Still Room at the Bottom: Nano Particles with Macro Impacts
Prof. Theresa Mary Allen, a veteran in the drug-delivery field for over 30 years, is a pioneer in the field of long-circulating liposomes and ligand-targeted nanomedicines for anticancer drugs and gene medicines. She has over 200 peer-reviewed publications and is an inventor on several patents. The product Doxil® (Caelyx® in Europe), the first anticancer nanomedicine approved in the world, came out of pioneering research in her laboratory at the University of Alberta. She has also been active in the area of new drugs from natural products, which has resulted in two drugs proceeding into phase II clinical trials. Her recent work in developing ligand-targeted therapeutics for small molecule therapeutics and gene medicines is at the leading edge of this exciting new field, and the methods she developed are widely used throughout the field. She has given over 270 invited lectures and presentations in over 25 countries around the globe.
She is a founding member and strategic advisor of the Centre for Drug Research and Development (CDRD), which is a novel hybrid organization devoted to advancing promising medical discoveries from academia to a commercially attractive stage. CDRD (www.cdrd.ca) evolved from the recognition by the founders of the pressing need to improve the translation of medical discoveries made in the universities and teaching hospitals into new drugs and technologies that result in economic and health benefits for Canada and beyond. For her scientific work, Dr. Allen has been recognized as a Fellow of the Royal Society of Canada, appeared in Who’s Who in Canada, and received awards including the International Bangham Award for excellence in liposome research, Cygnus Award (Controlled Release Society) for excellence in guiding graduate student research, Novartis Award 2000 (Pharmacological Society of Canada), ASTECH Award, and Canadian Society for Pharmaceutical Sciences (CSPS) Leadership Award, among many other accolades. She was elected to the CRS College of Fellows in 2012.Induction into the Royal Society of Canada.
She is a registered technologist in medical technology from Ottawa General Hospital (1961) and secured B.Sc. Honours in biochemistry from the University of Ottawa (1965) and a Ph.D. in oceanography from Dalhousie University (1971). She built a strong foundation by performing postdoctoral research training in chemistry, pharmacology, and biochemistry at McGill University, University of Alabama, and University of Miami, respectively. After finishing postdoctoral trainings, she joined the University of Alberta as an assistant professor in pharmacology (1977), where she pursued her research interests for 32 years, rising to the rank of professor. During this time, she also advised a multitude of companies and academic institutions via her consulting service. She currently serves as an adjunct professor at the University of British Columbia in Vancouver, Canada, and is an emerita professor of the University of Alberta. She has an H-index of 81 with 27,720 citations.
Q Please tell us about how your research in the field of oceanography and different postdoctoral trainings ultimately contributed to the successful development of cancer medicine using nanotechnology.
A My interest in medicine began with the training I had in medical technology early in my career and my subsequent undergraduate degree in biochemistry. A longtime interest in the oceans and in scuba diving then led to my acceptance into a Ph.D. program in oceanography at Dalhousie University, with a major in biological oceanography, where I did research at the Fisheries Research Board of Canada inWith Demtri Papahadjopoulos, Alex Bangham, and Dan Lasic in Berlin (all three now deceased).
Halifax toward my Ph.D. degree, looking at variations in proteins between different populations of herring. This led to a postdoctoral fellowship at McGill University working on structure and function of the acetylcholine esterase protein, which in turn led to an invitation to join a group at the University of Miami who were doing the first work on the structure and function of the acetylcholine receptor molecule (AchR). The protein was isolated from the electrical organs of the electric ray, and my scuba diving experience was useful in collecting these fish from the Caribbean waters. The AchR was the first receptor to be purified, imaged, and reconstituted into artificial membranes, and my participation in this research led to an interest in liposomes as model membranes. Work with the reconstitution of AchR and band 3 proteins from red blood cells led to a position as a junior faculty member at the University of Alberta.
I continued my contacts with my oceanography colleagues, which led to an invitation to visit Enewetak Atoll (site of the explosion of the first hydrogen bomb) in the Marshall Islands, and I got funding to collect marine invertebrates to screen for new drug activity. Our collections from around the world were screened for cytotoxic activity, and several drugs with potent anticancer activity were identified. Simultaneously, my laboratory was continuing to explore liposomes as model membranes for mechanisms of fusion, reconstitution of membrane proteins, and eventually as drug carriers. This led ultimately to the research from my laboratory that most people at CRS are familiar with in the use of nanoparticles as carriers of anticancer drugs and gene medicines.
Q Please share your experiences with R&D and commercialization of Doxil®, the first anticancer nanomedicine approved in the world.
A Doxorubicin was discovered in the 1950s from the screening of soil-based microbes for anticancer compounds, so it is derived from a natural product. It is still used to treat a wide range of cancers, usually in combination chemotherapy. The severe adverse side effects of this drug, particularly its cardiotoxicity, were known by the late 1960s, so a search began for new formulations of doxorubicin. As early as the mid-1970s, Gregory Gregoriadis and his colleagues were writing about the potential of liposomes as drug carriers, and this coincided with the early clinical use of doxorubicin and recognition of its side effects. Doxorubicin was, therefore, an obvious drug to test in liposomal formulations, and indeed my laboratory and several others began making and testing liposomal doxorubicin formulations in the 1970s. Several problems with the formulations had to be overcome, including increasing its encapsulation, slowing the release rate, and increasing the circulation half-life. In particular, my laboratory became interested in overcoming the rapid removal of liposomes into the mononuclear phagocyte systems, and I went back to my earlier research with red blood cell membranes and screened red blood cell surface molecules for their ability to keep liposomes in circulation. This led to the identification of GM1 as a candidate molecule and my approach to Liposome Technology Inc. (LTI), a new company forming in the San Francisco area, where I had colleagues. The GM1 molecule, although effective, was not ideal. Collaborative research between my laboratory and LTI resulted in the identification of a lipid-anchored PEG molecule for incorporation into the product to be taken to clinical trials. The AIDS epidemic was beginning in San Francisco around that time, and Kaposi’s sarcoma was a big problem in those days, so the company identified Kaposi’s sarcoma (eligible for fast track approval) for the first clinical trials, leading quickly to the first clinical approval for Doxil® . Other clinical approvals followed, including ovarian cancer, multiple myeloma, and breast cancer (except in the United States).
Q How do you look at cancer research in the present compared with five decades ago? In your perspective, has the research community been successful in addressing the disease? What can be done better both scientifically and financially?
A Five decades ago there were few anticancer drugs approved and a lot of possibilities for “low hanging” fruit, so the pace of discovery of new anticancer drugs was rapid. In the intervening decades, most of the “easy” drugs coming from synthetic and natural product research programs were discovered, and many successful combination chemotherapy regimens have been identified. Also, most of the approved drugs that benefited from incorporation into drug delivery systems have been identified and tested, but usually in monotherapy, not in combination. We are just now seeing the successful testing of combination drug products in nanoparticles. We are in a completely new ball game now, with improved understanding of the molecular mechanisms underlying cancers, the identification of new targets, and the development of personalized medicine approaches to cancer and the use of biomarkers to identify patients that will benefit from newer therapeutics, including gene medicines against new targets. We have also seen huge increases in the complexity and expense of developing new therapeutics against the new molecular targets. The scientific and financial challenges for the development of new oncology therapeutics have increased dramatically, and even more so has the challenge increased to develop successful drug delivery systems for cancer drugs with complexities such as biomarkers, targeting, drug combinations, and so on.
Q Could you please mention some of the current technologies and companies performing research and development in the field of oncology that have potential benefits in the future?
A Some of the more exciting clinical results recently in the drug delivery field have come from three areas: antibody-drug conjugates with several recent approvals (Seattle Genetics, Genentech); delivery of nucleic acids in solid-core lipid nanoparticles, likely to soon receive approval (Alnylam); and delivery of combination small molecule therapeutics in lipid nanoparticles (Celator), with excellent clinical results at the phase III level.
Q Please highlight a few key journal articles published from your research work.
A My most cited articles, all with over 1,000 citations, are those related to the development of long-circulating liposomes and ligand-Targeted nanoparticles.
Allen, TM, Cullis, PR. Drug delivery systems: Entering the mainstream. Science 303(5665): 1818-1822 (2004), 2,958 citations. This article outlines the promise of drug delivery systems and has been, of great surprise to me, our most popular article.
Papahadjopoulos, D, Allen, TM, Gabizon, A, Mayhew, E, Matthay, K. Sterically stabilized liposomes: Improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc. Nat. Acad. Sci. 88(24): 11460-11464 (1991), 1,577 citations. Demitri Papahadjopoulos and I were joint first authors on this popular article that was one of the first to talk about the pharmacokinetics and pharmacodynamics of long-circulating liposomes.
Allen, TM, Hansen, C, Martin, F, Redemann, C, Yau-Young, A. Liposomes containing synthetic lipid derivatives of poly (ethylene glycol) show prolonged circulation half-lives in vivo. Biochim. Biophys. Acta, Biomembr. 1066(1): 29-36 (1991), 1,292 citations. This was our first popular article showing the use of PEG to make long-circulating liposomes.
Allen, TM. Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2(10): 750-763 (2002), 1,183 citations. Another popular review article that summarized our experience in the development of ligand-targeted liposomal anticancer drugs that showed improved therapeutic outcomes over nontargeted liposomal drugs.Terry with Hannah and Chezy Barenholz in Israel on Chezy’s 70th birthday.Outreach, South Africa, Council for Scientific and Industrial Research.
Q Based on your consulting experience, what are some of the major challenges in the field of large-scale manufacturing/R&D of chemicals and biologicals?Photography hobby on a consulting trip to India
A The new environment of molecular medicine, new pharmacological targets, and personalized therapies presents a considerable challenge for drug delivery systems. Until recently our success came from the use of clinically approved small molecule therapeutics that were usually off patent (so cheaper) and were developed and used as monotherapies with a “one size fits all” approach. Improvements in therapeutic index resulting from these products were often biased toward the reduction in side effects rather than to improvements in response rates. As new targets are being discovered from genetic testing, new therapeutics and more personalized medicine approaches are being adapted to take advantage of these new targets. The result will be that the patient populations who will benefit from these new therapeutics are becoming smaller (even as small as n = 1, in theory), although the response rates to more selectively targeted therapeutics should increase.
In the drug delivery area the developmental expenses and the costs of the resulting products are likely to increase substantially. Newer products will contain some or all of the following: combinations of therapeutics, one or more molecules for site-specific targeting, biomarker and/or imaging capabilities, and sensing molecules that can respond to external or internal triggers to control the rate of drug release. As the complexities of the formulations increase, so do the expenses and difficulties associated with their manufacture and quality control. Hence, the development costs will increase and will remain higher than those seen traditionally for small molecule therapeutics or “classical” liposomes. In addition, stakeholder groups are now demanding price/benefit analyses, meaning that new products must demonstrate considerable outcome benefits before they are able to command prices that can recoup the investment in their development.
The research community in the drug delivery field must recognize these new challenges and adapt by developing new approaches more closely aligned with the new reality, since both the scientific and the financial challenges in the current environment have increased exponentially.
Q What are some of your favorite hobbies and travel destinations?
A As many of my colleagues know, I have always enjoyed photography and travel to remote areas with wildlife and interesting cultures—a hobby I share with several of my scientific colleagues (and I have even photographed a few scientific meetings). Since my retirement I continue to consult and advise in the drug delivery area, but I have more time for photography and have developed a website (www.allenfotowild.com) and have started to sell my photographs. Those of you who have visited my house have also seen my organic vegetable garden and greenhouse and have sampled the produce.