Day 1 :
Northeastern University, USA
Time : 09:30-10:10
Vladimir Torchilin is a university distinguished Professor and Director at Northeastern University, Center for Pharmaceutical Biotechnology and Nano-medicine, Boston. He completed his Graduation and MS in Chemistry at Moscow University. He completed his PhD and DSc in Polymer Chemistry and Chemistry of Physiologically Active Compounds in 1971 and 1980, respectively. In 1991, he joined MGH/Harvard Medical School as Head of Chemistry Program, Center for Imaging and Pharmaceutical Research, and Associate Professor of Radiology. He was the Chair in Department of Pharmaceutical Sciences from 1998-2008. His research interests include “liposomes, lipid-core micelles, biomedical polymers, drug delivery and targeting, pharmaceutical nano carriers and experimental cancer immunology”. He has published more than 350 original papers (which received more than 30,000 citations), more than 150 reviews and book chapters.
Tumor therapy, especially in the case of multidrug resistant cancers, could be significantly enhanced by using siRNA down-regulating the production of proteins, which are involved in cancer cell resistance, such as Pgp or survivin. Even better response could be achieved such as 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. Additionally, these nano preparations can be loaded into their lipidic core 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 nano preparations inside tumors, we made them sensitive to local tumor-specific stimuli, such as lowered pH, hypoxia, or overexpressed certain enzymes, such as matrix metalloproteases. Using pH-, hypoxia-, or MMP2-sensitive bonds between different components of nano preparations 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.
University of Innsbruck, Austria
Time : 10:10-10:50
Andreas Bernkop-Schnürch was educated in pharmacy (M.Sc.) and in microbiology and genetics (D.Sc.), University of Vienna, finishing his doctorate in 1994. In 2003 he was appointed to a chair in pharmaceutical technology at the University of Innsbruck. Since 2013 he heads the Institute of Pharmacy there. He invented and pioneered thiolated polymers – thiomers – as a new generation of mucoadhesive polymers. Various medicines based on thiomers have already passed clinical trials and a first product will soon reach the global pharmaceutical market. He is the founder of several biotech companies and author of over 300 research articles and reviews. As of June 2016 his H-index is 61.
Within of the last decade biologics became the new, pioneering generation of therapeutics in treatment of numerous diseases. Their fast majority, however, is working through the parenteral route being less accepted and inconvenient, as the oral route for administration of biologics emerged to be problematic mostly due to the enzymatic barrier (I), the mucus gel barrier (II) and the absorption barrier (III) of the GI-tract. To overcome these barriers, a huge variety of strategies were established. Among these different strategies, lipophilic emulsifying delivery systems - having already been established more than 30 years ago for the oral administration of the peptide drug cyclosporine - are nowadays attracting more and more academic and industrial research groups, as the number of encouraging in vivo data and late stage clinical trials is strongly increasing. Among lipophilic emulsifying delivery systems in particular self-emulsifying drug delivery systems (SEDDS) are in focus of research and development. Despite their hydrophilic character biologics can be incorporated in the lipophilic phase of SEDDS via complexation with lipophilic excipients. Once emulsified in the GI-tract to lipid droplets in the size of 30-200 nm, SEDDS provide a protective effect towards a presystemic metabolism without taking the risk of any side effects. Furthermore, SEDDS exhibit comparatively high mucus permeating properties and can be taken up by epithelial cells in an efficient manner. Moreover, SEDDS can be produced very simply and cost effectively. Because of these properties they seem to be a promising tool for oral administration of biologics.
Time : 11:10-11:50
The ability of a drug molecule to reach the right protein in the correct intracellular compartment of the target cell type, in the desired tissue following a systemic dose, is governed by a complex network of active and passive transport processes. Furthermore, the same biological mechanisms that ensure on-target exposure are also responsible for the delivery of drug to off-target sites, potentially causing negative outcomes. Understanding the concentration of drug at target (D@T) is therefore one of the “3 pillars of successful drug discovery” [Morgan et al 2012].
While it is possible to tweak the structure of small molecules to increase their uptake into the target environment, this is often at the cost of decreased potency or metabolic stability. Furthermore, macromolecules (proteins and oligos) have less flexibility in their pharmacophores and are often excluded from biological compartments due to their size and charge.
This challenge has given rise to the field of targeted drug delivery strategies, ranging from covalent modification to create pro-drugs to complex formulations to encapsulate the payload molecule and deliver it to the target. Each approach has the potential to effect the on and off target exposure and will inevitably add to the cost of the final medicine.
Finally, the capability to accurately measure the concentration of a drug molecule at the site of action remains a significant challenge, but is crucial to our ability to select the best molecule and evaluate the added benefit of a delivery system. Methodologies that are able to determine drug location and concentration, while preserving the structure of the surrounding tissue, continue to improve in reproducibility and resolution.
This presentation will aim to
- Clarify targeted VS Enhanced uptake
- Review the formulation options to improve delivery
- Explore a way to quantify the value of a given delivery system
- Outline experimental methods available to measure the location and concentration of drugs in a given tissue
- Share some of the GSK experiences in this challenging field.
The Hebrew University of Jerusalem, Israel
Time : 11:50-12:30
Prof. (emeritus) Goldblum is Head of the Molecular Modeling and Drug Design and Discovery Unit at the Institute for Drug Research of the Hebrew University. Following a BSc in Chemistry and Physics and a MSc in QM studies of molecular spectra, Goldblum's PhD is in Organic Reaction Mechanisms (Hebrew University) followed by Postdoc studies of Quantum Biochemistry (Paris), and of QSAR and QM reaction mechanisms (California). Back at Hebrew U, Goldblum performed research of protein reactions and interactions using semiempirical QM and developed MNDO/H for dealing with H-bonding in relatively large molecular systems. Since 2000, Goldblum's group focuses on applications of his prize winning generic algorithm (ACS "emerging technologies", Washington D.C. 2000) for finding sets of best solutions in extremely complex combinatorial problems. ISE (Iterative Stochastic Elimination) has been applied to protein structure and conformations, to protein-protein and protein-ligand interactions, to molecular properties and to the discovery of drug candidates.
Toll-like receptors (TLR) are receptors of innate immunity that recognize Pathogen Associated Molecular Patterns. They play a critical role in many pathological states, in acute and chronic inflammatory processes. TLR9 is a promising target for drug discovery, since it has been implicated in several pathologies, including defense against viral infections and psoriasis. Immune-modulators are promising molecules for therapeutic intervention in these indications. TLR9 is located in the endosome and activated by dsDNA with CpG motives encountered in microbial DNA.
Here we report on a combined approach to discover new TLR9 antagonists by computational chemistry and cell based assays. We used our in-house Iterative Stochastic Elimination (ISE) algorithm to create models that distinguish between TLR9 antagonists ("actives") and other molecules ("inactives"), based on molecular physico-chemical properties. Subsequent screening and scoring of a dataset of 1.8 million commercially available molecules led to the purchasing of top scored molecules, which were tested in a new cell based system based on human PRRs stably expressed in NIH3T3 fibroblasts. As described previously, this cell line shows a very low endogenous PRR-activity and contains a reporter gene which is selectively activated by the integrated human PRR enabling rapid screening of potential ligands. IC50 values of each of these top scored molecules were determined. Out of 60 molecules tested, 56 showed antagonistic activity. We discovered 21 new highly potential antagonists with IC50 values lower than 10 μM, with five of them having IC50 values under 1μM.