Day 1 :
Keynote Forum
Gjumrakch Aliev
GALLY International Biomedical Research Consulting LLC., USA
Keynote: Conjugates of γ-carbolines and phenothiazine as new multitarget inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer disease
Biography:
Gjumrakch Aliev authored and coauthored more than 500 publications in the fields of neurodegenerative diseases research (Alzheimer disease), as well as cardio- and cerebrovascular disease, cancer, and electron microscopy. He is an outstanding teacher, scholar, and a renowned scientist in the area of cellular molecular physiology, and cardiovascular, and neurodegeneration-mediated pathologies including Alzheimer disease (AD). He is nationally and internationally reputed in his area. Dr. Aliev’s accomplishments in the area of biochemistry and cellular biology have tremendous implications for drug design towards CNS Neurological Disorders, AD, cancer, and cerebrovascular and neurodegeneration related pathologies. He is world-renowned expert in electron microscopy. His work has been published in numerous prestigious journals such as Nature Clinical Cardiology, J. Neuroscience, Scientific Reports, Circulation Research, New England journal of Medicine, Blood, J. Cellular and Molecular Medicine, Atherosclerosis, CNS Neurological Disorders & Drug Targets, international J. Biochemistry and Cell Biology, and many others which reflect his leading role in his research areas. He is currently the Editor in Chiefs for “Central Nervous System Agents in Medicinal Chemistry”, “Applied Cell Biology”, “World Journal of Neuroscience”, “Open Journal of Psychiatry”, “Journal of Aging Science”, “Cardiovascular & Hematological Agents in Medicinal Chemistry”, “Immunology, Endocrine and Metabolic Agent in Medicinal Chemistry” as well as which by itself shows the voluminous and outstanding work he has accomplished in the area of cellular and molecular biology as well as aged associated clinical sciences. He is one of most cited authors in his fields with high impact factors.
Abstract:
The development of novel compounds that are able to modify the pathogenesis of neurodegenerative diseases appears to be as a promising approach among different drug discovery strategies in this emerging area. Taking into account the multifactorial nature of neurodegenerative diseases, focusing on the design of multitarget drugs that are capable to act simultaneously on different main biotargets, which are involved in the disease pathogenesis, seems to be very attractive and promising. During the past decade, previous studies have indicated that the progression of Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and some other neuropathological disorders is closely connected to dysfunctions in cholinergic and glutamatergic neuronal systems In addition, AD is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors (Figure 1). The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multi-target ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other relevant pathological conditions.
Keynote Forum
Esmaiel Jabbari
University of South Carolina, USA
Keynote: Nanomaterials in regenerative medicine and cancer therapy
Time : 11:00-11:30
Biography:
Esmaiel Jabbari is Tenured Full Professor of Chemical and Biomedical Engineering at the University of South Carolina. He directs the biomaterials, tissue engineering, and drug delivery laboratory which specialize on the design of 3D multi-cellular co-culture systems to study the effect of nanoscale spatiotemporal delivery of morphogens and physico-mechanical factors on the fate of stem cells. He has received numerous awards for his research program including the Berton Rahn Award in 2012 from the AO Foundation, the Stephen Milam Award in 2008 from the Oral and Maxillofacial Surgery Foundation, and elected for the College of Fellows of the American Institute for Medical and Biological Engineering (AIMBE) in 2013. He is the author of more than 250 books, book chapters, refereed journal articles and conference proceedings and he has mentored more than 130 scholars. He has served as the Academic Editor for PLOS ONE.
Abstract:
Nanomedicine is poised to shape the sustainability of industries and wealth of nations, and transform economies and societies on a global scale. The global market for nanomedicine was $250 billion in 2014 and it is expected to reach $550 billion by 2020. Nanotechnology is the solution to detection, diagnosis, and treatment of many diseases as biological processes and cellular mechanisms work at the nanoscale. Translation of nanoscale discoveries from the laboratory to the market promises new diagnostic tools, drug targeting systems, gene therapy platforms, biomaterials, regenerative tissue constructs, and personalized medicine. A major application of nanotechnology in medicine is in cancer therapy. A major contributing factor to mortality in cancer patients is relapse after therapy and developing resistance. Cancer recurrence and resistance is related to the existence of a very small population of initiating stem cells in the tumor tissue. The author will present strategies based on nanomaterials to selectively target chemotherapeutic agents to the stem cell sub-population of cells in the tumor tissue. Another important application of nanomedicine is in regeneration of skeletal tissues. In the process of bone formation, osteogenesis and vascularization are coupled by spatiotemporal regulation of paracrine signaling in which the invading vascular endothelial cells secrete osteogenic morphogens to stimulate cell differentiation and bone formation. The stratified structure of articular cartilage is rooted in the spatiotemporal gradients of morphogens that direct the formation of morphologically distinct cartilage zones. The author will present nanoparticle-based strategies for spatiotemporal release of morphogens for coupling osteogenesis and vascularization and to stimulate the formation of zonal architecture of articular cartilage
Keynote Forum
Robert J Lee
The Ohio State University, USA
Keynote: Lipid nanoparticles for delivery of therapeutic oligonucleotides
Biography:
Robert J Lee has received his PhD in 1994 from Purdue University. He was trained as a Postdoc at the University of Pittsburgh School of Medicine and worked at GeneMedicine Inc. as a Sr. Scientist and then at Endocyte Inc. as VP of R&D. He has been a Professor in the College of Pharmacy at The Ohio State University since 1997 and has more than 200 publications in the areas of targeted drug delivery systems and lipid-based nanoparticles. He has served regularly on NIH review panels and as the PI or Co-PI on many large NIH and NSF projects. He has collaborated extensively with biotech industry in his research on oligonucleotide delivery systems.
Abstract:
Oligonucleotides, including antisense oligos, siRNA, miRNA mimics, anti-miRs, are promising as therapeutic agents because of their ability to regulate expression of specific or networks of genes that are critical in human diseases. However, clinical translation of oligonucleotide therapeutics has had limited success partly due to their limited nuclease stability and obstacles in their in vivo delivery, especially to tissues other than the liver. To address these issues, a combination of chemical modifications and lipid nanoparticle (LNP)-based delivery strategy has been developed. Design of LNPs needs to balance the requirements of stability in circulation and ability to facilitate intracellular delivery. Additional consideration is needed to address hematological biocompatibility and effects on the immune system. Specific examples will be provided on several novel LNP formulations for therapeutic delivery of miR-29b mimics, anti-miR21, and antisense oligos to Akt-1 in murine tumor models.
Keynote Forum
Stephan T Stern
Nanotechnology Characterization Lab, USA
Keynote: Challenges in evaluation of nanomedicine pharmacokinetics and generic bioequivalence
Biography:
Stephan T Stern is Acting Deputy Director and Senior Principal Scientist at the National Cancer Institute’s Nanotechnology Characterization Laboratory (NCL), located at the Frederick National Laboratory for Cancer Research in Frederick, Maryland. The NCL assists in all phases of the nanomedicine drug development process, from early preclinical to late stage clinical trials, working with academic laboratories and the pharmaceutical industry. At the NCL, he oversees nanomedicine pharmacology and toxicology. Data generated from these studies support formulation optimization, regulatory filings, and environmental risk assessment. His research interests include novel drug formulation, bioanalytical method development, and pharmacokinetic modeling. Prior experience includes a postdoctoral fellowship at the University of North Carolina - Chapel Hill in the division of drug delivery and disposition, and curriculum in toxicology, and work within regulated areas of the pharmaceutical industry. He received his BS degree in biochemistry from the University of Rochester and his PhD in toxicology from the University of Connecticut at Storrs. He is a Diplomate of the American Board of Toxicology.
Abstract:
The success of nanomedicine (NM) drug delivery platforms relies upon their ability to influence drug disposition. Therefore, pharmacokinetic evaluation of NM is crucial to optimizing formulation properties and understanding how these properties result in therapeutic benefit. Comprehensive pharmacokinetic evaluation of NM requires quantification of several drug species, including NM encapsulated and encapsulated drug, and in some cases free and protein bound forms of the encapsulated drug as well. Indeed, the pharmacokinetic complexity of NM adds substantial difficulties to traditional pharmacokinetic and bioequivalence studies. This presentation will address the importance and challenges of monitoring the disposition and in vivo integrity of nanotechnology platforms, highlighting potential problems with current bioanalytical techniques, and introducing a new stable isotope tracer methodology currently under evaluation through a partnership between the FDA and NCI.
- Smart Drug Delivery Systems | Pharmaceutical Nanotechnology | Drug Delivery Technology | Drug Targeting and Design | Major Challenges in Drug Delivery | Recent Advances in Drug Delivery
Location: Greenspring4
Session Introduction
Marina A Dobrovolskaia
Nanotechnology Characterization Lab, USA
Title: Immunological properties of nanotechnology-based complex drug formulations and challenges in their preclinical characterization
Biography:
Marina A Dobrovolskaia
Abstract:
Delivery of drugs, antigens and imaging agents benefits from using nanotechnology carriers. Successful translation of nanoformulations into clinic involves a thorough assessment of their safety profiles, which among other end-points, includes evaluation of immunotoxicity. This presentation will discuss current knowledge and experiences from the US Nanotechnology Characterization Laboratory to highlight most prominent pieces of nanoparticle-immune system puzzle and discuss achievements, disappointments and lessons learned from past ten years of preclinical immunological characterization of nanomaterials. I will present translational case studies to highlight common challenges in the preclinical characterization of nanotechnology carriers and nanoparticle based complex drug formulations. The presentation will focus on areas such as structure-activity relationships, effects on blood coagulation system, activation of complement, effects on the immune cell function, endotoxin detection and quantification, nanoparticle interference with traditional immunological tests, and applicability of traditional in vivo immune function tests to engineered nanomaterials.
Biography:
Dr. Qing Li is a scientist at Medimmune, and her research focuses on antibody discovery, tissue specific drug delivery, and ADC development. Dr. Li received her PhD in chemistry from University of Minnesota, where she developed a novel method of engineering and preparation of Chemically Self-assembled Antibody Nanorings (CSANs) that can be used for drug delivery, imaging and cell surface engineering. Dr. Li completed post-doctoral training in Dr. Brent Iverson and Dr. George Georgiou’s lab at the University of Texas, Austin, where she co-developed a yeast-surface-display based high-throughput screening method of protease evolution for altered specificity and activity.
Abstract:
PEGylation has been widely used to improve pharmacokinetics of biologics. We have evaluated the effects of PEG size, shape and conjugation methods on the PEGylated diabodies. We modified diabody with PEGs of different molecular weight and shape, and applied different conjugation methods. We also measured hydrodynamic size of PEGylated diabodies with multi-angle light scattering. We found the pharmacokinetic properties of modified diabody significantly improved when Rh increased up to 6nm. In addition, PEGylation significantly reduced the non-specific binding of the diabody conjugates. Understanding the impact of PEGylation on pharmacokinetic and biophysical properties would help develop PEGylated diabody as therapeutics
Maslov M Y
Tufts University School of Medicine, USA
Title: Myocardial drug distribution following epicardial drug delivery: Potential impact of cardiac capillary perfusion in a swine model
Biography:
Mikhail Maslov has done his PhD and has been in biomedical research for 20 years. He is an expert in local myocardial drug delivery, infusion systems, cardiovascular pharmacology, heart failure and hemorheology. He has investigated myocardial pharmacokinetics and pharmacodynamics following epicardial drug delivery and evaluated role of compromised myocardial energy metabolism in the development of heart failure. He has contributed to the global pre-clinical studies of Entresto, a new drug designed to treat heart failure.
Abstract:
Statement of the Problem: Optimal therapeutic concentrations of antiarrhythmic, inotropic, angiogenic and regenerative agents in the heart can exceed the toxic threshold for other organs. Local epicardial drug delivery (LEDD) to the left ventricle aims to overcome this limitation. However, the global myocardial drug distribution following LEDD is vague. Myocardial drug distribution following LEDD is governed by diffusive, convective forces, and blood flow. We aimed to characterize the three-dimensional (transmural, longitudinal and circumferential) myocardial pharmacokinetics by site-specific point-source and distributed-source release of epinephrine, a model small hydrophilic drug, to the epicardial surface in a large animal model.
Methodology & Theoretical Orientation: A living swine model was used to evaluate epinephrine deposition and distribution in the heart following LEDD using biocompatible polymeric point-source release and alternatively distributed-source release.
Findings: LEDD via point-source release, and to a greater extent via distributed-source release, generated transmural epinephrine gradients directly beneath the site of application, longitudinally down the length of the heart and around the circumference toward the lateral and inferior walls, but not towards the interventricular septum. In both cases these gradients extended further than might be predicted from simple diffusion. Drug distribution away from the release source, down the axis of the left ventricle, and selectively towards the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in myocardial drug deposition and clearance. The role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent.
Conclusions: The coronary vasculature significantly shapes the distribution within the myocardium following LEDD in large animal models. Optimal design of epicardial drug delivery systems must consider these underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets.
Maura Murphy
iCeutica Operations LLC, USA
Title: Bioavailability enhancement using submicron particles
Biography:
Maura Murphy is a formulation development scientist, specializing in solid dosage form development of poorly soluble small molecules. She graduated from the University of Texas with a BS in Pharmacy, and the University of Maryland at Baltimore with a PhD in Pharmaceutical Sciences. She has nearly 20 years of product development experience, having worked at Schering-Plough, Genzyme, Vertex, and Pharmaceutics International before her current position as the Senior Director of R&D at iCeutica
Abstract:
Statement of the Problem: Many compounds exhibit low oral bioavailability due to poor dissolution in-vivo. The poor dissolution is typically due to low water solubility, and improving oral bioavailability of poorly soluble compounds has been a focus of formulation development for many years. Advancements which have been successful include particle size reduction, SEDDS, and amorphous solid dispersions.
Objective: The objectives of this session are to review the current tools available for oral bioavailability enhancement with a focus on particle size reduction, and to introduce a new tool, SoluMatrix Fine Particle Technology™.
Methodology: Drug substance particles can be milled to the submicron size utilizing wet media milling or dry attritor milling. With the dry milling method, the drug substance is milled with excipients and media to produce a free-flowing powder containing submicron particles of the drug substance.
Findings and Conclusions: Multiple case studies demonstrate that submicron particles can improve dissolution and the pharmacokinetics of orally administered poorly soluble drugs. Benefits included increased oral bioavailability, reduction in food effect, more rapid absorption, and thermodynamic stability.
Nina Mezu-Nwaba
United States Food and Drug Administration, USA
Title: Future of biomarkers in drugs, biologics, and device development: A US FDA initiative
Biography:
Dr. Nina Mezu-Nwaba is a Captain with the United States Public Health Service and a Senior Compliance Officer in the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration. She has over 20 years of clinical, retail, and regulatory experience, with expert knowledge in OB/GYN, Gastroenterology, Surgical and Urology products. Dr. Mezu-Nwaba has been with the FDA for over 17 years and has held positions at the Office of Generic Drugs, the Center for Drug Evaluation and Research, CDRH Office of Device Evaluation, and CDRH Office of Surveillance and Biometrics. She obtained her Doctor of Pharmacy from the University of Maryland at Baltimore, a Masters in Biomedical Science from Georgetown University, and a Masters in Public Health from the Johns Hopkins Bloomberg School of Public Health. Dr. Mezu-Nwaba has represented the FDA in Berlin, Puerto Rico, and the U.S. as the Liaison for International Standards committees. She actively participates in community health outreach, mentoring, as well as international humanitarian missions. Dr. Mezu-Nwaba seeks to bridge gaps in health-disparities through voluntary service with the Commissioned Corps, Health and Human Services, MI Foundation in Nigeria, Rotary Club, and serving the USPHS in Indian Health Reservations and other U.S. locations.
Abstract:
Statement of the Problem: Biomarkers are a core part of medical treatment used in diagnosing, detecting, and treating diseases. However, some nonspecific biomarkers may pose challenges due to poor predictive value for forecasting subsequent clinical course in patients with suspected infections, adverse events, and disease state progression. The purpose of this study is to review the evidence for biomarkers and their role in diseases, describe the future direction of biomarkers, and support the Biomarker Qualification Program, which was established to support the United States Food and Drug Administration (FDA), Center for Drug Evaluation and Research’s (CDER's) work with external stakeholders to develop biomarkers that aid in the drug development process.
Findings: Biomarkers are applicable in drug, biologic, and device development and are regulated by the FDA. Biomarkers such as troponin have their place in early detection of cardiac injury. Other well established applications of biomarkers include blood pressure, pulse oximetry, creatinine clearance, hemoglobin A1C, which are crucial for baseline therapy assessment. Non-specific biomarkers, such as WBC, D-dimers, C-reactive protein and criteria to diagnose sepsis have also played a part in improving therapy. The importance of including biomarkers in drug, device and biologic development derives from its potential innovative benefit in targeted patient care and personalized medicine.
Conclusion & Significance: Emerging studies have evaluated biomarkers for critical conditions, such as early detection of sepsis or assessment of oxygen levels for predicting retinopathy in premature neonates. Biomarkers can aid as useful means towards monitoring medical device treatment outcomes as well. Further research is needed for evaluation of current therapy and detection of early stages of cancer. Other findings can contribute to the encouragement of novel biomarkers development for future medicinal and research use.
Ahmed Alalaiwe
Prince Sattam Bin Abdulaziz University, Saudi Arabia
Title: The oral bioavailability behavior of AuNPs conjugated with Chitosan
Biography:
Ahmed Alalaiwe has his expertise in evaluation of nano metals bioavailability. His open and contextual evaluation model based on IVIVC creates new pathways for improving new drug delivery systems. He has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. He is currently a Vice-Dean for Preparatory Deanship in Prince Sattam Bin Abdulaziz University, Saudi Arabia beside his wok duty in researching/teaching in College of Pharmacy at the same university.
Abstract:
The unique properties of gold nanoparticles (AuNPs) such as their controllable size, shape and surface chemistry among other metal alloys make them highly attractive models in many medical purposes. Due to the ease to functionalize, AuNPs could be coupled with different surface chemistry to be used as drug delivery systems (DDS), biological senses and biomedical imaging. In this project, we graft 3 nm AuNPs with chitosan as an enhanced oral absorption agent and investigate the AuNPs bioavailability behavior after an oral dose in rats. The syntheses of these particles are prepared using citrate method. In vitro characterization will be conducted using Transmission Electron Microscopy and Dynamic Light Scattering techniques. While detection of AuNPs in biological samples will be quantified using ICP-MS. Finally, the data will be assessed using a phoenix software to obtain the pharmacokinetic parameters.
Sameer Alshehri
University of Nebraska Medical Center, USA
Title: Investigation of BBN-HPMA conjugates for targeting Gastrin Releasing-Peptide (GRPR) Receptor
Biography:
Sameer Alshehri has received his MS degree in pharmaceutics from Massachusetts College of Pharmacy and Health Sciences University, Boston in 2015. He then started his PhD studies at University of Nebraska Medical Center in Pharmaceutical Sciences. Since then he has been actively participating in research-related radiopharmaceuticals. His main focus is designing targeted HPMA copolymers for treatment and imaging of bombesin receptor-expressing tumors such as prostate cancer
Abstract:
Background: Compared to small radiolabeled bombesin (BBN) peptide conjugates, targeting efficacy of macromolecular conjugates modified with BBN analogues in tumors expressing gastrin releasing-peptide receptor (GRPR) is largely unexplored. Our goal was to investigate the targeting efficacy of BBN-conjugated polymeric system in vitro and in vivo.
Methods: Four concentrations, 2, 5, 10 and 15 mol% of L-BBN peptide, were conjugated to HPMA copolymer. As a control, 10 mol% D-BBN-HPMA was synthesized. Using PC-3 human prostate cancer cell line, 1 hr cellular internalization studies for all conjugates and 4 hr cellular internalization studies as well as confocal imaging studies for the 10% L-BBN-HPMA and 10% D-BBN-HPMA were performed. Results: After 1 hr, cellular internalization studies showed high uptake of 10% L-BBN-HPMA by around 13.76% internalized activity compared to 0.61%, 3.58%, 6.00% and 9.35% for 2% L-BBN-HPMA, 5% L-BBN-HPMA, 10% D-BBN-HPMA and 15% L-BBN-HPMA, respectively. Similarly, after 4 hr, 10% L-BBN-HPMA showed higher internalized radioactivity (16.96%) compared to 10% D-BBN-HPMA (9.59%).The confocal imaging study showed higher fluorescent signal for 10% L-BBN-HPMA compared to 10% D-BBN-HPMA by two folds. Surprisingly, biodistribution studies showed higher retention in liver and spleen for all conjugates except 2% L-BBN-HPMA. Interestingly, the retention in spleen was found to be directly proportional to the concentration of peptide/polymer.
Conclusion: The results indicate that incorporating of BBN peptides in the HPMA copolymer construct enhances the internalization into PC-3 cells, with 10% molar concentration being the optimum concentration. However, due to high retention in liver and spleen, further modifications to the construct are needed.
Biography:
Abstract:
We present cyclic thiolsulfi nates as the fi rst tool to permanently modify thiol pairs while transiently binding lone thiols. This tool can be tuned to enable “click” coupling of cyclic thiosulfi nates and dithiols, in vivo thiol-pair selective probes and pharmacological chaperones, a less toxic alternative to current di-ene crosslinkers for creating biopolymers, active transport of cargo
across the cell membrane. 1,2-dithiane-1-oxide was synthesized, administered in human blood, human cell lines, and to an ALS mouse model, and shown to selectively crosslink the dithiol pair (8 Å distance) of Cu/Zn-superoxide dismutase (SOD1) by our proposed mechanism, stabilizing its quaternary structure. Salient characteristics of cyclic thiosulfi nate chemistry include: 1) binding one (lone) thiol reversibly, but crosslinking thiols indefi nitely; 2) crosslinking is driven by the enthalpies of disulfi de bond and water formation; 3) attributes of click chemistry including orthogonality with common protein functional groups, high reaction yields, compatibility with aqueous solvents, and much higher ring strain-dependence than molecules comprised only of period 2 elements.