Therapy of multidrug resistant cancers could be significantly enhanced by using siRNA down-regulating the production of proteins involved in cancer cell resistance, such as Pgp or survivin. Even better response could be achieved is such siRNA could be delivered to tumors together with chemotherapeutic agent. This task is complicated by low stability of siRNA in biological surrounding. Thus, the delivery system should simultaneously protect siRNA from degradation. We have developed several types of lipid-based delivery system, such as liposomes and polymeric micelles made of PEG-phospholipid or PEI-phospholipid conjugates, which are biologically inert, demonstrate prolonged circulation in the blood and can firmly bind non-modified or reversibly-modified siRNA. Additionally, these nanopreparations can be loaded into their aqueous core (liposomes) with soluble drugs, such as doxorubicin, or into the lipidic core (micelles) with poorly water soluble chemotherapeutic agents, such as paclitaxel or camptothecin. In experiments with cancer cell monolayers, cancer cell 3D spheroids, and in animals with implanted tumors, it was shown that such co-loaded preparations can significantly down-regulate target proteins in cancer cells, enhance drug activity, and reverse multidrug resistance.
In order to specifically unload such nanopreparations inside tumors, we made them sensitive to local tumor-specific stimuli, such as lowered pH, redox conditions, hypoxia, or overexpressed certain enzymes, such as matrix metalloproteases. Using pH-, hypoxia-, redox- or MMP2-sensitive bonds between different components of nanopreparations co-loaded with siRNA and drugs, we were able to make the systems specifically delivering biologically active agents in tumors, which resulted in significantly improved therapeutic response.
Audience take away:
• The advantages of using combination preparation of RNA/drug in treating multidrug resistant tumors;
• How to engineer liposome- and micelle-based drug delivery system for combination tumor therapy;
• How to make drug delivery systems responsive to local tumoral conditions.
Vladimir P. Torchilin is a University Distinguished Professor and Director, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston. He graduated from the Moscow University with MS in Chemistry, and obtained there his Ph.D. and D.Sc. in Polymer Chemistry and Chemistry of Physiologically Active Compounds in 1971 and 1980, respectively. In 1991, Dr. Torchilin joined MGH/Harvard Medical School as the Head of Chemistry Program, Center for Imaging and Pharmaceutical Research, and Associate Professor of Radiology. Since 1998 Dr. Torchilin is with Northeastern University. He was the Chair of the Department of Pharmaceutical Sciences in 1998-2008. His research interests include liposomes, lipid-core micelles, biomedical polymers, drug delivery and targeting, pharmaceutical nanocarriers, experimental cancer immunology. He has published more than 400 original papers, more than 150 reviews and book chapters, wrote and edited 12 books, including Immobilized Enzymes in Medicine, Targeted Delivery of Imaging Agents, Liposomes, Nanoparticulates as Pharmaceutical Carriers, Biomedical Aspects of Drug Targeting, Handbook of Nanobiomedical Research, Smart Pharmaceutical Nanocarriers and holds more than 40 patents. He is Editor-in-Chief of Drug Delivery, Current Drug Discovery Technologies and of OpenNano and on the Editorial Boards of many journals including Journal of Controlled Release (Review Editor), Current Pharmaceutical Biotechnology (Co-Editor), Bioconjugate Chemistry, Advanced Drug Delivery Reviews, Molecular Pharmaceutics. Among many awards, Professor Torchilin was the recipient of the 1982 Lenin Prize in Science and Technology (the highest award in the former USSR). He was elected as a Member of European Academy of Sciences. He is also a Fellow of American Institute of Medical and Biological Engineering, of American Association of Pharmaceutical Scientists (AAPS), and of the Controlled Release Society (CRS), and received the 2005 Research Achievements in Pharmaceutics and Drug Delivery Award from the AAPS, 2007 Research Achievements Award from the Pharmaceutical Sciences World Congress, 2009 AAPS Journal Award, 2009 International Journal of Nanomedicine Distinguished Scientist Award, 2010 CRS Founders Award, 2012 Alec Bangham Life Achievement Award, 2013 Journal of Drug Targeting Life Achievement Award, and 2013 Blaise Pascal Medal in Biomedicine from the European Academy of Sciences. In 2005-2006 he was a President of the Controlled Release Society. In 2011, Times Higher Education ranked him number 2 among top world scientists in pharmacology for the period of 2001-2010, and his H-index according to Google Scholar is 102 with more than 51,000 citations. His research was supported by more than $30 million (total) he received as grants from the government and industry over the last 20 years.