nano-sized drug delivery - ucla...nano-sized drug delivery prof. heather d. maynard department of...
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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
h"p://www.aber.ac.uk/bioimage/image/uwbl-‐0411-‐w.jpg
Closer Look at a Human Hair
Width of this line is 100 nm
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://www.engineer.ucla.edu/magazine/fall06/noslip.html http://cjmems.seas.ucla.edu/members/changhwan/main.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
Yurdumarkan et al, Chem. Commun. 2005, 3799-3801
Synthetic nano-materials can exhibit strong adhesion similar to gecko fingers
Nanotech products are already on the market
How Nano Effects You
*http://www.nano.gov/html/edu/home_edu.html
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)
According to the National Nanotechnology Initiative (NNI), “The worldwide workforce
necessary to support the field of nanotechnology is estimated at 2 million by
2015”*
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)
• 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
Starch Rubber
Teflon
DNA
HDPE
Cellulose
Nylon PVC
Polymers – Everywhere in Daily Life
It is estimated that half of all industrial chemists work in some area of polymer chemistry**
* 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
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)
Data from 2004 showed that plastics industry including suppliers accounted for 2.1
million jobs and $438 billion in shipments*
Duncan Nature Reviews 2003, 2, 347-360
Different Shapes and Sizes
The way the monomers are connected has a very large influence on the resultant properties
Transdermal Patch
Biodegradable Polymer Drug: Fentanyl (pain killer) Nicotine Name: Duragesic, Nicoderm, Habitrol, Prostep, Nicotrol Dosis: 72 hours (fentanyl)
Microspheres
Biodegradable Polymer Drug: luteinizing hormone-releasing hormone (LHRH) analog Name: Decapeptyl, Lypron depot Advanced prostate cancer Dose: ~3 months
Polymers in Medicine
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
• A nano sized “pill”
• They target tumors to deliver cancer drugs
• Nano “pills” can be modified to hone to a other Gssues in the body to deliver drugs for other diseases
Nano in Medicine
Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760
Tumors Grow Blood Vessels
Tumors need blood to grow larger than ~2mm in size
Duncan, R. Nature Reviews Cancer 2006, 6, 688-701
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.
Polymers Form Nano “Pills”
Duncan Nature Reviews 2003, 2, 347-360
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: AmBisome
Drug: doxorubicin Chemotherapy agent for ovarian cancer
Name of product: Doxcil Reduced cardiotoxicity
Http://www.doxil.com
Nano Carriers Example: Doxil
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
Nano Carriers Example: Abraxane
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?
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
What is a Protein?
http://en.wikipedia.org/wiki/Protein
Structure of protein called myoglobin which delivers oxygen to muscle tissues
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.
Protein Function
Commercial Protein Therapeutics
• Insulin – Helps to regulate blood glucose levels for people with diabetes.
• Interferon-α (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 are highly evolved and specific, so they make excellent drugs
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
Francesco M. Veronese et al., Drug Discovery Today 2005, 10, 1451-1458
Advantages of Protein-Polymer Conjugates
Protein-polymer therapeutics are nano-sized drugs with many advantages
• FDA approved • Protein resistant • Water soluble • Low immune response • Biocompatible
polyethylene glycol or polyethylene oxide or PEG or PEO
PEG – a Special Polymer
Interferon α +
Polyethylene glycol
Interferon α
PEG Intron A
Protein-Polymer Conjugates
PEG Intron requires only 1 injection per week, compared to three injections per week of Intron A
Data from the FDA
Attaching polymers to proteins is called “PEGylation”:
Duncan Nature Reviews Cancer, 2006
Protein-Polymer Conjugates on Market
www.debio.com/e/pdf/peg_e.pdf
Many of these nano-drugs are clinically used
Heredia & Maynard, OBC, 2007
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