Nano-Sized Drug Delivery

1. Nano-Sized Drug Delivery Prof. Heather D. Maynard Department of Chemistry and Biochemistry University of California, Los Angeles

2. 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

3. Outline of Today’s Lecture • What is nano? • Polymers are everywhere! • Why nanosized carriers are important in medicine • Protein-polymer nano-therapeutics

4. Outline of Today’s Lecture • What is nano? • Polymers are everywhere! • Why nanosized carriers are important in medicine • Protein-polymer nano-therapeutics

5. 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

6. Closer Look at a Human Hair Width of this line is 100 nm http://www.aber.ac.uk/bioimage/image/uwbl-0411-w.jpg

7. 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

8. Super-Repellent Nano-Materials http://cjmems.seas.ucla.edu/members/changhwan/main.html http://www.engineer.ucla.edu/magazine/fall06/noslip.html

9. Geckos Walk on Walls

10. Nano-Finger Tips Allow Geckos to Stick http://robotics.eecs.berkeley.edu/~ronf/Gecko/index.html

11. Man-Made Geckos

12. Super Adhesive Nano-Materials Synthetic nano-materials can exhibit strong adhesion similar to gecko fingers Yurdumarkan et al, Chem. Commun. 2005, 3799-3801

13. How Nano Effects You Nanotech products are already on the market

14. 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 forefrontof 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

15. Outline of Today’s Lecture • What is nano? • Polymers are everywhere! • Why nanosized carriers are important in medicine • Protein-polymer nano-therapeutics

16. “I just want to say one word to you – just one word…. plastics.”The Graduate (1967)

17. 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!!

18. Polymers – Everywhere in Daily Life DNA Starch Cellulose Rubber HDPE Teflon Nylon PVC

19. 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

20. Different Shapes and Sizes The way the monomers are connected has a very large influence on the resultant properties Duncan Nature Reviews2003, 2, 347-360

21. Transdermal Patch Microspheres Biodegradable Polymer Drug: Fentanyl (pain killer) Nicotine Name: Duragesic, Nicoderm, Habitrol, Prostep, Nicotrol Dosis: 72 hours (fentanyl) 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

22. Outline of Today’s Lecture • What is nano? • Polymers are everywhere! • Why nanosized carriers are important in medicine • Protein-polymer nano-therapeutics

23. 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

24. Tumors Grow Blood Vessels Tumors need blood to grow larger than ~2mm in size Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760

25. 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

26. Polymers Form Nano “Pills” Duncan Nature Reviews2003, 2, 347-360

27. 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

28. Nano Carriers Example: Doxil Drug: doxorubicin Chemotherapy agent for ovarian cancer Name of product: Doxcil Reduced cardiotoxicity Http://www.doxil.com

29. 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

30. Outline of Today’s Lecture • What is nano? • Polymers are everywhere! • Why nanosized carriers are important in medicine • Protein-polymer nano-therapeutics

31. What is a Protein?

32. 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

33. Protein Function Proteins regulate the function and structure of cells, tissues and organs Examples Hemoglobin carries oxygen through the body. Melaningives skin pigmentation and the iris color. Keratin provides structure of hair and nails. Serum Albuminmaintains blood pressure. Alcohol Dehydrogenasebreaks down alcohol in the liver.

34. 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.

35. 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

36. 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

37. Advantages of Protein-Polymer Conjugates Protein-polymer therapeutics are nano-sized drugs with many advantages Francesco M. Veronese et al., Drug Discovery Today2005, 10, 1451-1458

38. PEG – a Special Polymer polyethylene glycol or polyethylene oxide or PEG or PEO • FDA approved • Protein resistant • Water soluble • Low immune response • Biocompatible

39. Protein-Polymer Conjugates Interferon a Attaching polymers to proteins is called “PEGylation”: Interferon a + Polyethylene glycol PEG Intron A PEG Intron requires only 1 injection per week, compared to three injections per week of Intron A Data from the FDA

40. Protein-Polymer Conjugates on Market Many of these nano-drugs are clinically used www.debio.com/e/pdf/peg_e.pdf Duncan Nature Reviews Cancer, 2006

41. 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