A Focus on Ocular Delivery: Interview with Arto Urtti

Arto Urtti is a professor of biopharmaceutics at the University of Helsinki and University of Eastern Finland. At the University of Helsinki he has headed the Centre for Drug Research within the Faculty of Pharmacy. He has also been the editor-in-chief of the European Journal of Pharmaceutical Sciences (2001– 2011) and academic editor of PLoS ONE (2007–2012), and he serves as a scientific advisor for several international pharmaceutical companies. He has been a part of CRS’s governance in the past. His main research field is drug delivery, primarily ocular drug delivery. This involves technologies for controlled release, preclinical pharmacokinetics and modeling, and pharmaceutical nanotechnology (biomaterials for drug and gene targeting and for three-dimensional cell cultures).

Dr. Urtti received his Ph.D. degree in 1986 from the University of Kuopio, Finland. He obtained international research experience as a postdoctoral fellow in the Department of Pharmaceutical Chemistry, University of Kansas, and was a visiting professor at both the Department of Bio-Pharmaceutical Sciences, University of California, San Francisco (UCSF) and the Department of Pharmaceutics, University of Wisconsin. He has published over 300 peer-reviewed articles as well as 24 patents and patent applications. He has evaluated grant applications for the scientific funding bodies from more than 10 countries including the European Union (EUFP7, ERC), Medical Research Council (U.K.), Wellcome Trust, and French National Research Agency.

His research has been funded by the Academy of Finland, European Union, U.S. Food and Drug Administration (FDA), and the pharmaceutical industry. For his research contributions, Dr. Urtti has received numerous scientific awards including the American Association of Pharmaceutical Scientists Fellowship, honorary membership in the Finnish Pharmacists’ Association, invited membership in the Finnish Academy of Science and Letters, City of Kuopio Golden Recognition Medal, Albert Wuokko Prize, Millennium Distinction Award, European Federation for Pharmaceutical Sciences (EUFEPS) Distinguished Service Award, and EUFEPS Senate membership.

Q You have achieved great success in your career. Please mention some of your mentors and the experiences you have shared with them.

A Lotta Salminen, professor of ophthalmology, was my mentor during my Ph.D. studies. We investigated ocular pharmacokinetics and showed the role of pigment binding of pilocarpine and timolol in the eye as well as the surprisingly fast systemic absorption of ocular drugs. She introduced me to the international community of ocular drug research. Later, Frank Szoka was my mentor during my sabbatical at UCSF School of Pharmacy. During that period I learned a lot from him about nonviral gene delivery and nanomedicine in general. The research project was about DNA transfer to the retinal pigment epithelium. Frank’s research is very impressive: cutting edge, innovative, mechanistic, well-controlled, and free of hype. Excellent scientific role model.

Q You have spent your time in both the United States and Europe. How would you describe your personal and professional life challenges during the intercontinental

portion of your career? What advice will you offer current professionals for their scientific journeys?

A Research periods in the United States were great both scientifically and personally. Certainly, I recommend international postdoctoral and sabbatical research periods. Of course, there are challenges, such as moving with a family, school arrangements for the kids, and work career aspects for the spouse. For me and my family, the experiences were valuable and certainly worth the efforts. For example, the kids got experience that built their self-confidence in international environments. In the international research environment one becomes exposed to many cultures, people, research environments, and scientific discussions. International experience is an intellectual investment, and the research data generated during that period are only a small part of the whole thing. The international research period stimulates thinking, improving the understanding of science and perhaps other aspects of the world as well. Currently, the European Union is heavily supporting scientific mobility between EU countries. This is a fantastic development providing nice opportunities also for pharmaceutical scientists.

Q In today’s world, how important is it for an academician to be connected to industry? How did you get your first industrial collaboration?

A Well, this depends very much on the field, but in the field of drug delivery it is important. Industrial collaborations help to understand the needs in industrial research and development, and they introduce the Ph.D. students and postdocs to industrial issues and

personnel. This kind of mobility is nicely built into the Marie Curie programs in the EU, where Ph.D. students have training periods in companies. My first industrial grant was from Merck (U.S.A.), since my postdoctoral period in Kansas was partly supported by Merck. In fact, Merck granted me three-year funding in Finland to continue the project on ocular drug delivery after my postdoc period in the United States. Since then I have had many industrial collaborations with companies from Finland and other European counties, Japan, and the United States.

Q Please share details on some of the important projects at the Centre for Drug Research. What is its vision? Is it under an academic umbrella?

A The Centre for Drug Research in Helsinki is an academic umbrella organization, not a department in the administrative sense. It aims to develop new approaches for drug discovery and research. We have some exciting research related to drug delivery involving several research groups. For example, Vincenzo Cerullo’s team is doing cutting-edge work on cancer immunotherapy that is based on coating of adenoviruses with specific peptide mixtures. Marjo Yliperttula’s group is advancing nicely in the research on extracellular vesicle structure and function. This work leads to new insights in the design of targeted drug carriers. Alex Bunker is a computational physicist who has specialized in the molecular dynamics of liposomes. This work nicely complements the experimental research in the Centre. Finally, I would like to mention EU OpenScreen, the European international infrastructure for chemical biology and drug discovery where the Centre is one of the nodes. This is a new initiative that starts this year. It will provide biologists an avenue to screen large sets of chemicals against their biological targets, and for chemists it offers opportunities to include their compounds in the collections of EU OpenScreen for further biological testing. Perhaps, the field of drug delivery and targeting will also benefit from this screening activity.

Q Please share some of the important research publications coming out of your research lab. Outline the significance and contributions made to pharmaceutical sciences.

A Here are four important articles.

Bhattacharya, M, Sarkhel, S, Peltoniemi, J, Broadbridge, R, Tuomainen, M, Auriola, S, Urtti, A. Differentially cleaving peptides as a strategy for controlled drug release in human retinal pigment epithelial cells. J. Controlled Release 251: 37-48 (2017). This was the cover story in JCR recently with a preface from Kinam Park. The study introduces peptide sequences that can be used to control cargo compound release rate from the conjugate within the retinal pigment epithelial cells. The functionality of the concept was shown quantitatively with LC/MS analytics. This technology opens new possibilities for retinal drug delivery. Lajunen, T, Kontturi, LS, Viitala, L, Manna, M, Cramariuc, O, Róg, T, Bunker, A, Laaksonen, T, Viitala, T, Murtomäki, L, Urtti, A. Indocyanine green loaded liposomes for light triggered drug release. Mol. Pharm. 13: 2095-2107 (2016). Indocyanine green is an FDA-approved clinical imaging dye. The compound was used to induce near-IR light triggered drug release from liposomes. This feature may be useful in site- and time-controlled drug delivery.

Vellonen, KS, Soini, EM, Del Amo, EM, Urtti, A. Prediction of ocular drug distribution from systemic blood circulation. Mol. Pharm. 13: 2906-2911 (2016). This is the first publication that illustrates the pharmacokinetic principles and model for drug distribution from the blood stream to the posterior eye segment. Understanding ocular distribution is important in drug design in two ways: 1) targeting drugs to the eye from systemic circulation on purpose and 2) avoiding ocular exposure and potential retinal toxicity of drugs that are intended for other targets.

Del Amo, EM, Rimpelä, AK, Heikkinen, E, Kari, OK, Ramsay, E, Lajunen, T, Schmitt, M, Pelkonen, L, Bhattacharya, M, Richardson, D, Subrizi, A, Turunen, T, Reinisalo, M, Itkonen, J, Toropainen, E, Casteleijn, M, Kidron, H, Antopolsky, M, Vellonen, KS, Ruponen, M, Urtti, A. Pharmacokinetic aspects of retinal drug delivery. Prog. Retin. Eye Res. 57: 134-185 (2017). Comprehensive and analytical review of pharmacokinetics related to retinal drug delivery. Literature was critically reviewed and supplemented with new analyses of literature data and kinetic simulations to provide new insights. I think that this is good reading material for academic and industrial researchers who want to learn about retinal drug delivery.

Q You have been an editor of multiple international journals. Please share some of your insights on where drug science and publishing are progressing.

A One strong trend in drug science (and many other fields) is related to the improved efficacy of data use. Open public data sources will be launched, and this will give better chances to further analyze and model the data. Also, the various analytical tools are getting better at helping to generate new data at high sensitivity and resolution. I am sure that these trends will foster scientific progress. However, I am also worried about the publishing activities. There are numerous new journals popping up, and they are not maintaining good scientific standards. Another worrying trend is the “marketing” of research results by the research groups. I am in favor of the classic scientific idea of truth searching. Unfortunately, we see plenty of hype and marketing of drug delivery technologies even in good journals. I wonder about the reproducibility of all that research. This is wide problem, not only in the field of drug delivery.

Q Please mention research publications (other than your own) that you believe are key articles in the pharmaceutical field. 

A Maurice, DM, Mishima, S. Ocular pharmacokinetics. In: Pharmacology of the Eye. ML Sears, ed. Springer-Verlag, Berlin, Germany, pp. 19-116 (1984). Excellent, profound, and comprehensive treatise on ocular pharmacokinetics. David Maurice was always ahead of his time. Amidon, GL, Lennernäs, H, Shah, VP, Crison, JR. Theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12: 413-420 (1995). Starting point for biowaivers. Nice analysis of the roles of dissolution and permeability factors in drug absorption. Hidalgo, IJ, Raub, TJ, Borchardt, RT. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96: 736-749 (1989). Introduction of the Caco-2 model to pharmaceutical research. This study had a big impact on the ways that drug delivery issues are investigated. Fox, ME, Szoka, FC, Frechet, JMJ. Soluble polymer carriers for the treatment of cancer: The importance of molecular architecture. Acc. Chem. Res. 42: 1141-1151 (2009). Nice study that shows the fundamental importance of polymer shape on its plasma clearance. Ghetie, V, Popov, S, Borvak, J, Radu, C, Matesoi, D, Medesan, C, Ober, RJ, Ward, ES. Increasing the serum persistence of an IgG fragment by random mutagenesis. Nat. Biotechnol. 14: 637-640 (1997). Demonstrates the mechanism for the long persistence of IgG compounds in the plasma. Such antibodies became highly successful drugs in many indications.

Q What closing thoughts would you like to share?

A Drug delivery is an exciting field with ever-increasing importance. I have enjoyed working in this field, since it integrates nicely together chemistry, mathematic modeling, pharmaceutical sciences, and medicine. The multidisciplinary nature of the field makes it also fruitful for academic, industrial, and regulatory collaborations—great learning experiences. Certainly, I can recommend this field to young scientists, but it is important to find new approaches and niche areas that are not fully occupied already.