The 2014 Giulio Natta Medal in Chemical Engineering has been assigned by the Politecnico of Milan to Nicholas A. Peppas. The scientist, graduated in 1971 in biomedical engineering at the Athens School of Engineering (Greece), then moved to the US to reach doctoral degrees at MIT. He is currently covering one of the just six Cockrell chairs in Engineering and is the director of the Institute for Biomaterials, drug delivery and regenerative medicine of the Austin University, Texas.
As he himself told during the Lectio Magistralis given at the Politecnico, he chose to become a biomedical engineering while looking at the first heart transplant by south african Christian Barnard in 1967.
Peppas pioneered many fields in medical technology’s innovation: plastic materials for contact and intraocular lenses, special membranes for artificial kidneys, cartilages, systems for the oral delivery of insulin, calcitonin and interferon beta are just few examples of the many products which have been created in his labs. Many of these had a profound impact in the history of drug delivery and pharmaceutical development. More than 40 years later, Nicholas A. Peppas is still fully active in research with many new ideas to develop. His interests are now directed in maximising the potentiality of nanotechnologies to create the next generation of drug delivery systems, using a multidisciplinary approach to develop innovative solutions and solve complex problems.
The driving force that moved Nicholas Peppas to continuously invest energies and create new solutions for medical sciences, he told during the lecture, has always been the desire to help patients to reach a better quality of life, even if a disease is present. Patents and products coming from Peppas’s labs have been the subjects of many important deals in the pharma industry. Professor Peppas’s research articles reach more than 69 thousand citations, more than an half (36779) starting from 2009 onward (Google Scholar); the most cited paper is dated 19831 and it represent a milestone in the explanation of release mechanisms from a polymeric matrix of porous hydrogel.
Towards intelligent biomaterials
The future is focused of the creation of “intelligent” biomaterials using nanotechnology, a mean that, according to the scientist, might even allow remote diagnosis and therapy. A modern system of drug delivery and controlled release, he explained during the Lectio Magistralis, is no more based just on a careful choice of the polymeric matrix used to trap the active ingredient and on its dissolution properties. When we speak of “intelligent” biomaterials, the term it is not referred to as “artificial intelligence”. Innovative biomaterials are able to selectively recognise cells and deliver the drug on the basis of their chemical-physical properties.
An improved molecular design is the key to open new frontiers in drug delivery systems, said Peppas: multinational pharma companies shall use this approach as a plus for pharmaceutical development, to keep their innovative potential at a very high level and to renew expiring patents as a way to resist to competitive pressure coming from generic companies.
Peppas’s research on biomaterials which are able to modulate drug release by mean of their differential sensibility to pH, ionic strength, solvent composition or temperature, dates back to the ‘702,3. The future points toward personalised drugs and a “patient-friendly” model of medicine4: patient’s needs have to be considered the main driver for innovation, in order to increase quality of life. Professor Peppas made the example of insulin delivery, a very inconvenient therapy for diabetic patients because of the need of (multi) daily injections that may cause the formation of diffuse hematomas. The new oral formulations of insulin that he created is able to pass unaltered through the acidic ambient of the stomach and release the hormone just upon arrival at the small intestine. Not only insulin: at the Austin’s labs the group is working at delivery systems for other proteins, i.e. calcitonin to treat osteoporosis, growth hormone against dwarfism, coagulation factors VIII and IX for haemofilia and interferon b for multiple sclerosis.
All these innovative drug delivery systems are based on various combination of mucoadhesive polymer hydrogels and nanoparticles able to increase drug’s bioavailability5. Insulin-loaded microspheres have been tested in vivo on rats6, showing their capacity to resist to the stomach’s drastic pH conditions and to release insulin in the small intestine. The technology, explained Peppas, makes use of pH gradients within different body districts and allowed for a decrease of 40 percent in glucose level in rat’s blood.
Another technique used to increase intestinal bioavailability of proteins makes use of carrier nanoparticles functionalised with carbohydrates, wheat germ’s agglutinin or block copolymers, all having mucoadhesive properties in order to favour the ability to pass the intestinal barrier through capillary blood flow and undergo cellular uptake.
Nanotechnologies may also help, according to professor Peppas, in the creation of micro-infusion pumps, that patients may carry at their belt, needing smaller volumes thanks to the increased volume-surface ratio.
Intestinal drug targeting using siRNA
The so-called small interfering RNA (siRNA) are double helix small RNA fragments coding for approximately 20 amino-acids; the fragments have negative charge and are easily hydrolysed. siRNA are involved in the degradation of complementary mRNA; they favour gene silencing and they may be useful for the treatment of diseases involving altered gene expression8.
Peppas’s group is working to achieve site-specific oral delivery systems for siRNA, a complete break-through in innovation as none of the currently undergoing 24 clinical trials on siRNA is using oral delivery of the active ingredient. The new biomaterials should have a low cost of production and would allow high compliance to treatment by patients, said Peppas. The project is highly challenging, as gastrointestinal tract is characterised by a dynamic pH gradient (approx. 2 – 7,4); residence time too is highly variable. The drug delivery system shall allow the drug to pass the intestinal mucous barrier while remaining stable in the area of inflammation. Once the vector has reached the target cell, endocytosis shall occur and the drug shall be finally released within the cytoplasm.
The new biovectors showed their ability to win these challenges and they may find future use, said their inventor, to treat Chron’s disease or ulcerative colitis. To solve the problem, researchers associated a polyanionic, pH-sensitive carrier to a protective hydrogel that can be degraded by digestive enzymes: carboxylate groups located on the surface of the biomaterial are protonated at the acidic pH of the stomach. The so-formed hydrogel protects the more internal layers containing the nanogel-incapsulated active drug. Once into the intestine, the microgel swells and the internal nanogel containing the siRNA is thus released. This nanogel has a polycationic nature, thus facilitating cellular uptake and cytosolic release of the siRNA. The advanced biomaterial is thus consistent of three different layers: the core siRNA active ingredient, its protective polycationic nanogel and the external polyanionic microgel, and has been obtained by photopolymerisation coupled to micronisation techniques9.
Nicholas A. Peppas has spent his life to create innovative systems able to recognise and use thereof the different environmental conditions within the human body. The innovative biomaterials created in his labs had a profound impact on drug delivery and greatly helped to improve patient’s compliance and quality of life. These have been, for the Politecnico of Milan, the motivations for awarding him with the 2014 Giulio Natta Medal.
- R. Korsmeyer, R. Gurny, E. Doelker, P. Buri, N.A. Peppas, Mechanisms of solute release from porous hydrophilic polymers, Int. J. Pharmaceutics, 15, 25-35 (1983)
- N.A. Peppas, E.W. Merrill, Crosslinked poly(vinyl alcohol) hydrogels as swollen elastic networks, J. Appl. Pol. Sci. 21, 1763 (1977)
- T. Tanaka, Collapse of gels and critical end-point, Phys. Revs. Letters, 40, 820 (1978)
- R. Langer, N.A. Peppas, Advances in biomaterials, drug delivery and bionanotechnology, AIChE J., 49, 2990-3006 (2003)
- N.A. Peppas, Vecteurs de médicaments innovants et intelligents: leur applications pharmaceutiques, Ann. Pharm. Fr, 64, 260-275 (2006)
- A.M. Lowman, M. Morishita, M. Kajita, T. Nagai, N.A. Peppas, Oral delivery of insulin using pH-responsive complexation gels, J. Pharm. Sci., 88, 933-937 (1999)
- K.M. Wood, G.M. Stone, N.A. Peppas, Wheat germ agglutinin funtionalized complexation hydrogels for oral insulin delivery, Biomacromolecules, 9, 1293-1298 (2008)
- J.M. Knipe, J.T. Peters, N.A. Peppas, Theranostic agents for intracellular gene delivery with spatiotemporal imaging, Nano Today, 8, 21-38 (2013)
- J.C. Knipes, N.A. Peppas, Multiresponsive polyanionic microgels with inverse pH responsive behaviour by encapsulation of polycationic nanogels, J. Appl. Polym. Sci., 131, 40098 (2014)
The Natta’s Lecture
Natta’s Lecture is an award that the Department of Chemistry, Materials and Chemical Engineering of Politecnico di Milano assigns every year to an eminent Professor, who has distinguished himself in the world for his original studies and researches, and has reached outstanding achievements in the main areas of interest for the Department.
This award was first established in 2013 to celebrate the 50ths of the Nobel prize to Giulio Natta. The awarded scientist gives Lectio Magistralis at the beginning of the academic year of the Politecnico and a medal is assigned to him.
(source: Politecnico di Milano)
An outstanding records of success
Nicholas A. Peppas is the Cockrell Family Chair in Engineering No 6. He is professor of Chemical Engineering, Biomedical Engineering and Pharmacy and chairman of the Department of Biomedical Engineering, and Director of the Institute of Biomaterials, Drug Delivery and Regenerative Medicine of the University of Texas at Austin.
Peppas holds a Dipl. Eng., National Technical University of Athens (1971), a Sc.D. from MIT (1973), honorary doctorates from the Universities of Ghent (Belgium), University of Parma (Italy), University of Ljubljana (Slovenia) and University
He is the 2012 Founders Award recipient of the National Academy of Engineering (NAE). Peppas is an elected member of the National Academy of Engineering (NAE), the Institute of Medicine (IOM) of the National Academies, the National Academy of France, the Royal Academy of Spain, the Academy of Athens (Greece) and the Texas Academy of Medicine, Engineering and Sciences.
In 2008, AIChE named him on of the One Hundred Chemical Engineers of the Modern Era. He is President (2008-16) of the International Union of Societies of Biomaterials Science and Engineering (IUSBSE) and Chair (2014-15) of the Engineering Section of the American Association for the Advancement of Science (AAAS). Nicholas Peppas is also Fellow of several scientific societies.
(source: Politecnico di Milano)