Nano-Sized Drug Delivery
Prof. Heather D. Maynard
Department of Chemistry and
Biochemistry
University of California, Los
Angeles
Topic of Today’s Lecture
This talk will focus on my
research on combining synthetic
polymers with proteins from
Nature to produce nano-sized
medicines
Outline of Today’s Lecture
1. What is nano?
2. Polymers are everywhere!
3. Why nanosized carriers are
important in medicine
4. Protein-polymer nano-therapeutics
Outline of Today’s Lecture
1. What is nano?
2. Polymers are everywhere!
3. Why nanosized carriers are
important in medicine
4. Protein-polymer nano-therapeutics
What is Nano?
• Nanoscience is the study of objects
measured in nanometers
– 1-billionth of a meter
– ~80,000 times smaller than the diameter of a
single human hair
Closer Look at a Human Hair
Width of this line is 100 nm
http://www.aber.ac.uk/bioimage/image/uwbl-0411-w.jpg
What is Nano?
• Nanoscience is the study of objects
measured in nanometers
– 1-billionth of a meter
– ~80,000 times smaller than the diameter of a
single human hair
– New properties emerge at the nanoscale
• Size and shape matter
Super-Repellent Nano-Materials
http://cjmems.seas.ucla.edu/members/changhwan/main.html
http://www.engineer.ucla.edu/magazine/fall06/noslip.html
Geckos Walk on Walls
Nano-Finger Tips Allow Geckos to Stick
http://robotics.eecs.berkeley.edu/~ronf/Gecko/index.html
Man-Made Geckos
Super Adhesive Nano-Materials
Synthetic nano-materials can
exhibit strong adhesion similar to
gecko fingers
Yurdumarkan et al, Chem. Commun. 2005, 3799-3801
How Nano Effects You
Nanotech products are already on the market
According to the National Nanotechnology
Initiative (NNI), “The worldwide workforce
necessary to support the field of
nanotechnology is estimated at 2 million by
2015”*
UCLA is at the forefront of nanotechnology research
and education!!
There are many course that are now offered on the
subject, including my BioNanotechnology Course
(Chem140/240)
*http://www.nano.gov/html/edu/home_edu.html
Outline of Today’s Lecture
1. What is nano?
2. Polymers are everywhere!
3. Why nanosized carriers are
important in medicine
4. Protein-polymer nano-therapeutics
“I just want to say one word to you – just
one word…. plastics.”
The Graduate (1967)
Polymers
• Big molecules made of repeating units of
smaller molecules
– Small molecules are called “monomers”
– Monomers link together like a chain
– Results in new and exciting properties!!
Polymers – Everywhere in Daily Life
DNA
HDPE
Starch
Teflon
Cellulose
Nylon
Rubber
PVC
Data from 2004 showed that plastics industry
including suppliers accounted for 2.1
million jobs and $438 billion in shipments*
It is estimated that half of all industrial chemists
work in some area of polymer chemistry**
Therefore it is vital that chemistry students learn about
polymers. At UCLA we teach the chemical aspects of
polymers in a devoted course (Chem 181), as well as in
the Sophomore Organic Chemistry Series (Chem 30C)
* http://www.gcx-online.com/gcx/article.asp?magarticle_id=561
**Zumdahl, S. S. Chemical Principles; D. C. Heath and Co.’ Lexington,
Massachusetts, 1992, p. 947
Different Shapes and Sizes
The way the monomers are connected
has a very large influence on the
resultant properties
Duncan Nature Reviews 2003, 2, 347-360
Polymers in Medicine
Transdermal Patch
Microspheres
Biodegradable Polymer
Drug: luteinizing hormone-releasing
hormone
(LHRH) Polymer
analog
Biodegradable
Name:
Decapeptyl,
Lypron
depot
Drug:
Fentanyl (pain
killer)
AdvancedNicotine
prostate cancer
Dose:
~3 months
Name:
Duragesic, Nicoderm,
Habitrol, Prostep, Nicotrol
Dosis: 72 hours (fentanyl)
Moses, M.; Brem, H.; Langer, R. Cancer Cell, 2003, 4, 337
Outline of Today’s Lecture
1. What is nano?
2. Polymers are everywhere!
3. Why nanosized carriers are
important in medicine
4. Protein-polymer nano-therapeutics
Nano in Medicine
• A nano sized “pill”
• They target tumors to deliver cancer drugs
• Nano “pills” can be modified to hone to a
other tissues in the body to deliver drugs for
other diseases
Tumors Grow Blood Vessels
Tumors need blood to grow larger than ~2mm in size
Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760
EPR Effect
Tumors have “leaky” blood
vessels, which allow relatively
large nano-sized “pills” to
enter. This is called
Enhanced Permeability and
Retention (EPR) Effect .
Normal blood vessels are not
“leaky” and nano-particles are
prevented from entering.
This allows one to selectively
target tumors.
Duncan, R. Nature Reviews Cancer 2006, 6, 688-701
Polymers Form Nano “Pills”
Duncan Nature Reviews 2003, 2, 347-360
Nano Carriers Example: AmBisome
Drug: amphotericin B
antifungal infections for cancer patients
Name of product: AmBisome
Approved in 1997
Moses, M.; Brem, H.; Langer, R. Cancer Cell, 2003, 4, 337
Nano Carriers Example: Doxil
Drug: doxorubicin
Chemotherapy agent for ovarian cancer
Name of product: Doxcil
Reduced cardiotoxicity
Http://www.doxil.com
Nano Carriers Example: Abraxane
Drug: Paclitaxel
Chemotherapy for breast cancer
Name of product: Abraxane
Approved in 2005 ($134 million in sales that year)*
Chemotherapeutic bound to protein nano-particle
Http://www.abraxisbio.com
*Data from Small Times
Outline of Today’s Lecture
1. What is nano?
2. Polymers are everywhere!
3. Why nanosized carriers are important
in medicine
4. Protein-polymer nano-therapeutics
What is a Protein?
What is a Protein?
Proteins are natural polymers found in the body that
are made up of many small units that are called
amino acids.
Protein comes from Greek word proteios meaning
primary
Proteins are critical to life and
serve many different functions
Structure of protein called
myoglobin which delivers
oxygen to muscle tissues
http://en.wikipedia.org/wiki/Protein
Protein Function
Proteins regulate the function and structure of cells, tissues and
organs
Examples
Hemoglobin carries oxygen through the body.
Melanin gives skin pigmentation and the iris color.
Keratin provides structure of hair and nails.
Serum Albumin maintains blood pressure.
Alcohol Dehydrogenase breaks down alcohol in the liver.
Commercial Protein Therapeutics
Proteins are highly evolved and specific, so they make
excellent drugs
• Insulin
– Helps to regulate blood glucose levels for people with diabetes.
• Interferon-a (Intron A, Roferon)
– Used for the treatment of chronic hepatitis C in adults.
• Erythropoietin (Procrit, Epogen)
– Used to treat anemia caused by chemotherapy, HIV or kidney
disease.
– Glycoprotein which stimulates the production of red blood cells.
Proteins Degrade
Proteins must be injected – they are not taken orally
Proteins rapidly degrade in the body by natural mechanisms
This means that in order to have a sustained affect – the
patient must endure many injections
One Solution
By attaching polymer chains, the protein is protected from
degradation, circulates longer in the blood stream, has a
decreased immune response, and lasts longer in the body
This means fewer injections for the patient and better
compliance
Advantages of Protein-Polymer Conjugates
Protein-polymer therapeutics are nano-sized drugs with
many advantages
Francesco M. Veronese et al., Drug Discovery Today 2005, 10, 1451-1458
PEG – a Special Polymer
polyethylene glycol
or polyethylene oxide
or PEG
or PEO
•
•
•
•
•
FDA approved
Protein resistant
Water soluble
Low immune response
Biocompatible
Protein-Polymer Conjugates
Attaching polymers to proteins is called “PEGylation”:
Interferon
a
+
O
O
O
O n
Polyethylene glycol
O
Interferon
a
PEG Intron A
PEG Intron requires only 1 injection per week, compared to
three injections per week of Intron A
Data from the FDA
Protein-Polymer Conjugates on Market
Many of these nano-drugs are clinically used
Duncan Nature Reviews Cancer, 2006
www.debio.com/e/pdf/peg_e.pdf
Maynard Group Research
My group focuses on developing new synthetic methods to
generate this important class of materials, such that the
resulting protein-polymer conjugates have superior properties
Heredia & Maynard, OBC, 2007