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 medicine4. Protein-polymer nano-therapeutics

Outline of Today’s Lecture

1. What is nano?2. Polymers are everywhere!3. Why nanosized carriers are

important in medicine4. 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

http://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.htmlhttp://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 medicine4. 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 PolymerDrug: Fentanyl (pain killer) NicotineName: Duragesic, Nicoderm, Habitrol, Prostep, Nicotrol Dosis: 72 hours (fentanyl)

Microspheres

Biodegradable PolymerDrug: luteinizing hormone-releasing hormone (LHRH) analogName: Decapeptyl, Lypron depotAdvanced prostate cancerDose: ~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 medicine4. 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 tissues 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: AmBisomeApproved 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: DoxcilReduced cardiotoxicity

Http://www.doxil.com

Nano Carriers Example: Doxil

Drug: Paclitaxel Chemotherapy for breast cancer

Name of product: AbraxaneApproved 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 medicine4. 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

ExamplesHemoglobin 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- (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 DegradeProteins 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 SolutionBy 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

OO

OO

On

polyethylene glycolor polyethylene oxideor PEG or PEO

PEG – a Special Polymer

Interferon

OO

OO

On

+Polyethylene glycol

Interferon

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