Day 1 :
Midwestern University College of Pharmacy Glendale, USA
Time : 09:30 - 09:55
Volkmar Weissig, Sc.D., Ph.D. is a Tenured Full Professor of Pharmacology and Chair of the Department of Pharmaceutical Sciences. Dr. Weissig received his B.S., M.S. and Ph.D. degrees in Chemistry and his postdoctoral Sc.D. degree in Biochemistry and Pharmaceutical Biotechnology from the Martin-Luther University in Halle (Germany). Dr. Weissig holds 16 patents and he has published 98 research papers, review articles and book chapters. He also edited and published 8 books. In July 2009 Dr. Weissig was inducted into the World Technology Network as a Fellow. In October 2014 Dr. Weissig was elected President of the World Mitochondria Society.
About fifteen years ago, the National Institute of Health (USA) launched the National Nanotechnology Initiative to support, coordinate, and advance research and development of nanoscale projects. The impact of this new program on health-science related research and development became quickly visible. Broad governmental financial support advanced the start of new, and the deepening of already existing, interdisciplinary research. The anticipated merger of nanoscience with medicine quickly instigated the conceptualization of nanomedicine. The adoption of nanoscience terminology by pharmaceutical scientists resulted in the advent of nanopharmaceuticals. The term "nano" became tantamount to "cutting-edge" and was quickly embraced by the pharmaceutical science community. Colloidal drug delivery systems reemerged as nanodrug delivery systems; colloidal gold became a suspension of nano gold particles. In this presentation I shall review nanoscience related definitions applied to pharmaceuticals, discuss currently approved drug formulations which are publicized as nanopharmaceuticals and briefly review currently ongoing clinical trials within the broad field of nanomedicine. When confining the definition of nanopharmaceuticals to therapeutic formulations, in which the unique physicochemical properties expressed in the nanosize range, when man-made, play the pivotal therapeutic role, I shall argue that the current number of clincial trials neither reflects the massive investments made in the field of nanomedicine nor the general hype associated with the term "nano." However, I shall also emphasize the tremendous efforts currently underway worldwide, at the bench and in preclinical research, in order to make the big promise of the nano revolution a reality.
Solvo Biotechnology, Hungary
Keynote: Role of transporters in permeability of drugs – options for testing, modulation and targeting
Time : 09:55 - 10:20
Peter Krajcsi received his PhD in Medical Biology from the University in Szeged. He is currenty the Chief Scientific Officer of Solvo Biotechnology a manufacturer and service provider in the field of pharmaceutical and nutraceutical applications of membrane transporter technologies. He has published more than 75 papers in reputed journals and has been serving as an editorial board member of three journals.
Physiological cellular barriers of pharmaceutical importance express a large number of membrane transporters. Most membrane transporters either catalyze cellular influx or cellular efflux but some are bidirectional. The role of membrane transporters in modulation of permeability is increasingly recognized and is particularly critical for BCS / BDDCS Clas II-IV drugs. There is a significant cross-talk between transporters and enzymes of xenobiotic metabolism. The two systems may play complementary or compensatory roles. A number of assay systems are available to study transporter – drug interactions as well as transporter mediated drug – drug interactions (tDDI). Cellular assays as well as membrane assays are available. It is important that the expression systems used in transfectants mimic the physiological membrane environment. Physicochemical properties of drugs are important determinants of assay selections as transcellular transport assays (monolayer assays) may work even for intermediate-to- high passive permeability drugs but may not work for low passive permeability drugs. In contrast, membane uptake assays are ideal for low passive permeability substrates. Apically located intestinal efflux transporters (e.g. P-gp, BCRP) may limit absorption of substrate drugs. Inhibition of the efflux transporters by excipients my increase absorption, bioavailability. Targeting influx transporters may increase absorption and may play a role in tissue targeting too. Importantly, low influx transporter expression in target cells / tissue may lead to resistance to substrate drugs. Exploratory strategies to target influx transporters expressed in the blood – brain barrier have been described.
CytRx Corporation, Germany
Time : 10:35-11:00
Felix Kratz is a medicinal chemist with more than 25 years of pertinent experience in the preclinical development of anticancer drugs, prodrugs and protein conjugation chemistry and has profound knowledge of translational research from the laboratory to the clinic. He has successfully transferred aldoxorubicin, CytRx clinical lead compound, from bench to bedside that is based on an innovative drug delivery platform exploiting circulating albumin as a tumor-specific drug carrier. He has authored approximately 260 scientific publications, book articles and proceedings and is the inventor of over 20 patents and patent applications. As Vice President he heads the CytRx Drug Discovery Branch located in the Innovation Center Freiburg, Germany.
Albumin is playing an increasing role as a drug carrier in cancer therapy considering that numerous preclinical studies demonstrate an accumulation of albumin in experimental solid tumors. Principally, anticancer prodrugs can be covalently bound to exogenous or endogenous albumin, or antitumor agents are physically adsorbed to albumin forming nanoparticles as a galenic formulation. Clinically, the most advanced drug delivery system is an albumin-based nanoparticle with paclitacel (Abraxane®) approved for the treatment of metastatic breast cancer, pancreatic cancer and NSCLC. An alternative to physically adsorbing drugs is to attach the latter covalently to albumin. Aldoxorubicin, an albumin-binding drug of doxorubicin with acid-sensitive properties, that has reached an advanced stage of clinical development with results from a registrational phase III trial against second-line soft-tissue sarcoma expected in Q2 2016. The underlying drug delivery strategy is a platform technology based on two features: (a) in situ binding of the prodrug to the cysteine-34 position of endogenous albumin after intravenous administration due to a thiol-reactive maleimide group in the molecule; (b) release of albumin-bound drug at the tumor site due to the incorporation of an acid-sensitive cleavable bond between the drug and the carrier. The acid-sensitive linker contains a hydrazone bond, and CytRx have developed a broad spectrum of linkers based on this release mechanism (LADRTM – linker activated drug release technology) that have resulted in promising albumin-binding drugs in preclinical setting.
The Hebrew University of Jerusalem, Israel
Keynote: Computer-aided design of liposomal drugs: In silico prediction and experimental validation of drug candidates
Time : 11:00 - 11:25
Amiram Goldblum is the 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, his PhD is in Organic Reaction Mechanisms (Mechoulam, Hebrew U). He completed his Post-doctoral studies of Quantum Biochemistry (Paris), QSAR and QM reaction mechanisms (California). He receieved his first award at the American Chemical Society National Meeting in Washington DC 2000 for his algorithm called "Iterative Stochastic Elimination" (ISE) used to solve extremely complex combinatorial problems and focuses in recent years on Molecular Discovery by Chemoinformatics.
Liposomes are the most extensively clinically used drug delivery system. Since the FDA approval of the first nano-drug Doxil®, more than 12 other liposomal drugs were approved by the FDA and more liposomal drugs are under development. Doxil is based on the combination of high and stable drug loading which is also responsible for the controlled drug release as well as on the use of nano-pegylated liposomes. Pegylated nano-liposomes are important for treating cancers, neurodegenerative and inflammatory disorders, as they take advantage of the enhanced permeability and retention (EPR) effect and deliver drugs to the site of disease. Development of liposomal formulations is a time consuming process which requires major efforts. A more rational and less labor intense process is, taking advantage of computational modeling approaches capable of predicting whether an active pharmaceutical ingredient (API) could be loaded to and delivered by liposomes. Towards that end, Quantitative Structure– Property Relationship (QSPR) models were developed with iterative stochastic elimination and k-nearest neighbors approaches to predict drug loading efficiency (high vs. low) in liposomes. Chemical as well as formulation descriptors were employed and the resulting statistically validated models were used to screen a few thousand biologically active molecules from the Comprehensive Medicinal Chemistry database. Three drugs were selected for experimental testing of their loading into nano-liposomes, also taking into account challenges of nano-liposomal development. Two of the selected drugs were high-and one was low-loading, confirming the predictions. Ten other negative molecules from literature were also confirmed, to a total prediction accuracy of 92%. Screening results of CMC database were obtained by the two computational approaches (ISE and kNN). One of the tested drugs- mupirocin, was remotely loaded into pegylated nano-liposomes, and stabilized by intraliposomal hydroxypropyl-β-cyclodextrin to form nano-mupirocin, which was evaluated in vivo for its therapeutic efficacy. Mupirocin, an antibiotic with a unique mode of action is currently restricted to topical administration due to its rapid degradation in the blood. Intravenous administration of nano-mupiricin to mice in necrotizing fasciitis model showed significant superiority of nano-mupirocin over mupirocin. Our approach demonstrates the utility of QSPR models in screening API libraries for identifying candidates that should benefit from being administered as nano-drugs.