"DRUG DELIVERY TO THE TARGET” Today, the vast majority of clinically used drugs are low molecular-weight compounds (typically under 500 g mol-1 ) that exhibit a short half- life in the blood stream and a high overall clearance rate. These small molecules diffuse rapidly into healthy tissues and are distributed evenly within the body. As a consequence, relatively small amounts of the drug reach the target site and often therapy is associated with side effects. These disadvantages are especially pronounced with drugs that exhibit a narrow therapeutic index, such as anticancer, antirheumatic, and immunosuppressive agents. Inadequate drug distribution also involves administration of unstable molecules (proteins, siRNA, DNA) or delivery to difficult sites (brain, retina, tumours, intracellular organelles). In order to optimize the biodistribution of drugs to diseased organs, tissues or cells, a number of macromolecular delivery systems have been developed according to the concept of drug targeting first developed by Paul Ehrlich over a century ago, who described the “magic bullet” as a tool aimed at delivering precisely the drug at a disease site without harming healthy tissues. This idea was then developed into different directions, which include passive or active mechanisms of disease targeting and site-selective drug release. Generally, macromolecular delivery systems can be classified either as polymer-drug conjugates (polymer therapeutics) or as nanoparticle therapeutics depending on the specific components which are assembled to build up the “nanocarrier”. Both strategies aim at increasing the therapeutic index by making a greater amount of drug molecules available at the diseased site while reducing systemic drug exposure. In this session an overview of nanotherapeutic strategies is presented by four recognized scientists with a focus on definitions, concepts and applications that characterize the salient features of the drug-delivery systems mainly in the field of cancer disease. Paolo CALICETI (University of Padua). Targeting and Delivery of Antitumoral Drugs Over the last decades, many efforts have been made to create new colloidal drug delivery platforms with the concrete purpose of optimizing the pharmacological performance of bioactives and the dream of generating ideal drugs. As a result, last generation delivery systems are capable of complex functions which enable sequential overcoming of multiple biobarriers following a certain time/site-determined “logic” of events. These nanocarriers enable the use of preexisting drugs by providing longer circulation times, better tolerability, and site-specific delivery, factors that result in better patient outcomes. Historically, poor prognosis disorders, namely cancer, represent the field of medicine application to which multifunctional nanotechnology made the most prominent contributions. Passive targeting is usually associated to the enhanced permeation and retention (EPR) effect. According to the nanodimension, body circulating nanocarriers dispose preferentially into solid tumours that are characterized by enhanced permeability as compared to healthy tissues. Active targeting exploits cellular or sub-cellular functions involved in specific ligand/receptor recognition. In such a case, targeting moieties are introduced in the structure of the colloidal systems in order to recognize selectively specific receptors located on the membrane surface of cell and organelles. The combination of passive and active targeting with site-specific drug release can succeed in realization of highly performing nanomedicines. Arto URTTI (University of Helsinki, Finland). Nanoparticles in Drug Delivery Nanoparticles can be used to improve and target drug delivery. In this lecture brief introduction is given firstly to the pharmacokinetics (relevant physiology, impact of drug properties on ADME, importance of drug transporters). Thereafter, different classes of nanoparticles are introduced as well as their pharmacokinetic properties (organ and body level kinetics, sub-cellular kinetics). In principle, volume of distribution is decreased by the nanoparticles, but selectivity can be increased. It is important to realise that the nanoparticle-mediated drug delivery is feasible only if the drug distribution is otherwise inadequate. These cases include drug targeting of difficult, unstable molecules (proteins, siRNA, DNA), delivery to the difficult sites (brain, retina, tumours, intracellular organelles) and drugs with serious side effects (e.g. anti-cancer agents). The performance of the nanoparticulates depends on the size and surface functionalities in the particles. Also, the drug release and particle disintegration can vary depending on the system. The nanoparticle classes include micelles, polymeric micelles, polymeric particles, metallic nanoparticles, dendrimers, liposomes, electrostatic complexes, and multi-finctional hybrid systems. Pharmacokinetics of the particles can be tailored by proper nanoparticle design. Ronit SATCHI-FAINARO (University of Tel-Aviv). Rational design of multifunctional polymer therapeutics for cancer theranostics Drug delivery technologies including novel polymers promise to create new combination treatments. Multimodality-targeted polymer therapeutics that include anti-angiogenic agents and chemotherapeutics offer the potential for improved efficacy and diminished toxicity in the treatment of cancer and other angiogenesis-dependent diseases. Using molecular imaging techniques, dormant and fast-growing tumor mouse models were successfully established to intrav itally, non- invasively follow-up tumor progression and response to these polymer therapeutics. Recently some novel combined anti-angiogenic and antitumor polymer-drug conjugates that target both the tumor and its microenvironment were designed and characterized. These conjugates include combined anti-angiogenic and chemotherapeutic drugs, such as TNP-470 and paclitaxel, respectively. Some also incorporate bisphosphonates as targeting moieties for bone metastases and osteosarcomas or RGD peptidomimetics that target αVβ3 integrins overexpressed on tumor endothelial cells and several tumor cells. These novel architectures will potentially shed light on the molecular mechanisms underlying tumor dormancy and hopefully transform cancer into a chronically-manageable disease. Stephen HANESSIAN (Université de Montréal, Canada). Strategies Toward Tumor-directed Chemotherapeutic Agents Most solid tumors possess defective vascular architecture, increased vascular permeability and leaky vessels. The enhanced permeability and retention (EPR) effect allows the passage and distribution of micro/nanoparticulate devices, offering therapeutic windows for the delivery of drug substances. To take advantage of these defects of the tumor vasculature, drugs have been linked to macromolecular structures, polymers or micro/nanocarriers as vectors. However, the retention time in diseased tissues is generally low. Therefore, it is imperative that nanoparticulate drug carriers be capable of residing in defined locations for longer periods of time, while releasing therapeutic agents in the appropriate environment at the requisite rate and dose. Sustained and elevated tissue concentrations were achieved with intra-articularly administered Ultrasmall SuperParamagnetic Iron Oxide nanoparticles (USPIOs) when an external magnet was applied on the joint. Colloidal dispersions of USPIOs add a unique function to nanoparticles due to their magnetic properties. A strategically interesting way to achieve site-selective delivery is by chemical attachment of therapeutic agents to USPIOs via a cell-specific labile linkage, and steering the drug-USPIO assembly to specific diseased areas in the body under the influence of an external magnetic field. This implies that the drug-nanoparticle assembly must be internalized by cells, that this uptake be enhanced by an external magnetic field and, subsequently, that the drug be released intracellularly to exert its expected therapeutic effects. Selected readings M. E. Davis, Z. Chen and D. M. Shin, “Nanoparticle therapeutics:an emerging treatment modality for cancer”, Nature Review Drug Discovery 2009, 7, 771-782. H. Ringsdorf, M. J. Vicent and R. Duncan, “Polymer therapeutics: clinical applications and challenges for development”, Advanced Drug Delivery Reviews 2009, 61, 1117–1120 (and references therein reported). R. Haag and F. Kratz, “Polymer Therapeutics: Concepts and Applications”, Angewandte Chemie International Edition 2006, 45, 1198-1215. P. Caliceti and F. M. Veronese, “Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugated”, Advanced Drug Delivery Reviews 2003, 55, 1261-1277. E. Segal and R. Satchi-Fainaro, “Design and development of polymer conjugates as antiangiogenic agents”, Special Theme issue: Polymer Therapeutics: Clinical Applications and Challenges for Development, Advanced Drug Delivery Reviews 2009, 13, 1159-1176. F. Cengelli, J. A. Grzyb, A. Montoro, H. Hofmann, S. Hanessian, and L. Juillerat-Jeanneret, “Surface- functionalized ultrasmall superparamagnetic nanoparticles as magnetic delivery vectors for camptothecin”, ChemMedChem 2009, 4, 988-997. L. Paasonen, B. Romberg, G. Storm, M. Yliperttula, A. Urtti and W. E. Hennink, “Temperature- sensitive poly(N-(2-hydroxypropyl)methacrylamide- mono/dilactate)-coated liposomes for triggered contents release”, Bioconjugate Chemistry 2007, 18, 2131-2136. Paolo Caliceti, born in Verona in 1959, married 2 children, is Full Professor in Pharmaceutical Technology of Faculty of Pharmacy, at the University of Padua, Italy. He got the master degree in 1984 in Pharmaceutical Chemistry and Technology and PhD degree in 1989 in Pharmaceutical Sciences from the University of Padua. In the same university he had permanent positions as Assistant Professor (1989-1998) and Associate Professor (1998-2002). Throughout the years, he covered the following positions: Guest researcher at Glaxo (Verona, Italy, 1984); visiting scientist at National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases of National Institute of Health (Bethesda, USA, 1985); Post doctoral fellowship of Soleko Company (1989); Post doctoral fellowship of National Council of Research on Chemical Sciences Center for Study of Chemistry of Drugs and Biologically Active Products of National Council of Researches (CNR) (1989); invited scientist at Enzyme Engineering Laboratories of the Institute of Experimental Cardiology Research Center of Academy of Sciences (Moscow, Russia, 1990); invited scientist at Drug Delivery e Molecular Immunology of SmithKline Beecham Pharmaceuticals Laboratories (King of Prussia ,PA, USA, 1994). Since the first years of his scientific activity he dedicated much of the interest in studying formulations for protein delivery. About 25 years ago, he started his scientific activity working on protein-PEGylation when PEGylation was moving the first steps in the pharmaceutical scenario. He strongly contributed to the progresses of this technology and he is still actively involved in this research area. Throughout the years he moved his scientific interest to other aspects of drug delivery: non- conventional formulations including supramolecular drug delivery systems, namely micelles, bioconjugates, and nano- and microparticles. His main topics of research are: 1. Modification of bioactive peptides and proteins with soluble polymers; 2. Production of lipid and polymeric biodegradable nano-/micro-particles for slow and controlled drug release by classical or supercritical techniques; 3. Development of multifunctional macromolecules for active or passive drug and protein delivery; 4. Preparation and in vitro and in vivo characterisation of new cyclodextrin based drug carriers; 5. Gold nanoparticles as drug delivery systems. He is author and co-author of over 130 original papers and reviews, 7 international patents, 5 italian patents and over 150 contributions to congresses. His research activity has been granting either by public or private institutions (EU, Italian and foreign programs) and he is involved in several collaborations with outstanding international academic and industrial research groups working in the field of drug delivery. Main collaborations are: 1. Prigen (Italy); 2. Fidia Pharmaceuticals (Italy); 3. Sigma Tau (Italy); 4. Italfarmaco (Italy); 5. University of Munich (Germany); 6. University of Nottingham (UK); 7. ULB (Belgium); 8. Tel Aviv University (Israel), 8 Centro de Investigation Principe Felipe (Valencia, Spain). He is member of the editorial board of few international drug delivery journals. He is president of CRS Italian Chapter. Dr. Ronit Satchi-Fainaro received her Bachelor of Pharmacy from the Hebrew University, Israel (1995) and her Ph.D. from the University of London, UK (1999). Together with Professor Ruth Duncan, she developed PDEPT (Polymer Directed Enzyme Prodrug Therapy), a novel two- step approach to target cancer. During her Ph.D., she received the British Council scholarship, Overseas Research Student award, Wingate scholarship and The A. M. Cook Prize for Ph.D. Thesis. She then completed a two-year postdoctoral appointment at Tel Aviv University working on protein biochemistry, for which she holds several patents. Ronit spent two years as a Fulbright and Rothschild Scholar at Harvard University and Children’s Hospital Boston working with Dr. Judah Folkman on novel polymer-conjugated angiogenesis inhibitors to target tumor vasculature. In 2002, she was appointed Instructor at Boston Children’s Hospital and Harvard Medical School. Since October 2005, she is a Senior Lecturer at the Department of Physiology and Pharmacology at the Sackler School of Medicine at Tel Aviv University and a Visiting Associate Professor at Harvard Medical School and Children’s Hospital Boston. Her research interests include investigations relating to tumor biology, tumor dormancy, mechanism of action of angiogenesis inhibitors, self-assembly of polymeric architectures and novel approaches to target cancer. Throughout, she has maintained an interest in understanding the biological rationale for the design of polymer therapeutics suitable for transfer into clinical testing. Her research laboratory focuses on the design and characterization of novel drug delivery platforms, including dendrimers and hyperbranched polymer–based nanoparticles, and the design of highly- selective targeting molecules integrating biology, chemistry, protein engineering, computational approaches, material sciences and nanotechnology to selectively guide drugs into pathological sites. Ronit’s vision is that novel approaches to target anticancer, anti-angiogenic drugs and siRNAs to endothelial and tumor cells to potentially treat angiogenesis-dependent diseases could transform cancer into a chronically- manageable disease. Ronit has published about 30 articles and reviews in prestigious biological and chemical journals. She has filed 12 patents, and her work has been recognized via international awards including the CRS-3M Outstanding Research Award in Drug Delivery (1999), CRS- Ethypharm Outstanding Pharmaceutical Paper Award (2003), Alon Fellowship for outstanding young investigators (2006-2009), The EACR Young Cancer Researcher highly commended Award (2005) and the Juludan Prize for the Advancement of Technology in Medicine (2010). Her scientific achievements were also acknowledged by inclusion in the “40 under 40” list of the The Marker Journal in 2008 and in the 50 most promising women of the Calcalist Journal in 2009. She was awarded the ISF, BSF, ICA, ICRF, Ministry of Health and several other grants for her work at TAU.