Nanopharmaceutics and Advanced Drug Delivery

Biography

Abstract

Biography

Andrew David Miller is well known as a leading Chemist Expert in the understanding and exploitation of molecular mechanisms in biology. The overall goal of his academic research has been and continues to be the design and creation of advanced therapeutics and diagnostics that address unmet medical need in the treatment of chronic diseases (such as cancer, diabetes, pain and some infectious diseases). From 1990-2010, he was a Member of academic staff in the Chemistry Department of Imperial College London (UK) where he founded the Imperial College Genetic Therapies Centre (GTC) in 1998, and became Full Professor of Organic Chemistry and Chemical Biology in 2002. Since 2010, he has been affiliated with King’s College London (UK) and more recently with the Veterinary Research Institute (VRI) in Brno, Czech Republic, where he is the Director of OPVVV Project FIT and its Key Foreign Scientist (KFS). He Co-Founded KP Therapeutics Ltd in 2016 with a pipeline of Precision Therapeutic Approaches (PTAs) in discovery & development for the diagnosis and treatment of chronic diseases. He has currently published nearly 250 papers, book chapters and alike, including at least 26 patents and patent applications. He is also Principal Writer of the first textbook of chemical biology “Essentials of Chemical Biology”, John Wiley & Sons.

Abstract

Biography

Kent Peterson is a graduate with an honors from Boston University’s Graduate School of Management, and a Member of American Mensa Society. He has lead Fluid Imaging Technologies since joining as the founder of the firm 12 years ago. The Company has sold over 600 FlowCams in over 52 countries. Ship-based FlowCam sys­tems have also been at work sampling from every ocean in the world. He has served on a number of boards and is active in community affairs. He has also been named Mainebiz Business Leader of the Year. His achievements include: Fluid Imaging Technologies’ Awards and recognitions include, the Governor’s Award for Business Excel­lence, the SBA New England Exporter of the Year Award, and the Portland Regional Chamber’s Robert R Masterton Award.

Abstract

Flow imaging microscopy has proven to be an important tool for the analysis of subvisible particulates in parenteral drugs. Now, due to the combined resolving power of blue LED light and patented oil immersion technology, flow imaging microscopes can image and analyze particles as small as 300 nm. The ability to detect transparent particles and differentiate them based on morphology yields significantly more detailed and accurate information than can be acquired using common laser diffraction and light obscuration techniques. Along with sophisticated statistical pattern recognition algorithms, these systems can be used to distinguish between different particulate types such as silicon oil, protein aggregates, and air bubbles. This presentation will present the techniques used to accomplish this.

Biography

Robert k Prud’homme is a professor in the Department of Chemical and Biological Engineering at Princeton University. He is the founding director of the Program in Engineering Biology. His research program focusses on polymer self-assembly applied to drug delivery. The development of Flash Nano Precipitation (FNP) in his laboratory enabled the encapsulation of poorly soluble drug compounds and oligonucleotides for therapy directed towards cancer, TB, and injections. FNP is a scalable and continuous process that is enables integrated processing and spray drying for low cost oral and aerosol formulations. Under sponsorship by the Bill and Melinda Gates Foundation, the process is being adopted to formulate new compounds coming from TBA, MMV, and DNDi.

Abstract

The intravenous delivery of composite gel microparticles (cGMPs) offers a platform for localized treatment of lung cancer. We describe a method for fabrication of cGMPs with average diameters of 35 to 100 μm using shear emulsification and microfluidic droplet generation. We characterized the particles and describe the performance of these particles in vivo. Biodistribution of the cGMPs was selective to the lung after intravenous injection and particle clearance from the lung occurred in 7 weeks. One-week biodistribution studies demonstrated that larger, uniform particles produced by microfluidics provided optimal targeting to lung tissue. We demonstrated that highly loaded cGMPs containing a long wavelength fluorophore allow in vivo analysis of particle biodistribution without the need for ex-vivo organ analysis. The release of camptothecin conjugates from the nanopartricles, and thus, gel microparticles, is tuned from minutes to days by altering the polarity of the nanoparticle core.

Biography

Patrick J Sinko is a Pharmacist (BS, Rutgers 1982) and a Pharmaceutical Scientist (PhD, University of Michigan 1988). He joined Rutgers, The State University of New Jersey in 1991 and rose through the academic ranks where he is currently a Distinguished Professor (II) and the Parke-Davis Endowed Chair in Pharmaceutics and Drug Delivery in the Ernest Mario School of Pharmacy. He is the Principal Investigator of an active research laboratory that focuses on biopharmaceutics, pharmaceutical formulations and molecular-, nano- and micro-scale drug delivery with specific applications to the treatment or prevention of HIV/AIDS, breast, brain and lung cancer, chemical terrorism countermeasures. He has received prestigious National Institutes of Health FIRST and MERIT awards and his lab has been continuously funded by the NIH for over 25 years.

Abstract

Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer (BC) with possible microinvasions into the breast stroma. DCIS accounts for more than 16% of new BC diagnoses in women. DCIS progresses to Invasive Ductal Carcinoma (IDC) over time in 39-53% of patients, if left untreated. The vast majority of BC cases originate in the mammary duct. In this presentation, a nanoscale delivery system will be described that utilizes transpapillary delivery to achieve molecularly targeted, pathway-specific therapy in cancerous areas of the mammary duct. Our preliminary results with a nanosuspension of ciclopirox (CPX) in an orthotopic model of BC established the concept that sustained ductal exposure could completely suppress BC occurrence in vivo. For these studies polymeric NPs (nanoparticles) as well as lipid-polymer hybrid (LPH) NPs were the primary delivery vehicles. In order to achieve sustained precision treatment, HER2, transferrin receptor and/or EGFR were targeted using peptide ligands covalently bound to the surface of NPs. Ligand surface densities of 5% and 10% were evaluated and it was found that surface functionalized NPs enhanced binding and uptake into target cells. Cytoxicity was significantly increased with EGFR or TfR targeted NPs as compared to CPX alone or non-functionalized CPX-loaded NPs. A synergistic effect was observed when CPX was administered with gedatolisib, a PI3K/Akt/mTOR inhibitor resulting in a dose reduction index of ~6. In addition, the treatments were effective not only in BC cells but also cancer stem-like cells. Our efforts in addition to describing these studies and results, the engineering of the NPs to enhance ductal retention and specificity will also be described.

Biography

Simon C W Richardson is a Founder, Director and CSO at Intracellular Delivery Solutions Ltd, and Reader (Associate Professor) in Membrane Trafficking and Drug Delivery, at the University of Greenwich, UK. The driving theme behind his research is the intracellular delivery of antisense and RNAi to the cytosol. He is currently leading the Cell Biology Research Cluster within the Faculty of Engineering and Science, located at the Medway campus. His lab is currently working with several technologies based upon attenuated virulence factors that have very low in vitro toxicity profiles (and are minimally disruptive to the cell), and very high efficiency intracellular delivery profiles. We are also examining several methodologies to modulate protein stability and intracellular trafficking to aid the oral delivery of vaccines.

Abstract

Many protein toxins have evolved to access a variety of relatively inaccessible intracellular compartments in order to exert virulence. Counted among this number are proteins such as ricin toxin, shiga toxin, diphtheria toxin and anthrax toxin. These proteins display diverse architecture ranging from AB5 to AB configurations and depending upon the specific B chain in question, entertain a number of strategies from direct membrane penetration to utilizing retrograde trafficking pathways to access a plethora of intracellular compartments including the cytosol. Typically the A chain will exhibit catalytic activity proportional to both cellular intoxication and virulence. However given the facile nature of protein recombination, attenuation is relatively simple. Here we describe the ability of attenuated anthrax toxin (ATx) to manipulate endocytic cargo sorting for the purposes of drug delivery, traversing intracellular compartmental boundaries for nucleic acid delivery. We report not only the efficiency with which siRNA and antisense effectors are delivered but also the mechanisms they utilize to traverse the barriers responsible for intracellular compartmentalization. Attenuated Atx:ASO complexes had transfection efficiency approximately equivalent to Nucleofection®. In HeLa cells, at 200 pmol ASO expression of the target gene was 5.4±2.0% relative to an untreated control after 24 h. Using 200 pmol ASOs, Nucleofection® reduced Synt5 expression to 8.1±2.1% after 24 h. PA:LFn-GAL4:ASO transfection of non- or terminally-differentiated THP-1 cells and Vero cells resulted in 35.2±19.1%, 36.4±1.8% and 22.9±6.9% (respectively) target gene expression after treatment with 200 pmol of ASO and demonstrated versatility. Nucleofection® with Stealth RNAi™ siRNA reduced HeLa Synt5 levels to 4.6±6.1% whereas treatment with the PA:LFn-PKR:siRNA resulted in 8.5±3.4% Synt5 expression after 24 h (HeLa cells). These data underscore the tractability of this approach to both antisense and siRNA delivery.

Biography

Vladimir P Torchilin, PhD, DSc is a University Distinguished Professor of Pharmaceutical Sciences and Director, Center for Pharmaceutical Biotechnology and Nanomedicine of Northeastern University, Boston, USA. His interests include drug delivery and targeting, nanomedicine, multifunctional and stimuli-sensitive pharmaceutical nanocarriers, biomedical polymers, experimental cancer therapy. He has published more than 400 original papers, more than 150 reviews and book chapters, has written and edited 12 books, and holds more than 40 patents. Google Scholar shows more than 52,000 citations of his papers with H-index of 102. He is Editor in Chief of Current Drug Discovery Technologies, Drug Delivery, and OpenNano; Co Editor of Current Pharmaceutical Biotechnology and on the Editorial Boards of many other journals. He received more than $30 M from the governmental and industrial sources in research funding. He has multiple honors and awards and in 2011, Times Higher Education ranked him number 2 among Top World Scientists in Pharmacology for the period of 2000-2010.

Abstract

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 is such 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. We have developed several types of lipid-core polymeric micelles based on PEG-phospholipid or PEI-phospholipid conjugates, which are biologically inert, demonstrate prolonged circulation in the blood and can firmly bind non-modified or reversibly-modified siRNA. 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. This is illustrated by the efficient treatment of MDR (multi-drug resistance) cancer cells with combi-nations of siRNA-Pgp or siRNA-survivin stabilized in polymeric mixed mi-celles and doxorubicin, or tariquidar (Pgp inhibitor) and paclitaxel loaded into the same lipo-some or lipid-core polymeric micelle. In order to specifically unload such nanopreparations 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-, redox-conditions, hypoxia-, or MMP2-sensitive bonds between different components of nanopreparations 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. We have also developed approaches to target individual intracellular organelles to initiate the apoptosis in resistant cancer cells.