Lab profile: Samir Mitragotri

Under the skin

Drug discovery has advanced over the last few decades, leading to a plethora of advanced therapies based on peptides, proteins, and nucleic acids. But biological barriers such as the skin, walls of the intestine, blood-brain barrier, and immune system, which have evolved to protect the body against external environment, limit the ability of modern medicine to introduce and navigate drugs through the human body. A fundamental understanding of these barriers is essential in the search for new strategies to overcome them.

Samir Mitragotri is Mellichamp Chair Professor in the Department of Chemical Engineering at the University of California Santa Barbara and Founding Director of the Center for Bioengineering (CBE). He is an elected member of the National Academy of Engineering and many other learned societies including the American Association for the Advancement of Science. The author of over 200 publications and 100 patent applications, he is also Associate Editor of the Elsevier publication, Journal of Controlled Release and Editor-in-Chief of a new journal Bioengineering and Translational Medicine.

Materials Today spoke to Samir Mitragotri about his approach to drug delivery…

How long has the group been running?

I have been running my group at UCSB for 17 years.

How many people are in your group?

I have a group of about 20 individuals comprising graduate students, post-doctoral associates and visiting scientists.

What are the major themes of research in your lab?

Our research is focused on drug delivery and some of the body’s key barriers including skin, intestinal epithelium and immune system. We have established a fundamental knowledge base of the transport properties of skin. We have also developed mathematical models of skin permeation as well as experimental tools to study the biophysics of skin structure-function relationship.

Based on this understanding, we have developed novel technologies to enable transdermal delivery of proteins, peptides and siRNA, which otherwise have to be injected using needles. We have also developed a fundamental understanding of trans-epithelial transport properties in the intestine and discovered novel permeation enhancers based on this understanding. Using this knowledge, we have devised novel technologies, in particular intestinal patches, for oral delivery of proteins such as insulin and calcitonin. We have also created unique bio-inspired nanoparticles with novel physical, chemical and biological properties to enable targeted drug delivery for the treatment of cancer and cardiovascular diseases. One of our key efforts has been focused on developing synthetic particles that mimic the structural and functional features of red blood cells and platelets.

How and why did you come to work in this area?

I was originally trained as a chemical engineer with no background in biology or physiology. But when an opportunity presented itself to engage in research on drug delivery, I was fascinated by the thought that someone like me without prior training in biological sciences could work in this area. My early fascination with the field was quickly converted into passion. The discovery of new drugs has advanced by leaps and bounds over the last few decades but delivery methods commonly used on patients are still rather simplistic. In this mismatch, I saw an opportunity where engineers could make a significant contribution by first understanding some of the underlying challenges and then developing new technologies.

What facilities and equipment does your lab have?

Our laboratory benefits from excellent shared facilities at UCSB. We routinely use advanced characterization tools including spectroscopy and electron microscopy to understand the features of our nanoparticles and their impact on drug delivery. Some of the tools that we actively use include nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), x-ray diffraction (XRD) and secondary ion mass spectrometry (SIMS) and microscopy tools such as confocal atomic force microscopy (AFM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM).

Do you have a favorite piece of kit or equipment?

In general, I am a big fan of all kinds of microscopy techniques. Seeing is believing!

What has been your highest impact/most influential work to date?

In general, I am very excited about our work on transdermal drug delivery. Transdermal delivery has many features that one desires in an ideal drug delivery system. It is painless, controllable, provides sustained drug release if required and can be easily terminated. It also offers a potential means of delivering drugs that would otherwise have to be injected using needles and syringes. However, transdermal delivery is limited to a handful of small molecules because of the skin’s high permeability barrier.

We have developed several technologies including low-frequency ultrasound, pulsed microjet injector, high throughput skin experimentation, skin penetrating peptides and ionic liquids to increase skin permeability to proteins, peptides and nucleic acids. Our research has allowed delivery of macromolecules across the skin. Specifically, we have developed an ultrasound-based technique that delivers proteins through the skin. The same method has also been used to harvest skin fluid for non-invasive glucose monitoring in diabetic patients. Using ultrasound and a novel surfactant blend, we developed a way of solubilizing tissues without protein denaturation.

We have also developed a combinatorial discovery approach (INSIGHT) that allows the discovery of rare formulations that can deliver macromolecules. Recently, we discovered a novel peptide that simultaneously enhances delivery of siRNA across the skin barrier and cell membranes for the treatment of various skin disorders. We have also designed novel ionic liquids as broad spectrum topical antibiotics against bacteria, viruses and fungi, that are simultaneously capable of delivering drugs into skin.

Collectively, these technologies have significantly expanded the types of molecules that can be delivered transdermally.

What is the key to running a successful lab? And how do you balance running a research group alongside the CBE?

The key is to have a great team to support all the activities in the lab and the center. I am very proud of my students, too. They are bright, independent and hard-working individuals. That makes my job a lot easier and fun! I am fortunate to be surrounded by such outstanding team players.

How do you plan to develop your lab and the CBE in the future?

The CBE is a hub for UCSB’s research and teaching in bioengineering, and is a nucleus for the Department of Bioengineering.  A new building for bioengineering is under construction at UCSB and is scheduled to be ready by mid-2017. Overall, there is a high level of enthusiasm for bioengineering at UCSB. We anticipate that with continued support from the students, faculty and administration, the Center will morph into a Department of Bioengineeing in the near future.

Key publications

1. D. Paithankar, B. H. Hwang, G. Munavalli, A. Kauvar, J. Lloyd, R. Blomgren, L. Faupel, T. Meyer, S. Mitragotri. Ultrasonic delivery of silica-gold nanoshells for photothermolysis of sebaceous glands in humans: Nanotechnology from the bench to clinic. J Control Release 206 (2015) 30
2. A. C. Anselmo, M. Zhang, S. Kumar, D. R. Vogus, S. Menegatti, M. E. Helgeson, S. Mitragotri. Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting. ACS Nano 9 (2015) 3169
3. M. Zakrewsky, K. S. Lovejoy, T. L. Kern, T. E. Miller, V. Le, A. Nagy, A. M. Goumas, R. S. Iyer, R. E. Del Sesto, A. T. Koppisch, D. T. Fox, S. Mitragotri. Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization. PNAS 111 (2014) 13313
4. P. Kolhar, A. C. Anselmo, V. Gupta, K. Pant, B. Prabhakarpandian, E. Ruoslahti, S. Mitragotri. Using shape effects to target nanoparticles to lung and brain endothelium. PNAS 110 (2013) 10753
5. S. Barua, J.-W. Yoo, P. Kolhar, A. Wakankar, Y. R. Gokarn, S. Mitragotri. Particle shape enhances specificity of antibody-displaying nanoparticles. PNAS 110 (2013) 3270
6. T. Hsu and S. Mitragotri. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. PNAS 108 (2011) 15816