NANO TECHNOLOGY OR MAGIC

BULLET IN MEDICAL SCIENCE ?

Dr. Shruti Bhat

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Disclaimer :
This presentation has been compiled for educational purposes only and for free dissemination of
information within the scientific community. It does not have any commercial or other implications.
The author thanks all those related with picture / diagram , reference sources cited in this
presentation.
 OUT LINE OF TALK
• Nano science, definitions, rationale and advantages of nano
technology
• Different nano materials and their possible applications in medicine.
• Different types of nano technology available; Case studies and
reviews.
• Regulatory considerations for nano technology drugs
• Nano business environment.
• Nano technology products on the horizon
• Closing thoughts
 NANO OBSERVED

• Life sciences :- drug delivery, Lab-on- a –chip, drug

design
• Security :- molecular barcoding, chemical detection.
• Materials :- powder, polymers
• Electronics :- LCD, semi-conductors, memory
• Energy :- Solar cells, fuel cells, membranes
• Nano tools :- STM. AFMs
Definition :-

Nano particles are solid colloidal particles ranging in size

from 10 nm to 1000nm (1 micron). They consist of
macromolecular materials in which the active principle is
dissolved, entrapped or encapsulated and/or to which the
active principle is adsorbed or attached to and can be used
for therapeutic disease management, silicon chip, bio-
medical applications etc..
The application of nano materials for medical diagnosis,
treatment of failing organs or prevention and cure of human
diseases is generally referred to as nano- medicine.

Whereas the branch of nano- medicine devoted to the

development of bio-degradable or non-bio dgradable
prostheses falls within the purview of nano-biomedical
science and engineering
Some terms in Nano-science include:-

• Nano structure :- 1 to 100 nm

• Nano- crystals :- Crystalline solid with grain sizes 1to 100
nm
• Nano coatings :- individual layers or multi-layer surface
coating in the range 1 to 100 nm
• Nano powders :- extremely fine powders with average
particles size in range of 1 to 100 nm
• Nano fibres :- fibers with a diameter in the range of 1 to
100 nm
Then why nano tech based drug products ?

Because of their combination of properties- including sub-

cellular size and controlled release capability and
susceptibility to external activation- devices/delievry
systems produced using nano technology enable new
applications in biological and medical science and focus
on formulating therapeutics agents in bio-compatible nano
composites such as nano particles, nano capsules, micellar
systems and conjugates.
Nanosizing=Nanotechnology ?

Not necessarily !!!!!

 “Nanosizing” of Drugs
Deals with “Particle size reduction” of drugs . And leads to:
– Increase surface area
– Enhance solubility
– Increase rate of dissolution
– Increase oral bio-availability
– Produce rapid onset of therapeutic action
– Decrease the dose needed
– Decrease fed/fasted variability
– Decrease patient to patient variability
 What is Nano technology?
• Research and technology development at the atomic or
macromolecular levels, in the length scale of approximately 1-100 nm
range…..by

• Creating and using structures, devices and systems that have novel
properties and functions because of their small or intermediate size.
…and has

• Ability to control or manipulate on the atomic scale…….offering

• Solutions to human health challenges in treating cancer, neurological

and psychiatric disorders, vaccines, gene therapy and protein
therapeutics.
Rationale and evolution of concept of nano
technology-
The fact that most drugs have not only positive
pharmacological effects , but they also exhibit side
effects , makes the concept of drug targeting very
attractive. This concept was visualised by Paul Ehrlich in
19th C where in he described a “ magic bullet” which
guides a drug directly into its target cell and the drug will
not affect surrounding cells.
Advantages of nano technology for drug therapy :-

1. Rapidly growing area of science

2. Anticipated to lead to the development of NDDS.
3. Private sector, academia and federal agencies spend
more on this area of science.
4. Permits solubilization of insoluble and chargeable drugs
5. Long plasma circulation especially to achieve sustained
release of drugs
 Advantages of nano technology for drug therapy :..
Contd./-

6 - Passive targeting:- Nano particles provide targeted

(cellular/tissue) delivery of drugs , to improve oral
bioavailability, to sustain drug/gene effect in target tissue,
to solubilize drugs for intravascular delivery and to
improve the stability of therapeutic agents against
enzymatic degradation, especially of proteins, peptides and
nucleic acid drugs.
Active targeting…..

7- : Due to their subcellular and sub-micron size, nano

particles can penetrate deep into tissues through fine
capillaries, cross the fenestration present in the epithelial
lining (e.g.liver) and are generally taken up efficiently by
the cells. This allows efficient delivery of the therapeutic
agents to target sites in the body.
Active targeting…..

8- By modulating polymer characteristics, one can control the release of

therapeutic agent from nano particles to achieve desired therapeutic
level in target tissue for required duration for optimal therapeutic
efficacy.

9- Nano particles can be delivered to distant target sites either by

localized delivery using a catheter –based approach with a minimal
invasive procedure or they can be conjugated to a bio-specific ligand
which could direct them to the target tissue or organ.
PLATFORM TECHNOLOGY
AVAILABLE
Four different types of nano-technology are
available :
1. Polymersomes :- eg. dendrimers
2. Hydro gel matrices :- e.g. micelles, dendrimers- micelle
combination
3. Bio-degradable nano particles :- e.g. red blood cells,
gelatin, PEG etc.
4. Nano vesicles/ nano fiber mats : e.g. buckey balls, nano
mats etc.

1-3 are normally used in delivery systems and 4 primarily

used in implants.
Polymersomes have a significant advantage due to their
stability, the ability to introduce multiple functions easily
and to engineer the ideal micro- environmental for the
molecule, while eliminating leakiness. For e.g., to achieve
oral administration of proteins, insulin, vaccines (where
mucosal response is desired) and other biologicals, this
technology is being co-developed with hydrogel matrice
technology
Nano vesicles and nanofiber mats are echogenic contrast
agents, which are amenable to parenteral administration,
offering the dual capability of drug delivery and tissue
/cell targeting. The stabilized micro bubbles/ contrast
agents when exposed to an ultrasonic beam at the imaged
area, can be stimulated to release its contents , thereby
delivering the drug to the visualized area.
Complex nucleic acids with modified spermines, which
have been shown to result in cell specific targeting. The
goal is to develop hepatocte and macrophage targeting
complexes of DNA. The former is for gene therapy, while
the latter serves to enable genetic vaccines to be
efficacious.
NANO MATERIALS-
CARRIERS
Requirements of an ideal vector (or NANO
MATERIAL ) for drug targeting are as
follows:-
1. Carrier is capable of extended circulation in the
bloodstream
2. It must be small enough to gain access to target tissues
and tarot cells.
3. It must have flexible tropisms for applicability in a range
of disease targets
4. It must be able to deliver the active moiety into the cells
and following endocytosis and
5. It must be capable of escaping endosome –lysosome
processing.
 Nanomaterials
• Multifunctional materials that interact with biological systems in well
controlled ways
• Exhibit unique properties and functions because of their small size.
• Include such structures as:
– Carbon nanostructures
– Dendrimers
– Metal oxides (FeO, TiO2, ZnO)
– Quantum dots (CdSe)
– Some liposomes
– Engineered gene circuits, Chitosan, PEG, PEG coated lactic acid,
polyalkyl cyanoacrylate, polyglutaraldehyde, gelatin, solid lipid
nanoparticales, silicon micro-chip
 Dendrimers
• Spherical polymeric molecules
• Series of chemical shells built on a small core
molecule (each shell is called a generation).
• Made from a core and alternating layers of 2
monomers: acrylic acid and diamine.
• Molecular structure has the form of a tree with many
branches.
• Can serve as nano-devices for delivery of therapeutics.
Dendrimer Structure
 Applications of dendrimers in nano
technology based drug product
development
• Biologic nanodevices based on
dendrimers are being developed with the
potential to :
– Recognize Cancer cells
– Diagnose cause of cancer
– Delivery of drug to target
– Report location of tumor
– Report outcome of therapy (cancer
cell death)
– (http://www.nano.med.umich.edu,
James Baker, Univ. of Michigan)
The body distribution and elimination patterns of
macromolecular systems are dictated mainly by their
physicochemical properties , partile size, hydrophilicity and
surface properties .After IV injection :-

• particles greater than 5-7 • Particles with a diameter

microns in diameter are
cleared by capillary
filtration mainly in lungs.
less than 5 microns are
generally cleared from
circulation by cells of the
reticula- endothelial
system (RES)
CASE STUDIES
Bio degradable vesicles ….
Some examples of innovative Nano
vesicle materials :-

• Carbon nano strutures ( in implants )

• Bucky balls ( in implants )
• Nano tubes ( in implants )
• Nano wires ( in implants )
• Nano whiskers ( in implants )
• Dendrimers ( delivery systems- implants combination
products)
 Carbon Nanostructures
• Source of pure carbon (like graphite and diamond).
• Based on fullerene molecules which are closed and convex
cage molecules containing only hexagonal and pentagonal
faces.
• Examples of carbon nano structures:
– Buckyballs
– Nanotubes
– Nanowires
– Nanowhiskers
 Carbon Nanotubes
• Carbon nanotubes
– elongated fullerenes.
– resemble graphite sheets
wrapped into cylinders
– Length to width ratio is
very high (few nm in
diameter and up to 1 mm in
length)
 Carbon Buckyballs
• Buckyballs
– spherical fullerenes (C60 is
most stable and symmetrical
and resembles a soccer
ball).
– named after architect R.
Buckminster Fuller .
– 1996 Nobel prize in
Chemistry awarded for their
discovery.
 Some Properties of Carbon
Nanostructures
• High tensile strength
• Physically stable
• Chemically reactive with free radicals
– Derivatives can be formed
• More hydrophilic than fullerenes
• New organic molecules can be generated
• Other atoms can be placed inside its “cage” (doping with alkali
metals)
– Superconducting properties
– Optical properties (endohedral fullerenes)
Several Nanocarbon Structures
 Leading the Way…Drug-Eluting Stents

Drug-eluting stents “represent the pinnacle of the

combination product field, which harnesses the strengths
of the device industry and those of the drug or biologics
industry to produce technologies that could not be
developed by either sector alone.”

 
[Swain E. Blazing New Paths for Product Introductions.
MDDI Sept/Oct 2003. Available on www.devicelink.com]
CASE STUDIES
 REGULATORY
CONSIDERATIONS
 Regulatory Considerations for Nano
technology Drugs include…….
• Nomenclature
• Quality
• Safety
• Environmental Impact
 Nanomaterials are not new to FDA

• Many approved products currently on the market with

components manufactured in the nano scale range (drugs,
sunscreens, cosmetics…).

• Most drugs act at their site of action as individual molecules

that are in the nano size range
Quality Considerations
– Critical attributes of nano technology products might include:
• Particle size and size distribution
• Surface area, surface chemistry, surface coating, porosity
• Hydrophilicity, surface charge density
• Purity, sterility
• Stability (aggregation, protein adsorption)
• Does in vitro behavior reflect in vivo behavior
– Manufacturing and Controls
– Drug release parameters and bio-equivalence testing
considerations.
 Preclinical Safety Assessment
• Current required studies for drug applications generally
include:
– In vivo short-term and long-term toxicity in rodent and
non-rodent species, ADME, pharmacology, safety
pharmacology, genotoxicity, developmental toxicity,
irritation studies, immunotoxicology, carcinogenicity
and other possible studies.
– Additional studies might be requested based on drug-
specific considerations.
 Preclinical Safety Assessment
(cont’d)
• Studies in In vitro models
– Target binding/receptor screens
– Cellular uptake
– Cytotoxicity
• Studies in In vivo models
– Efficacy/proof of concept
– Imaging studies
– Special toxicology studies (functional studies?)
– Mechanisms of tissue uptake and tissue clearance
 Environmental Considerations
• Depend on reported physical characteristics and biological effects of
specific nanomaterials.
• 1. Facility design considerations
• Limiting cross contamination between different products
manufactured in the same facility.
• Limiting contamination by components of machinery used in the
manufacturing process
• 2. Impact of nanotechnology products on the environment
• Disposal of unused/expired products.
• Potential environmental impact of material entering the
environment after administration.
 NANO BUSINESS
ENVIRONMENT
(Reviews on pharma products on horizons of
commercialization developed on nano- particles- platform
technology)
Nano tech- Product Examples
• Wound Care –

dermal fibroblasts seeded on a 3-D bioabsorbable

scaffold. For hard to heal wounds, e.g diabetic
foot ulcers.
[Dermagraft, Advanced Tissue Sciences]
Nano tech- Product Examples…contd./..

• Orthopedics – titanium spinal fusion cage and absorbable collagen

sponge with recombinant bone morphogenic protein (rhBMP-2). For
lumbar fusion, degenerative disc disease.
[InFUSE, Medtronic]

• Drug Delivery / Oncology – implanted polymer wafer with

chemotherapeutic agent. For sustained-release drug delivery to treat
malignant glioma.
[Gliadel, Guilford Pharmaceuticals Inc.]
Nano tech- Products on the Horizon

Oncology
• Light Infusion Technology - photosensitizer drugs
activated by light-emitting diode devices for solid tumor
destruction [Light Sciences Corp.]

Diabetes
• Bioartificial Pancreas – active Islet of Langerhans cells
that sense and secrete insulin, and thin sheet of polymer
seeded with living islets, implanted in peritoneal cavity.
[Islet Sheet Medical]
Nano tech Products on the Horizon…contd./-

• Controlled-release microchip drug delivery systems - “Pharmacy-

on-a-Chip”. Microfabricated silicon microchip, stores drugs in
reservoirs covered by gold or polymer membrane. Automatically
releases medications at programmed intervals.
[research conducted at U. of Toronto, MIT, U. of Texas-Austin,
Cornell U.]
• Cardiology applications
– hybrid drug-device for cardiac arrhythmias
– biologics to create a sinus atrial node, the heart’s natural
pacemaker
– cell therapy for heart muscle tissue regeneration
 NANO BUSINESS ENVIRONMENT

Altair Technologies Inc. Nano material manufacturing

Bio Sante Pharmaceuticals Nano particlulate- based vaccine adjuvant and delivery
system
FEI Co. Nano- profilometry (SNP) imaging systems

Flamel Technologies , S.A. Bio-pharmaceutical drug delivery systems.

Harris & Harris group , Inc. Nanotech venture capital group

JMAR Technologies, Inc. Plasma lithography at sub-100nm level

MFIC corporation Fluid materials processing systems

Nanogen, Inc. Nanochip molecular biology workstation

Nanophase technologies corp. Nanocrystalline materials

Nano-properietary Inc. Carbon nanotube technology

NVE Corp. Spintronics

Pharmacopia, Inc. Drug discovery and chemical dvelopment process

Skye Pharm PLC Integrated drug discovery

SYMYX technologies Nanomaterial discovery

Veeco Instruments Inc. Nanoman, PicoForce, Nanoscope

SELECTED NANOBIO-TECHNOLOGY COMPANIES DEVELOPING BIO-ANALYSIS APPLICATIONS

Technology Companies Platforms

SPM Hitachi High technologies (London) Electron -beam lithography (on market)
Image scientific Instruments (Madison) Leap-atom probe microscope (on market)
Veeco (Woodbury, NY) Near-field scanning optical microscope (on market)

Arrays Affymetrix (Santa Clara) High- density oligonucleotides (GeneChip) arrays (on market)
BioForce Nanosciences (Ames, IA) Nanoarrays- 10,000 fold-smaller than conventional arrays (on market)
Nanogen (SanDiego) Oligonucleotide arrays with polarised features ( on market)
Nanolink (Chicago) Dip-pen nanolithography system ( on market)

Molecular tags Dendritic nanotechnologies (Mt.Plesant, MI) Dendrimers ( on market)

Evident Technologies 9 Ocean Optics USA) Semi conductor nanocrystal quantum dots ( on market)
Genicon Sciencies ( SanDiego) 2 color microarray kit resonance light- scattering detection and imaging instrument

Nano Plex ( Mountain View CA) Nano- bar codes particles kit ( on market)
Nanosphere (Chicago) Gold- nanoparticle probes and detection systems
Quantum Dot ( Haywood CA) Quantum-dot conjugates ( steptavicin, protein A, biotin- on market)

Microfluidics Caliper Technologies (MountainView CA) Microfluidics ( Lab Chip- on market)

Fluidigm ( San Francisco) Multi-layer soft lithography microfluidics
Nanostream (Pasadena CA) High through put screening platforms
Surface Logix ( Brighton, MA) High through-put screening platforms using soft lithography and biosurface chemistry
S E L E C T E D N AN O-B IOT E C H N OL OGY C OMP AN IE S D E V E L OP IN G ME D IC AL D E V IC E S

Focus Com p a n y P la tfo rm un de r de ve op m e nt

Tis s ue engineering A ngs tronM edic a (Newton) Nanos truc tured hy drox y apatile artific ial bone m atrix

NanoM ateria (Chic ago) Nanos truc tured m aterial for heart, c artilage and nerve regeneration

pS iM edic a ( the M alverns , UKB)ioS ilic on for bone im plants

B ioS ens ors A gilent )P alto CA ) Nanopore s equenc ing (in c ollaboration with Harvard univers ity )

454 Life S c ienc es ( B ranford,PCT)

ic oTiter s equenc ing plate

US G enom ic s (W oburn) S ingle-s trand DNA s equenc ing

nanom ix (E m ery ville, CA ) Nanotube c hem ic al bios ens ors

Nano bio-technology companies developing drug delivery and therapeutic applications
Focus Company
Therapeutics Alinis BioSciences (Emeryville CA)
ALZA ( MountainView, CA)
Nanocrystal Technologies (King of Prussia, PA)
NanoMed Pharmaceuticals (Kalamazoo, MI)
Star - Pharma ( Melbourne)
Drug delivery Advectus Life Sciences (West Vancouver)
Bio Delivery Sciences (Newark)
BioSante Pharmaceuticals (Lincolnshire)
C-Sixty ( Houston)
Cytimmune Sciences ( College Park, MD)
NanoCarrier (Chiba, Japan)
NanoBio (Ann Arbor, MI)
NanoSpectra BioSciences (Houston)
Tageromes (Palo Alto, CA)
Platforms
Polyfunctional nanoparticles
Lipid nano particles with PEG coating doxorubicin liposomes-( on market)
NanoMill technology for creating nanocrystals
Nanotemplate engineering for drug and vaccine delivery systems
VivaGel anti-HIV dendrimer (Phase-I)
NanoCure systems for delivery of anti cancer drugs across blood- brain barrier.
BioOral nanochelates cigar-shaped structurs comprised of lip bilayers
Nanoparticulate platform (CAP) for drug delivery (Phase-I)
Fullerene - based drug delivery
Tumor necrosis factor bound to colloidal gold nanocrystal for targetting
tumors, vectors with docking site for gene therapy.
NanoCap micellar nanoparticle for water- insoluble drugs (under development)
Anti-microbial nanoemulsions (Phase-I)
Nanoshells for optical therapies
Injectable nanospheres for therapeutic or diagnostic agents
Closing thoughts…

• Very young field, will grow quickly

• Watch for new sources to cover this emerging industry
• No indexing specific to nano tech-combination products
• Non-standard terms used in science.
• Active work on nano- technology are focused in the
domains of orthopedic, dental, bladder, neurologic,
vascular, cartilage and cardiovascular applications.
• Incorporates many technologies
– Biomaterials & Coatings
– Genomics & Proteomics
– Tissue Engineering
– Micro- & Nano technology
– Advanced drug delivery
– ‘Traditional’ drugs & devices
 Industry Predictions
• Focus on disease cure (drugs, biologics) rather than treatment
(devices)
• Ultimate disease cures will come from biotech, unless pharma
industry co-opts it
• Nano tech- products “cannibalize” existing products; replace drugs
. Few large manufacturers have both drug and device components
• Cross-industry partnerships and acquisitions
• Disparate industries must work together
Future image of Nanoparticles
Information sources
• Frost & Sullivan
– Medical Device Technology Alert; Inside R&D;
Advanced Manufacturing Technology; High-Tech
Materials Alert; Advanced Coatings and Surface
Technology

• Espicom Publications
– Drug Delivery Intelligence File; Cardiovascular Device
Business; Drug Delivery Insight; Medical Industry
Week
thru- www.google.com
Information sources (cont.)
Web Sites
• Medical Devicelink – www.devicelink.com
• BIO – Biotechnology Industry Organization www.bio.org
• SCIRUS – www.scirus.com
• AdvaMed - www.advamed.org
• MDMA (Medical Device Manufacturers Association) –
www.medicaldevices.org
• Society for Biomaterials - www.biomaterials.org
• FDLI (Food & Drug Law Institute) www.fdli.org
• AAMI (Association for the Advancement of Medical
Instrumentation) – www.aami.org

.
Thank you