1959 at CalTech
•
" Why can’t be compress 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.

5. NANO ≈ < 100 nm

6. Nanomedicine:
EC European Technology Platform
(ETP)

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.
……………………….
Diagnostics,
targeted
drug
delivery
and
regenerative medicine
constitute the core
disciplines of nanomedicine.”

8. Nanomedicine:
European Science Foundation (ESF)
“The field of Nanomedicine is the
science and technology of
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 subdisciplines which are in many ways
overlapping and are underpinned
by common technical issues.”

9. The numbers of nanomedicine
The total market for
nanobiotechnology products is
$19.3 billion in 2010 and is
growing at a compound annual
growth rate (CAGR) of 9% to reach
a forecasted market size of $29.7
billion by 2015.

10. Number of publications containing “nanoparticles” in Medline
14000
12000
10000
8000
6000
4000
2000
0
1990 1995 1999 2001 2003 2005 2007 2009 2011

12. 1966

13. 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

14. Topics in nanomedicine
• Diagnosis:
Prevention and Early Detection of diseases: Use
nanodevices to detect specific changes in diseased
cells and organism.

15. Nanoparticles (NP):
Smart Nanostructures for diagnosis
and therapy

16. 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

17. • Targeting: nanoparticles control over
delivery.
• Drugs are concentrated to target. Less
systemic toxicity.
• Less drug is necessary
• Drugs are protected inside NPs and are not
degraded. Longer halflife

18. • Multi-functionalization: Control over delivery
location, drug dosage, and drug release
characteristics is possible

19. An ideal Multi-functional nanoparticle vector
Anticorpo
Polietilenglicol
Evita che NP venga
(PEG)
digerita nei lisosomi
Indirizza la NP verso un
antigene specifico sulla la NP venga
Evita che
cellula da colpire
rimossa dal circolo
Tat peptide
Determina Fusione e
Probe magnetico
ingresso della NP nella
cellula
Permette imaging
tramite MRI
Farmaco

21. Examples of nanoparticulate carriers
+
+ +
+
+
+
LIPOSOME
S
DENDRIMER
S
SILICA NP
SOLID‐LIPID
NP
POLYMERIC
NP
QUANTUM DOTS
MICELLES
POLYMERIC MICELLE
GOLD NP
+
+
+ ++
+
LIPOPLEX
NANOTUBES
MAGNETIC

22. Carbon-based: Buckyballs and
Nanotubes
C60 1nm

23. What are Carbon Nanotubes?
Carbon nanotubes are
hexagonally shaped
arrangements of carbon
atoms that have been
rolled into tubes.

25. Nanotubes are members of the
fullerene structural family, which
also includes the spherical
buckyballs. The ends of a
nanotube might be capped with a
hemisphere of the buckyball
structure. 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 18 centimeters in length (as
of 2010).
Nanotubes are categorized as
single-walled nanotubes (SWNTs)
and
multi-walled
nanotubes
(MWNTs)
Human hair fragment
(the purplish thing) on
top of a network of
single-walled carbon
nanotubes

26. Single-walled
• Most single-walled
nanotubes (SWNT) have
a diameter of close to 1
nanometer, with a tube
length that can be many
millions of times longer..

27. • 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).
Armchair (n,n)

28. •
•
•
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.
Multi-walled

29. 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.

30. •
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.
Strength

31. Electrical properties
•
Depending how the graphene sheet
is rolled up, the nanotube can be
metallic; semiconducting or moderate
semiconductor.

32. 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.

33. 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.

34. 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.

35. Potential and current
applications of CNT

36. 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

37. Proposed as a vessel for transporting drugs
into the body. The drug can be attached to the side or trailed
behind, or the drug can actually be placed inside the
nanotube
Nanotube
Nanocap

38. Covalent Functionalization
Non-Covalent Functionalization

39. Funzionalizzazione non covalente (DNA)

40. final usage, however, may be limited by
their potential toxicity.
Under some conditions, nanotubes can cross
membrane barriers and can induce harmful
effects: inflammation, epithelioid granulomas
(microscopic
nodules),
fibrosis,and
biochemical/toxicological changes in the lungs.
Determining the toxicity of carbon nanotubes
has been one of the most pressing questions
in
nanotechnology.Unfortunately
such
research has only just begun and the data are
still fragmentary and subject to criticism.
Preliminary results highlight the difficulties in
evaluating the toxicity of this heterogeneous
material. Parameters such as structure, size
distribution, surface area, surface chemistry,
surface charge, and agglomeration state as
well as purity of the samples, have
considerable impact on the reactivity of carbon
nanotubes..
Their
Toxicity

41. Lipid-based NPs :Liposomes and
solid lipid nanoparticles (SLN)
50 – 500 nm
40-1000nm

42. •LIPOSOMES are the smallest spherical structure
technically produced by natural non-toxic
phospholipids and cholesterol.

43. Metal-core nanoparticles

44. gold nanoparticles (1-20 nm) are produced by reduction
of chloroauric acid (H[AuCl4]),
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. 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

47. Polymeric/Dendrimers
(e.g.PLGA, PAA, PACA)
spherical polymers of uniform
molecular weight made
from branched monomers are proving
particularly adapt at providing
multifunctional modularity.

48. Polymeric
PLGA POLY-LACTIC-GLYCOLIC ACID
PLGA Poly-Lactic-Glycolic Acid

49. Polyacrylamide (PACA)

50. In solvente organico
In acqua

51. Dendrimers are repetitively
branched molecules.
PAA= POLI
AMMINO AMMIDE
PLGA
PAA

52. Polyamidoamines (PAA or PAMAM)

53. HYDROGELS
Polymers or 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.

54. Mesoporous
silica (SiO2)

55. 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

56. Quantum dots
• Crystalline fluorophores
• CdSe semiconductor core
• ZnS Shell
3 nm

57. 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
First attempts have been made to use quantum dots
for tumor targeting under in vivo conditions.
Generically toxic

58. Quantum Dot Properties
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
58

59. 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

61. Quantum Dots
QD technology helps cancer researchers to observe fundamental
molecular events occurring in the tumor cells by tracking the
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.

62. Quantum Dots for Imaging of Tumor Cells
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
Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50. 62

63. 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. 63

65. Nano-particulate pharmaceuticals
Brand name
Emend
(Merck & Co. Inc.)
Rapamune
(Wyeth-Ayerst Laboratories)
Abraxane
(American Biosciences, Inc.)
Rexin-G
(Epeius Biotechnology
corporation)
Olay Moisturizers
(Procter and Gamble)
Trimetaspheres (Luna Nanoworks)
Description
Nanocrystal (antiemetic) in a capsule
Silcryst
(Nucryst Pharmaceuticals)
Nano-balls
(Univ. of South Florida)
Enhance the solubility and sustained release of silver
nanocrystals
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.
Nanocrystallized Rapamycin (immunosuppressant) in a
tablet
Paclitaxel (anticancer drug)- bound albumin particles
A retroviral vector carrying cytotoxic gene
Contains added transparent, better protecting nano zinc
oxide particles
MRI images

66. Company Product
CytImmune Gold nanoparticles for targeted delivery of drugs to tumors
Nucryst
Antimicrobial wound dressings using silver nanocrystals
Nanobiotix Nanoparticles 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.

67. Some liposome -based pharmaceuticals

68. Open Problems
Manufacturing NPs for medical use:
Putting the drug on the particle
Maintaining the drug in the particle
Making the drug come off the
particle once application is done
Purity and homogeneity of
nanoparticles
SOLUTION:
Assessment of NPs:
Dynamic structural
features in vivo
Kinetics of drug
release
Triggered drug release

69. Open Problems
Toxicity:
short term - no toxicity in animals
long term- not known
Toxicity for both the host and the environment should be addressed

70. Open Problems
Delivery:
Ensuring Delivery to target
organ/cell
Removal of nanoparticles
from the body
SOLUTION:
detection of NPs
at target, organs
, cells
, subcellular
location et al.
Tissue
distribution

71. Open Problems:
Targeting the brain
• 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

72. The blood-brain
barrier (BBB)
NPs

73. Open Problems
GMP Challenges
• No standards for:
Purity and homogeneity of nanoparticles
Manufacturing Methods
Testing and Validation

74. Summary
• 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
• to “re-cage” the drug when it is no longer desired
• Removal of nanoparticles from the body
• Mathematical modeling of nanostructures
• Barrier crossing (BBB, G.I., et al.)