Day 2 :
- Protein Interactions as Targeted Therapeutics
Drug Discovery and Development
Current Issues In Bioavailability & Bioequivalence
Pharmaceutical Innovations in 21St Century
Herbal Drug Interactions
Location: Baltimore, MD, USA
Session Introduction
Mircea Alexandru Mateescu
University of Quebec, Canada
Title: New concepts in formulation of Bioactive Agents
Biography:
Mircea Alexandru Mateescu has a PhD from Bucharest Polytechnic University and is a receiver of a “Honorary Laurea” from Rome University “La Sapienza”. He has been a full-time Professor at UQAM since 1994. His research relates to Multifunctional Proteins and to Drug Targeting. He is the Co-inventor of more than 30 patents covering therapeutic enzymes and new excipients for drug delivery. He has developed fruitful collaborations with pharmaceutical companies and was involved in several technological transfers. He published more than 130 papers in reputed journals, one book and 8 book-chapters. He is the holder of Bombardier Prize (1999) for Technological Innovation, of Venezia Prize (Italian Chamber of Commerce, 2012), and Research-Career Prize (UQAM, 2014).
Abstract:
Every year there are new therapeutic applications of proteins as carriers for bioactive agents of as active principles in treatment of various dysfunctions. Particular characteristics of proteins represent noteworthy cases of Molecular Self-Assembly in nature. Proteins drastically change their structure following various processing events such as heating, pH modification or action of ionic agents. These structural alterations can be useful for the utilisation of proteins as carriers (micro- and nano-spheres) for various bioactive agents or as biomedical materials (suture for surgery, skin grafts). However, these drastic alterations can be damaging for orally administered proteins susceptible to gastric acidity and proteolytic denaturation. New approaches in protein formulation are needed related to specific requirements for these biomolecules which can lose their activity due to processing temperature or to residual humidity remaining after coating. The proposed concepts are related to compacted pharmaceutical compositions containing one or more therapeutic enzymes designed for oral administration. The biopharmaceutical product could be under monolithic or multiparticulate forms and obtained without the application of an external polymer-based enteric coating. The self-assembled uncoated proteins are able to generate in situ an outer layer which will offer a gastro-protection and keep product availability. An example of excipient-free pancreatic enzyme will be discussed. The colonic delivery of an anti-inflammatory enzyme system based on a vegetal histaminase and on catalase will be also presented.
Pompilia Ispas-Szabo
Université du Québec à Montréal, Canada.
Title: Self-assembling of bioactive agents – a way to generate new drugs. The case of mesalamine: sucralfate complexes
Biography:
Pompilia Ispas-Szabo is Adjunct Professor at Université du Québec à Montreal (UQAM, Canada) and a Research & Development scientist in pharmaceutical industry. She completed her M.Sc in Physical Chemistry at Bucharest University and the Ph.D. at UQAM. Co-inventor of new excipients proposed as matrices for controlled drug delivery or new products, she worked in various Canadian pharmaceutical companies (Smartrix Technologies, IntelGenx Corp., Aptalis Pharma, etc.), being involved in the development of innovative products or technological platforms. Co-author of 10 patents/applications, more than 30 papers in reputed journals, one book, two book-chapters, member of Controlled Release Society and AAPS, and reviewer for several international journals, she is recognized for her contribution to academic and industrial innovation.
Abstract:
Macromolecular self-assembly represents an interesting way to produce materials for various therapeutic applications (targeted drug delivery, bioactive encapsulation). Considerable interest relates to the design of polymer- or peptide-based self-assembled biomaterials due to the possibility to generate different specific properties by new arrangements at molecular level. Differently from existing approaches which explore mainly the drug-excipient association in order to improve solubility, we are proposing a new alternative – the drug-drug self-assembling, using two different active molecules. Mesalamine (5-aminosalicylic acid, MES) is an efficacious active ingredient used for the long-term therapy of inflammatory bowel disease. However, its oral administration is frequently associated with systemic side effects caused by drug absorption in the upper gastrointestinal tract. Sucralfate (SUC) is a non-systemic site protector prescribed in the treatment of inflammation and gastric ulceration. The anti-inflammatory action of MES in association with bioadhesiveness and mucosal healing properties of SUC were considered promising for the development of a new compound containing both molecules, aimed as an improved treatment of ulcerative colitis. The present case investigated the capacity of the two active agents to interact and generate a new and stable entity via self-assembling. Spray-drying was used to co-process the two active principles from an aqueous mixture. Preliminary in vitro studies with oral solid dosage forms based on the obtained MES-SUC complexes have shown a controlled MES release, opening the perspective of a new colon-targeted delivery system and a novel class of compounds with therapeutic application in inflammatory bowel diseases.
Biography:
Margarida Barroso is an Associate Professor at the Center for Cardiovascular Sciences, Albany Medical College in Albany, NY. She received her PhD, in Genetics from the University of Lisbon/Gulbenkian Institute of Sciences in Portugal and was a Post-doctoral fellow at the Department of Molecular Biology, Princeton University. She is in a faculty instructor in several international imaging courses and has two issued patents on FRET imaging technology. She belongs to the following scientific societies: American Society of Cell Biology (ASCB), Biophysical Society, Histochemical Society, and Sigma Xi. Since 2008, she is a member of the governing Council of the Histochemical Society. She has published more than 25 papers in reputed journals and acts as a reviewer for several internationally recognized journals.
Abstract:
Traditional cancer therapy generally leads to harmful side effects, thus warranting development of targeted therapies, which are better tolerated by cancer patients. Our goal is to develop in vivo non-invasive optical imaging assays for optimization of anti-cancer drug targeted therapy. We have established a fluorescence lifetime Förster Resonance Energy Transfer (FL-FRET) non-invasive whole-body in vivo tomographic imaging technique that can discriminate bound and internalized near-infrared (NIR)-labeled transferrin (Tfn) from free, soluble NIR-Tfn. This FRET-based assay exploits the homodimeric nature of transferrin receptor (TFR) that binds two molecules of Tfn in close proximity to determine dimerization and internalization of TFR-Tfn complexes into cancer cells. The Tfn FRET assay has been validated in vitro by visible and NIRFRET microscopy. FL-FRET tomographic imaging in vivo has been used to measure the internalization of tail-vein injected NIR-Tfn into human breast T47D tumor xenografts in live nude mice. Quantification of FRET donor % (FD%) in T47D tumor xenografts in vivo, indicates a higher proportion of FD% with increasing acceptor:donor ratio, demonstrating tumor uptake of NIR-Tfn. Tfn uptake concentration curve shows high sensitivity of FL-FRET imaging using NIR-Tfn as low as 10µg/ml of blood. Furthermore, relative high FD% for holo-Tfn (iron-loaded) compared to that of apo-Tfn (iron-depleted) demonstrates specific TFR-mediated uptake of holo-Tfn by T47D tumor xenografts, as expected since iron-depleted apo-Tfn shows reduced binding affinity towards TFR. In conclusion, we have successfully demonstrated the quantitative receptor-mediated uptake of Tfn into human breast tumors in vivo using a novel non-invasive NIR FL-FRET tomographic imaging assay.
Taosheng Chen
St. Jude Children’s Research Hospital, USA
Title: Targeting Xenobiotic Receptors PXR and CAR In Drug Toxicity and Resistance
Biography:
Taosheng Chen completed his Ph.D. from the University of Vermont, and postdoctoral studies from the University of Virginia. He is an Associate Member (Associate Professor) and Director of the High Throughput Screening Center at St. Jude Children’s Research Hospital. Prior to joining St Jude, Taosheng was a Senior Research Investigator at Bristol-Myers Squibb, and a Research Scientist at SAIC-Frederick, National Cancer Institute. Taosheng serves on the Editorial Boards of several journals, and on NIH Grant Review Panels. He has authored more than 80 publications. His research laboratory studies the roles of nuclear receptors in therapeutic efficacy and toxic effects (http://www.stjuderesearch.org/chen/).
Abstract:
Xenobiotic receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate drug toxicity and resistance, which are the leading causes of treatment failure and for which no clinically safe and effective remedy is available. PXR and CAR play central roles in activating the expression of CYP3A4, a major enzyme responsible for metabolizing more than 50% of clinically prescribed drugs, and ALAS1, a rate-limiting porphyrin biosynthesis enzyme that increases the levels of hepatotoxic protoporphyrin IX (PPIX), both contributing to drug-induced liver toxicity. Elevated MDR1 level is associated with drug resistance. MDR1 expression is induced by CAR and PXR. While PXR is ligand-inducible, CAR is constitutively active. Therefore, inhibitors of PXR and CAR (i.e., antagonists of PXR and inverse agonists of CAR) may prevent drug-induced liver toxicity and overcome drug resistance. By using a chemical biology approach we have identified and optimized PXR antagonists and CAR inverse agonists, investigated their mechanisms of action by performing structural and functional analysis, and evaluated their in vivo activities by using humanized animal models. Our data indicate that it is feasible to prevent drug-induced liver toxicity and overcome drug resistance by targeting PXR and CAR using mechanism-guided chemical agents.
Biography:
Margarida Barroso is an Associate Professor at the Center for Cardiovascular Sciences, Albany Medical College in Albany, NY. She received her PhD, in Genetics from the University of Lisbon/Gulbenkian Institute of Sciences in Portugal and was a Post-doctoral fellow at the Department of Molecular Biology, Princeton University. She is in a faculty instructor in several international imaging courses and has two issued patents on FRET imaging technology. She belongs to the following scientific societies: American Society of Cell Biology (ASCB), Biophysical Society, Histochemical Society, and Sigma Xi. Since 2008, she is a member of the governing Council of the Histochemical Society. She has published more than 25 papers in reputed journals and acts as a reviewer for several internationally recognized journals.
Abstract:
Traditional cancer therapy generally leads to harmful side effects, thus warranting development of targeted therapies, which are better tolerated by cancer patients. Our goal is to develop in vivo non-invasive optical imaging assays for optimization of anti-cancer drug targeted therapy. We have established a fluorescence lifetime Förster Resonance Energy Transfer (FL-FRET) non-invasive whole-body in vivo tomographic imaging technique that can discriminate bound and internalized near-infrared (NIR)-labeled transferrin (Tfn) from free, soluble NIR-Tfn. This FRET-based assay exploits the homodimeric nature of transferrin receptor (TFR) that binds two molecules of Tfn in close proximity to determine dimerization and internalization of TFR-Tfn complexes into cancer cells. The Tfn FRET assay has been validated in vitro by visible and NIRFRET microscopy. FL-FRET tomographic imaging in vivo has been used to measure the internalization of tail-vein injected NIR-Tfn into human breast T47D tumor xenografts in live nude mice. Quantification of FRET donor % (FD%) in T47D tumor xenografts in vivo, indicates a higher proportion of FD% with increasing acceptor:donor ratio, demonstrating tumor uptake of NIR-Tfn. Tfn uptake concentration curve shows high sensitivity of FL-FRET imaging using NIR-Tfn as low as 10µg/ml of blood. Furthermore, relative high FD% for holo-Tfn (iron-loaded) compared to that of apo-Tfn (iron-depleted) demonstrates specific TFR-mediated uptake of holo-Tfn by T47D tumor xenografts, as expected since iron-depleted apo-Tfn shows reduced binding affinity towards TFR. In conclusion, we have successfully demonstrated the quantitative receptor-mediated uptake of Tfn into human breast tumors in vivo using a novel non-invasive NIR FL-FRET tomographic imaging assay.
Keerat Kaur
New York Medical College, USA
Title: Characterizing the benefits of pharmacological treatments for promoting the regenerative capacity of cardiac progenitor cells
Biography:
Keerat Kaur is currently a PhD student in Department of physiology at New York Medical College, NY. she have completed her undergraduate and master degree in the field Human Genetics from Guru Nanak Dev University, Amritsar, India. Presently, she is working on the project entitled ‘Examining pharmacological approaches for enhancing the cardiac regenerative capacity of adult stem cells’. In the ongoing project, she is trying to characterize the benefits of pharmacological treatments for enhancing the potential of adult tissue- derived stem cells to form myocardial tissue. As, stem cell therapy has been widely accepted for its ability to give rise to differentiated cells, we are constantly developing new culture conditions that would allow to enhance the number of stem cells and also differentiate them into mature cardiac tissue. In the second project, she is examining the capability of human bone marrow cells to produce functional cardiomyocytes which can later become a source of fully differentiated cells for transplantation. The long term goal of her study is to focus on procedures that would allow the adult stem cells as a real target for clinical management.
Abstract:
Stem cell therapy has been widely used in attempts to repair and regenerate the diseased heart. Since the heart does contain endogenous cardiac progenitor cells (CPCs), heart tissue itself has served as a stem cell source for cardiac repair. Impediments in using CPCs for treating human patients are that the cells are present in low numbers within the heart and require heart biopsies, which may not be efficacious for severely diseased individuals. Two major objectives in optimizing the therapeutic utility of CPCs are to enhance their cardiac regenerative capacity and expand their numbers without sacrificing their cardiac competency. Our laboratory has focused on utilizing pharmacological approaches for promoting the myocardial potential of adult stem cells. Two of the drugs we have investigated are the DNA demethylation reagent 5-azacytidine and the G9a histone methyltransferase inhibitor BIX01294.
Meghana Vidiyala
Ascent Pharmaceuticals, USA
Title: Development and characterization of lidocaine transdermal system with self-emulsifying nanosystem (sens)
Biography:
Dr. Meghana Vidiyala from Ascent Pharmaceuticals, USA
Abstract:
The objective of this work is to develop and characterize Nano-emulsion based transdermal system (NTS) having Lidocaine in Nano-emulsion form. This second generation Nano-emulsion based transdermal drug delivery system has several advantages over traditional gel and transdermal systems (TS). NTS are therapeutically more effective compared to gel and conventional transdermal patches. Nano-emulsion components including surfactants and co-surfactants enhance skin permeability thereby increasing therapeutic efficacy and bioavailability of the drug molecule. Moreover, the release profile can be modulated by altering the ratio between surfactant, co-surfactant, and solvents.
Anamaria Orza
Emory University School of Medicine, USA
Title: Shaped magnetic composites as targeted molecular imaging tools
Biography:
Anamaria Orza focuses primarily on the area of development of innovative architectural nano camposites for biomedical applications. Prior to her arrival at Emory in the fall of 2013, Dr. Orza served as a postdoctoral researcher at the Center for Integrative Nanotechnology Sciences at the University of Arkansas at Little Rock. Dr.Orza has been recognized as a European Union fellow, receiving her PhD in Chemistry from Babes Bolyai University, Romania and working in close collaboration with Liverpool University, United Kingdom. Dr. Orza has authored and co-authored 2 patents and over 32 papers in leading journals and at leading international conferences in the field (with over 170 citations) and 2 book chapters in the fields of Applied Nanotechnology in Cancer Research and Tissue Engineering. anamari
Abstract:
In this study, we report on the synthesis and characterization of shaped iron oxide core palladium shell (Fe2O3-Pd) as three-modality image agents in Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Photo-Acoustic (PAT) imaging. Four shapes were synthesized such as: triangular plates, tetrapods, pyramidal structures and pentagon shaped nanoparticles. We report for the first time their synthesis using an original approach by uniformly fusing multiple components and by controlling their structural (i.e., size, shell thickness, dimer shape) and physical characteristics (i.e., optical, and acoustic). To confer enhanced properties for efficient targeted capability, the surface of the nanoparticles was modified with (i) the amphiphilic di-block polymer and (ii) functionalized with the ligands targeting transferrin receptor (Tr). As a result, the newly created shaped nanoparticles were characterized via different optical and imaging techniques (HR-TEM, STEM, XPS, EDX, Z-potential, and UV-VIS). We show that the shaped Fe2O3-Pd nanoparticles are stable and biocompatible in given Fe concentrations range and display shaped control MRI/CT/PAT attenuation intensity. The attenuation intensity subsequently decreases as follows: tetrapods>pyramidal>pentagons>triangular plates. Moreover, these shaped nanoparticles enable targeting imaging of tumor cells that have a high expression of the transferrin receptor. These findings conclude that the designed Fe2O3-Pd are promising contrast agents for targeted MRI/CT/PAT molecular imaging.
Deborah Quintanilha Falcão
Universidade Federal Fuminense, Brazil
Title: Nano-delivery Systems of Natural Products: Development Challenges and Future Prospects
Biography:
Deborah Quintanilha Falcão has completed her PhD at the age of 32 years from cooperation between Universidade Federal do Rio de Janeiro (Brazil) and Université Montpellier I (France) and postdoctoral studies from Oswaldo Cruz Foundation (Brazil). Actually she is professor of Pharmaceutical Technology at Faculty of Pharmacy from Universidade Federal Fluminense (Brazil). She has published more than 15 papers in reputed journals, 5 book chapters and serving as an editorial board member of repute.
Abstract:
Spices have been used since ancient times for a large number of purposes, such as medicinal, perfume, preservative and to confer aroma and flavour to food. They still play an important role in the traditional medicine as part of pharmaceutical preparations and several monographs are reported in the official pharmacopoeias. Extracts obtained from medicinal plants are generally complex mixtures of organic substances produced as plants secondary metabolites. Increased cases of opportunistic diseases emanating from side effects associated with synthetic drugs continue to necessitate incremental efforts in searching for effective biological substitutes with little or no side effects. Therefore, many studies have been performed with medicinal plants in order to overcome this problem, intending the discovery of new molecules of therapeutic interest. In this regard, the application of nanotechnology tends to make this more feasible due to the ideal small size of the particles, releasing the substance in the correct location and time. The choice of wall material and production method is therefore of paramount importance and combined with the ability to modify drug release, makes such nanosystems ideal candidates for therapeutical purposes presenting a wide range of applications. The nanotechnology combined to the natural products chemistry can bring an important contribution to the development of new delivery systems, promising candidates as new products with important perspective on health improvement. The aim of this work is to offer an overview on nanoencapsulation of natural products covering development challenges and future perspectives.
Gozde Unsoy
Middle East Technical University, Turkey
Title: Doxorubicin loaded magnetic chitosan nanoparticles for pH responsive targeted drug delivery
Biography:
Gozde Unsoy has received her PhD in Biotechnology from Middle East Technical University (METU), Turkey under Dr. Ufuk Gunduz in 2013. Her PhD thesis focused on the discovery of novel targeted drug delivery systems has been chosen for the “Best Thesis of the Year Award†at METU. She is currently studying on the in vitro and in vivo efficacy anti-cancer drug loaded nano carriers developed by her as a Post-Doctoral Research Scientist. She has published more than 18 papers in reputed journals and is serving as an Editorial Board Member of repute.
Abstract:
Chitosan coated magnetic iron-oxide nanoparticles (CSMNPs) can be targeted to the tumor site under magnetic field and maintain pH dependent drug release. Among various materials, chitosan has a great importance as a pH sensitive, natural, biodegradable, biocompatible and bio-adhesive polymer. CSMNPs were in-situ synthesized at different sizes by ionic crosslinking method. XRD and XPS analyses proved that synthesized iron-oxide was magnetite (Fe3O4). Chitosan coating on magnetite was detected by FTIR and chitosan amount was 23% in TGA. CSMNPs were found super-paramagnetic by VSM. Average core size was 8 nm in TEM and hydrodynamic diameter was 103 nm in DLS. The anti-cancer drug doxorubicin was loaded on CSMNPs (Dox-CSMNPs) and loading was confirmed by FTIR. 30% of doxorubicin was released at pH 4.2 in first 7 hours. Dox-CSMNPs are efficiently taken up by MCF-7 and 1 µM Doxorubicin resistant MCF-7 (MCF-7/Dox) breast cancer cells. CSMNPs increase the efficacy of Doxorubicin by increasing the cellular uptake of drug and overcome the resistance of Doxorubicin in resistant cells. When these drugs are loaded on CSMNPs, the anti-proliferative efficiencies of drugs increases and resistance to these drugs is eliminated. In vitro cytotoxicity analyses also revealed that IC50 values of drug 13 fold decreases when loaded on CSMNPs. Pro-apoptotic Puma and Noxa genes were up-regulated while anti-apoptotic Bcl-2, Survivin and cIAP-2 genes were down-regulated in Dox-CSMNP treated cells. This study provides new insights to the development of pH responsive magnetic targeted drug delivery systems to overcome the side effects and resistance problem of conventional chemotherapy.
Vassilios Papadopoulos
University of Athens, Greece
Title: The safety of biological medicines for rheumatoid arthritis
Biography:
Dr. Papadopoulos is a graduate of the School of Pharmacy of the University of Athens. He completed his PhD in Health and Life Science at Université Pierre et Marie Curie, Paris and post-doctoral studies in France and Australia. In 1988, he joined the faculty of Georgetown University School of Medicine, where he rose through the ranks to become Professor and Chair of the Department of Biochemistry and Molecular Biology, Associate Vice President for research and then Director of the Biomedical Graduate Research Organization. In 2007, he moved to Montreal as the Executive director and chief scientific officer of the Research Institute of the McGill University Health Centre. He is Professor in the Faculty of Medicine at McGill University and holds a Canada Research Chair in Biochemical Pharmacology and the Phil Gold Chair in Medicine. Dr. Papadopoulos has published over 300 papers, holds numerous patents and serves on national and international advisory committees. He is an elected foreign member of the National Academies of Medicine and Pharmacy in France, fellow of the American Association for the Advancement of Science, and fellow of the Canadian Academy of Health Sciences.
Abstract:
Biotechnological medicines have improved the treatment of various diseases and the quality of life of patients. The administration of a drug may lead to adverse events that may or may not be documented. These events affect disease progression and health expenditures. Rheumatoid Arthritis (R.A.) is an autoimmune disease for which biotechnological medicines are prescribed. RA has serious economic impact. Especially, the annual cost of RA is 41 billion Euros in the U.S.A. and 45billion Euros in Europe, which are increasing dramatically with appearance of an adverse event.
M Shahnawaz Khan
National Sun Yat-Sen University, Taiwan
Title: Graphene oxide and gold nanorods conjugate for controlled release of doxorubicin by using 808 nm laser
Biography:
Will be Updated Soon
Abstract:
Graphene oxide (GO), a close derivative of graphene has unlocked many pivotal steps in drug delivery due to their inherent biocompatibility, heavy drug loading capacity and high aqueous solubility. We used a novel plant material called Gum arabic (GA) to increase the solubility of GO as well as to chemically reduce it in the solution. GA functionalized GO (fGO) exhibited increased absorption in near infra-red region (NIR) which was exploited in photothermal therapy for cancer. To augment the shape and size related problems of GO (which in turn affect their rheological properties), we have conjugated them with gold nanorods (GNRs) using in situ synthesis of GO@GNRs via seed mediated method. To the above conjugate, Doxorubicin (DOX) was attached at ambient temperature (28±2°C). Release kinetics of DOX with and without NIR exposure was also studied followed by in vitro photothermal killing of A549 cell lines. Enhanced NIR induced drug release as well photothermal property was observed which makes fGO@GNRs-DOX ideal for chemotherapy as well as photothermal therapy.