Nanotechnology & Nanomedicine

Hans Bluyssen, 21-10-2015

Nanorobot – Sending the sperms

Nanorobot – Seeking cancer cell

Nanorobotic Artery Cleaner

Nanorobot – repairing nerve cell

Ability to enter cells and

correct DNA or a

deficiency.

Repair cells, tissue, and

even organs.

Carry tiny cameras and be

powered from the

electrolytes in the blood.

Break up blood clots or

even kidney stones.

Engineering and manufacturing at the

scale of a nanometer or nanoscale

(nanometer = 10-9 meter), a hundred-

thousandth the width of a human hair.

Examples of nano-substance are- Atom

diameter 0.15 nm, diameter of double

strand DNA 2 nm, and cell 10.000 nm.

Nanotechnology

What is Nanoscale

1.27 × 107 m

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0.22 m 0.7 × 10-9 m

Fullerenes

C60

12,756 Km 22 cm 0.7 nm

10 millions times

smaller

1 billion times

smaller

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Carbon

Nanotube

Fullerenes

Nanotechnology

Creation of functional devices in the nanometre range

and the exploitation of the unique properties of these

devices in various fields

Compared to Human Hair

A Human Hair is about 100,000nm wide

Cells themselves are very complex and efficient nano-

machines.

Most areas of nanoscience aim to learn from biological

nanosystems.

Where all the action is: the cell (10-30 um) !

Watering flowers or flooding the neighborhood?

treating atherosclerosis with lipid lowering drugs

arteriosclerosis:

- begins at the cell

- > focal lesions in the arteries

- leads to myocardial infarction

and stroke

arterial plaque

some lipid lowering drugs:

effects on plaques

can save lives

effects on immune

system

effects on liver Can endanger large

companies

muscles:

can lead to cell death

can endanger human life

!!!!!Solution: Nanomedicine

Science’s growing ability to work at the molecular

level, atom by atom, combining biological

materials and the rules of physics, chemistry,

and genetics to fabricate minute synthetic

structures. Nanomanufacturing?

The ultimate goal is to develop a highly functional

system of biosensors, electronic circuits, nano-

sized microchips, molecular ‘‘switches,’’ and

even tissue analogs for growing skin, bones,

muscle, and other organs of the body.

Nanobiotechnology

Nanomedicine

The application of

nanotechnology to

disease treatment,

diagnosis,

monitoring,

control of biological

systems

NANOTECHNOLOGY TOOL BOX

• NANOPORES • NANOTUBES

• NANOPARTICLES • NANOCRYSTALS

• NANOFIBERS • NANOARRAYS

• NANOELECTRONICS • NANOPROBES

• NANOCANTILEVERS • NANOSHELLS

• NANORIBBONS • NANOCOATINGS

• NANOCOMPOSITES • BUCKYBALLS

Drug encapsulation and delivery

with nanoparticles

Vehicles for delivery:

- coated solid particles

- vesicles

- liposomes

- micelles

- polymers

- solid lipid nanoparticles

- silica nanoparticles

Nanoparticles

•8Re F, Moresco R, Masserini M. Nanoparticles for neuroimaging. Journal of Physics D: Applied Physics. 2012;45(7):073001.

Nanomedicine

A vehicle for delivery of therapeutics into the body

Small molecule drug compounds, DNA/genes, proteins, vaccines,

etc.

Administration routes to reach systemic circulation or infected

organs and cells: oral, intravenous, inhalation, ocular, topical

Functionalized

nanoparticles

Nanoparticle as delivery system for drugs

or genes for tissue and cell

Functionalized

nanoparticles

Silica nanocapsules

Porous hollow silica nanocapsules

Nanoparticles/nanocapsules as drug

delivery carriers to cancer

Porous hollow silica nanocapsules for

Cefradine delivery (antibacterial chemical)

Functionalized

nanoparticles

The goal of nanomedicine is to develop

safer and more effective therapeutic and

diagnostic modalities

•McNeil SE. J Leukoc Biol, 2005. 78(3): p. 585-94.

•doi:10.1189/jlb.0205074

Functionalized

nanoparticles

Interesting facts about nanomedicine A. Interest in the area has grown exponentially B. Drug delivery is the most productive area

C. Drug delivery is the most established technology in the nanomedicine market

Nature Biotechnology 2006, Vol. 4, pp.1212-1217

Drug targeting by nanoparticles or nanocapsules offers the

following enormous advantages:

-reduces dosage, ensures the pharmaceutical

effects, and minimizes side-effects;

-protects drugs against degradation and enhances

drug stability.

Nanoparticles can penetrate through small capillaries and

are taken up by cells, which allows efficient drug

accumulation at target sites.

A sustained and controlled release of drugs at target sites

over a period of days or even weeks is possible.

Nanoparticles and Drug delivery

Nanoparticles with diameter less than 200nm are not

screened out of circulation by liver and spleen.

Nanotech based drug delivery is less toxic as well as

inexpensive.

Nanoparticles and Drug delivery

Trafficking of nanoparticles

Nanoparticles

eventually act as

reservoirs for

sustained release of

encapsulated

therapeutic agent at

target cells.

-Intracellular

-Extracellular

Nanoparticle use in Cancer Treatments

• Because of their small size, nanoparticles

can pass through interstitial spaces

between necrotic and quiescent cells.

• Tumor cells typically have larger

interstitial spaces than healthy cells

• Particles collect in center bringing

therapeutics to kill the tumor from inside

out.

Nanotechnology in Health Care

Thermal ablation of cancer cells assisted

by nanoshells coated with metallic layer

and an external energy source – National

Cancer Institute

• Thermal ablation of

cancer cells

− Nanoshells have metallic

outer layer and silica core

− Selectively targeted to cancer

cells

− The nanoshells are heated

with an external energy

source killing the cancer cells

Drug Delivery

1

3

2

4

1) A nanoparticle carries the pharmaceutical agent inside its core, while its shell is functionalized with a ‘binding’ agent

2) Through the ‘binding’ agent, the ‘targeted’ nanoparticle recognizes the target cell. The functionalized nanoparticle shell interacts with the cell membrane

3) The nanoparticle is ingested inside the cell, and interacts with the biomolecules inside the cell

4) The nanoparticle particles breaks, and the pharmaceutical agent is released

Source: Comprehensive Cancer Center Ohio University

Because of their small sizes, nanoparticles are taken up by cells where large particles would be excluded or cleared from the body

A Drug Delivery Nanoparticle A. Nanoparticles for drug delivery can be metal-, polymer-, or lipid-based. Below (left) an example of the latter, containing SiRNA encapsulated, and functionalized with a specific antibody. SiRNA can control often lethal inflammatory body responses, as shown in the microscopic images below (right)

Science 2008, Vol. 316, pp 627-630

antibody

lipid

SiRNA Healthy tissue Sick tissue treated with non-targeted nanoparticles

Sick tissue treated with targeted nanoparticles

B. C.

Dendrimers Dendritic polymers = Dendrimers

Polyamidoamine (PAMAM)

phosphorous-based, Polylysine

Highly branched structures –

Molecular “hooks” – to attach

Cell identification tags,

fluorescent dyes, enzymes

ideal building blocks in nanochemistry for the creation of

more complex three-dimensional structures.

Dendrimers &

Therapeutics

The Michigan Nanotechnology Institute for Medicine

and Biological Sciences

What are Quantum Dots?

• At the heart of the fluorescence of Qdot® nanocrystals is the

formation of excitons. The exciton can be thought of as

analogous to the excited state of traditional fluorophores;

however, excitons typically have much longer lifetimes (up to

~µseconds).

• Qdot® nanocrystals are also extremely efficient machines for

generating fluorescence; their intrinsic brightness is often many

times that observed for other classes of fluorophores.

• Another practical benefit is that the photostability of Qdot®

nanocrystals is many orders of magnitude greater than that

associated with traditional fluorescent molecules; enables long-

term imaging experiments.

Tuneability of Qdot® nanocrystals. Five different

nanocrystal solutions are shown excited with the same

long-wavelength UV lamp; the size of the nanocrystal

determines the color.

widely exploited in

the development

of multicolor

assays

Qdot® bioconjugate is a generic term to describe

Qdot® nanocrystals coupled to proteins,

oligonucleotides, small molecules, etc., which are used

to direct binding of the quantum dots to targets of

interest.

Quantum Dot Bioconjugate

Laminin in a mouse

kidney section was labeled

with an anti-laminin

primary antibody and

visualized using green-

fluorescent Qdot® 565

IgG.

PECAM

(platelet/endothelial cell

adhesion molecule; CD31)

was labeled with an anti–

PECAM-1 primary

antibody and visualized

using red-fluorescent

Qdot® 655 IgG.

Nuclei were stained with

blue-fluorescent Hoechst

33342.

Targeting QD’s for intracellular imaging

Ligand coated QDNC

QD release

Ingestion

Decomposition

labeling

Nano Letters 2008., Vol. 8, pp3887-3892

A. Using a drug-delivery-like mechanism, a targeted lipid-based nanoparticle (TNP) encapsulating QD’s specifically ‘attacks’ a cell having the receptors that pair with its ligand coating. Upon ingestion and destruction of the TNP, the QD’s are set free and accumulate on intracellular structures

C. QD (red)intracellular uptake is enhanced when using the QDNC instead of the free QD’s

B.

D. Imaging of nucleus (blue) and cytoplasm (other) after 30 min (left) and 3 hours after uptake

Water soluble quantum dots to image sentinel lymph nodes which

are used for diagnosing breast cancer.

Antibody-Modified Quantum dots for the sensitive imaging of the

tumour tissue on a tumour-bearing mouse.

QD Localization of a Tumor

It is possible to overlap

X-ray images with

infrared images to localize

a tumor.

Anatomical context +

QD’s emission:

tumor location.

Annu. Rev. Biomed. Eng. 2007. Vol. 9, pp. 257–288

Diagnosis

A. Detection of multiple biomarkers simultaneously

B. A specific phenotype of cancer

cells has a particular combination

of biomarkers on its membrane

D.

C. Different phenotypes show different

aggressiveness on their metastatic behavior

tumor

Blood

vessels

Cancer cells

metastasis Source: www.cancernews.com

Multiplex Diagnosis

•Nature Protocols 2007. Vol. 2, pp. 1-15

A. Four quantum dots of different diameter (i.e. different color) are respectively

functionalized with four different antigens. Allowing for the distinction of two distinct

phenotypes

Each peak correspond

to the emission of a

specific QD/antigen

The peak intensity

correlates to the

concentration of a

specific QD

Aggressive cancer cells

Mild cancer cells

As a result

cancer cells

of different

phenotype

are colored

differently

Nanotech in Disease Imaging &

Therapeutic Monitoring

in vivo imaging system including the

relationship between metastasis of

cancer and the onset of angiogenesis

and the efficiency of anticancer drugs.

Imaging

Diagnosis using

Nanothermometers Cancer cells appears to have a more elevated temperature than normal

cells. Therefore, a local temperature mapping can be used to determine

the spread of a tumor

A gold nanoparticle is functionalized with a PEG coating, which itself

is assembled to a layer of smaller QD’s. The emission properties of

the nanoparticle change with temperature due to the

stretching/contraction of the PEG

Thermal image of a healthy and cancerous breast

healthy sick

•Source: 9th European Congress of Thermology, Krakow, Poland Angew. Chem. Int. Ed. 2005, Vol. 44, 7439 –7442

•Credits: Mathies Lab, UC-Berkeley

•Quake Lab, Stanford

•Agilent, Inc.

Lab-on-a-Chip One of the more promising areas of nanofluidics is its potential for

integration into microfluidic systems, i.e. MicroTotal Analytical Systems

or Lab-on-a-chip structures

Lab-on-a-Chip

Lab-on-Chip in Health Care

The microfluidic channel with nanowire

sensor can detect the presence of altered

genes associated with cancer – J. Heath, Cali. Insti. of

Technology

The nanoscale cantilever detects the

presence and concentration of various

molecular expressions of a cancer cell – A. Majumdar, Univ. of Cal. at Berkeley

• Detection and Diagnosis

• Lab on chips help detection

and diagnosis of diseases

more efficiently

• Nanowire and cantilever lab

on chips help in early

detection of cancer

biomarkers

BioCOM Chip

•Three cantilevers coated with three

different antibodies, are exposed to

prostate-specific antigen (PSA)

•The left cantilever bends as PSA binds

to the anti-PSA antibody on the

cantilever

•The other cantilevers do not bend

because their antibodies do not bind to

PSA.

•Min Yue, Katherine Dunphy, Henry Lin, Srinath Satyanarayana (http://www.nano.me.berkeley.edu/)

Ultra-sensitive biosensor for the detection of bio-markers using bio-compatible ZnO nanowires.

Diagnostics – Biosensors

ZnO nanowires

Novel Materials

Antibody

Antigen Electrode

BioMEMS – Micro and Nanofluidics

The Not-so-Distant Future

PDA

2008

??

Paramount

Lab-on-a-Pill

Today

From Housecalls to House Calls

Tomorrow

•http://www.biomedox.com/media

/nanotechnology-documentary-

revolutionizing-medicine-and-

healthcare_ebeb2ce1e.html

•https://www.google.pl/search?q=a

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Patients will drink fluids containing nanorobots

programmed to attack and reconstruct the molecular

structure of cancer cells and viruses.

Nanorobots could also be programmed to perform

delicate surgeries: nano-surgeons

Additionally, nanorobots could change your physical

appearance: nano-cosmetics

Nanotechnology & Medicine: Future

NANOHUMVEES TO

DESTROY TUMOR

CELLS

NANOBOTS TO CLEAN

ARTERIES

CONCEPTIONS OF A

FANTASTIC FUTURE FOR

NANOMEDICINE

Respirocyte

The artificial red blood cell or

"respirocyte“

Blood borne spherical 1-micron

diamondoid 1000-atm pressure

vessel with active pumping

powered by endogenous serum

glucose, able to deliver 236 times

more oxygen to the tissues per unit

volume than natural red cells and

to manage carbonic acidity

An onboard nanocomputer and numerous chemical and pressure

sensors enable complex device behaviors remotely reprogrammable by

the physician via externally applied acoustic signals.

Primary applications will include

-Transfusable blood substitution;

-Partial treatment for anemia,

-Perinatal/neonatal and lung disorders;

-Enhancement of cardiovascular/neurovascular procedures,

-Tumor therapies and diagnostics;

-Artificial breathing; and

-A variety of sports…….

Respirocyte

Artificial platelets (Clottocyte)

An artificial mechanical platelet

appears to halt bleeding 100-1000

times faster than natural

hemostasis.

A single clottocyte, upon reliably

detecting a blood vessel break,

can rapidly communicate this fact

to its neighbors, immediately

triggering a progressive controlled

mesh-release cascade.

Vasculoid The vasculoid is a single, complex, multisegmented

nanotechnological medical robotic system capable of duplicating

all essential thermal and biochemical transport functions of the

blood, including circulation of respiratory gases, glucose,

hormones, cytokines, waste products, and cellular components.

This nanorobotic system, a very aggressive and physiologically

intrusive macroscale nanomedical device comprised of ~500

trillion stored or active individual nanorobots, weighs ~2 kg and

consumes from 30-200 watts of power in the basic human model,

depending on activity level.

The vasculoid system

conforms to the shape of

existing blood vessels and

serves as a complete

replacement for natural blood.

Augmentation

Nanomedicine can make possible the re-engineering of

the human body, including the improvement of existing

natural biological systems and the addition of new

systems and capabilities not found in nature. Such re-

engineering is commonly called "augmentation".

Goals of Nanomedicine

Ultimate goal is to integrate detection, diagnostics, treatment and prevention of disease

into a personalized single platform

Influenza viruses kills 10 Mio people during world war I

Computer virus shoots down millions of PC’s worldwide in

year 2000

- Autonomous, self-replicating nano-agents: a danger for

the future ?

Potential problems of

nanotechnology in medicine

Nanotechnology Applications

Information Technology • Energy

Medicine Consumer Goods

• Smaller, faster, more

energy efficient and

powerful computing

and other IT-based

systems

• More efficient and cost

effective technologies for

energy production

− Solar cells

− Fuel cells

− Batteries

− Bio fuels

• Foods and beverages

−Advanced packaging materials,

sensors, and lab-on-chips for

food quality testing

• Appliances and textiles

−Stain proof, water proof and

wrinkle free textiles

• Household and cosmetics

− Self-cleaning and scratch free

products, paints, and better

cosmetics

• Cancer treatment

• Bone treatment

• Drug delivery

• Appetite control

• Drug development

• Medical tools

• Diagnostic tests

• Imaging

About $80B in products

incorporate

nanotechnology in the US

in 2009 with the leading

category being:

Consumer Products

Sporting Goods

Cosmetics, Clothes and Food

This is a 2 gigabyte

hard drive. It

weighs about 70

pounds. It was first

used in the 1980s.

Its cost at that time

ranged from

$80,000 to

$140,000.

Image by HighPoint Learning

2 GB in 1980s

$80,000

2 GB in 1990s

$200

2 GB in 2010

$5 Image by HighPoint Learning

Current research

shows that by

using

nanotechnology,

1000 GB of

memory can fit

on the head of

this pin. 1000 GB

is 1 Terabyte.

Image by HighPoint Learning

Nanomanufacturing is the use of mechanical,

chemical, or alternative physical processes at the

nano-level level to directly create, or indirectly direct

the crystalline merger of, atoms and micro-scale

materials into multi-faceted materials and inventions.

These materials incorporate nanoparticles, nanoshells,

nanopolymers, nanotubes, nanoctagons and

nanowires.

Nanomanufacturing

As millions of atoms are pieced together by

nanomachines, a specific product will begin to take

shape.

The goal of molecular manufacturing is to

manipulate atoms individually and place them in a

pattern to produce a desired structure.

Molecular manufacturing

Economic Impact of Nanotechnology

Market Size Predictions (within a decade)*

$340B/yr Materials

$300B/yr Electronics

$180B/yr Pharmaceuticals

$100B/yr Chemical manufacture

$ 70B/yr Aerospace

$ 20B/yr Tools

$ 30B/yr Improved healthcare

$ 45B/yr Sustainability

$1 Trillion per year by 2015

*2007 Estimates by industry groups, source: NSF