Hiroshi Maeda is the Director, BioDynamics Research Foundation and Professor Emeritus Kumamoto University (Med), Senior Invited Professor of Osaka University Medical School, Director, Special Appointee Professor of Tohoku University.
He is a world-renowned expert in macromolecular therapeutics. He created the world first polymeric-conjugate drug, SMANCS, approved for treatment of hepatoma in Japan. Consequently, he discovered the concept of EPR effect of macromolecular-drugs, ubiquitous mechanism for solid tumor selective targeting of polymeric drugs. He received MS, University of California, Devis, Fulbright student, Ph.D., M.D., Tohoku University. He published more than 450 papers in reputed journals. He was awarded Lifetime-Achievement-Award at Royal-Pharmaceutical-Society, Princess-Takamatsu-Award in Cancer Research, Tomizo-Yoshida-Award, highest award of Japan-Cancer-Assoc., and also selected as most cited influential scientist in pharmacology by Thomson Reuters 2014, and H-index of 120.
The EPR (enhanced permeability and retention) effect is a phenomenon observed in cancer and inflamed tissues, particularly involving tumor blood vessels. When biocompatible macromolecules or nanoparticles are injected into the blood vessels those nanoparticles will extravasate into the interstitial space of tumor tissue. Because of the incomplete anatomical architecture of tumor blood vessel they are leaky for blood plasma-components far more than normal blood vessel, where they are not leaky at all. Thus, selective tumor targeting of nano size drugs become possible. However, it is now known that large human tumors (> 2cm) tend to show a tendency of much elevated level of embolization or fibrin clot formation, thus blood flow is more frequently obstructed in large tumors in contrast to small tumor (5mm) in mice. This indicates that it is not easy to deliver the cancer drugs effectively to tumor by intravenous injection. As a matter of fact, in vivo distribution studies of traditional low MW anticancer drugs into the tumor tissue is minimal if not zero1,2).
We have reported tumor delivery can be improved by dilating tumor blood vessels using nitroglycerin or L-arginine, as in the case of cardiac infarct. Namely, tumor delivery could be augmented 2-3 folds by nitroglycerine, L- arginine, or hydroxyurea2,3).
Now, in addition to cancer chemotherapy, the EPR effect could be applied to open up other doors for cancer therapy. The first door is the photodynamic therapy (PDT), and the second door is the BNCT (borono neutron capture therapy). As will be demonstrated in the meeting, biocompatible polymer conjugates of photosensitizer [PS], such as zinc protoporphyrin (P-ZnPP), pyropheophorbide-a, chlorophyll and rosebengal, selectively accumulate in the tumor but not in the normal tissues. We have used biocompatible polymers of HPMA[N-(2-hydroxypropyl)methacrylamide] or SMA [styrene-co-maleic acid], and PEG in the past.
The first door, PDT (photodynamic therapy) is known for more than 100 years, but it has little impact on cancer therapy1). One reason of low impact is that only low MW photosensitizers (PS) such as LaserphyrinR or PhotofrinR is being used currently. They exhibit no EPR effect. When any PS are conjugated to a polymer (?40KDa), they will be selectively accumulated and retained in the tumor for long period (> days) (thus EPR), but no accumulation in the normal tissues like in the skin, which is the major target of adverse effect (dermal hypersensitivity). Second reason of failure of traditional PDT concerns the wave-length of irradiation light. The irradiation-light needs to fit with the excitation wave-length of PS in many cases, ? 400nm for above tetrapyrrole group are used. In contrast the light source being used in the past has been primarily 633 nm of HeNe laser. This means no generation of fluorescence nor singlet oxygen, and thus no therapeutic effect1,4,5).
The second door to be opened is that for BNCT. In the traditional BNCT boron-compounds being used are also low MW compounds such as boronophenylalanine (B-Phe), or BSH (disodium mercapto undecahydrododecaborate). Similar to classic PDT using low MW PS, no selective tumor accumulation is observed in the low MW boron derivatives, thus poor therapeutic result. We prepared new polymer (SMA) conjugate of glucosamine which makes a stable complex with boric acid. It shows about tenfold high tumor accumulation than normal tissues by EPR effect. Furthermore, free boric acid is released in weakly acidic pH of tumor tissue (pH 5-7) which will suppress glycolysis of cancer cells (Warburg effect). In large tumors, glycolysis is the major source of energy production in cancer cells. So with or without neutron irradiation tumor cell growth is effectively suppressed with this polymeric boric acid complex. Also, our preliminary observation showed glucosamine derivative of SMA-polymer affect intracellular signaling and suppress tumor cells growth.
All in all these two areas, PDT and BNCT with nano polymer technology, will open up future doors for cancer therapy in addition to currently developing chemotherapy of nanosize cancer drugs based on EPR effect.
Acknowledgement: Among many collaborators I am most indebted to Mr. Waliul Islam and Dr. Jun Fang in my Laboratory for their help.
Time: 10:45- 11:30
Director of CIBBIM-Nanomedicine (www.cibbim.eu), a research center focused on new biomedical nanotechnology-based applications. Director Assistant in Basic Research at the Vall d’Hebron Research Institute, Barcelona. Deputy director of CIBER-BBN, a center of national excellence in the field of nanotechnology and nanomedicine. Co-founder and Science Advisor of ARGON Pharma SL, and former member of the editorial Board of Nanomedicine-NBM and Eur. J. Nanomedicine. External science advisor of the European Nanomedicine Characterization Laboratory (EU-NCL). Holds 14 patents, most transferred to leading companies of the biotech and pharma sectors and coauthors more than 90 papers in high impact factor journals. Honorary Board member of Precision Nanomedicine journal, he also acts as coordinator and partner of several research international EU projects involving SME’s and large Pharma companies. Coordinator for technology transfer at CIBER-BBN, he was recently appointed as President of the European Society of Nanomedicine and Executive Board member of the International Society of Nanomedicine.
Colorectal cancer (CRC) has a high prevalence worldwide. Disease relapse and development of therapy-resistant metastases hinders an effective treatment and are sustained by the presence of cancer stem cells (CSC) within the tumor. Thus, it is of the utmost importance to
develop therapies that could also target this cell subpopulation. Specific delivery of chemotherapy to tumors by targeted nanotechnology-based drug delivery systems (nanoDDS) has great potential to increase the therapeutic index of drugs and improve treatment efficacy. Recently, CD44v6 demonstrated to be a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation properties. Therefore, it arises as a potential target for nanoDDS-based therapies. New innovative functionalized polymeric micelles (PM) have been designed to face the three main disease fronts: i) primary CRC, ii) metastasis and iii) CSC. PM comprising amphiphilic polymers chemically modified with anti-CD44v6 antibodies/peptides have been developed, extensively characterized and upscaled. Also, a screening among new and emergent drugs was carried out in order to select the most effective ones to be encapsulated within the PM. Appropriate in vitro and in vivo CRC models were also developed and used to assess the internalization, biodistribution, safety and therapeutic activity of the PM formulations in comparison and/or combination with conventional chemotherapeutic treatments. We will show relevant data to demonstrate that designed PM serve as platform for development of new therapies for CRC treatment, particularly regarding the prevention of CSC-driven cancer recurrence. PM targeted against CD44v6 using specific selected nanobodies (Fab) showed strong selectivity against CSC and significantly reduced tumorspheres formation and CSC selective internalization compared with free tested drugs (i.e., Niclosamide). Moreover, in vivo biodistribution studies in primary CRC tumor-bearing mice model showed Fab-PM were able to accumulate in tumor and suffer a slow clearance 48h after administration in comparison to non-targeted PM, clearly suggesting a positive active tumor retention.
Dr. Yukio Yoneda is a Professor Emeritus in Kanazawa University, where he worked as a Chairman Professor of Pharmacology from 1999 to 2015. He graduated from Osaka University Faculty of Pharmaceutical Sciences in 1972, and from the Graduate School in 1975. He was then appointed as an Assistant Professor in Kyoto Prefectural University of Medicine and completed his PhD from the same university in 1979. During this appointment as an assistant professor, he worked with Dr. Eugene Roberts, a finder of GABA in the brain, in the City of Hope Research Institute, CA, USA, as a postdoctoral research fellow for 14 months between 1980 and 1981. In 1982, he was promoted to a Senior Assistant Professor in Kyoto Prefectural University of Medicine. He moved to Setsunan University Faculty of Pharmaceutical Sciences as an Associate Professor in 1984, followed by promotion to a full Professor in 1997 and subsequent appointment as a Chairman Professor in Kanazawa University in 1999. He has been teaching Pharmacology in Osaka University after the retirement from Kanazawa University in 2015. He is still active in serving as an Associate Editor in several international reputed journals such as Neurochemistry International and Neurochemical Research, in addition to playing a role as the Editorial Board in other international reputative journals. He has published more than 350 research papers in reputed journals. His research interests have been lying on pharmacological profiling of amino acid signaling in neuronal and non-neuronal cells using molecular biological techniques. As a return of laboratory experimental results to the community, he has made several dietary supplement products enriched of theanine for online sales, which are all expected to be beneficial for the prophylaxis and/or treatment of different brain dysfunctions, besides the sustained bench work with colleagues in domestic and foreign universities.
Four times less incidence of cognitive declines is reported in elderly people with a custom to
drink green tea every day than daily coffee or black tea drinkers during the investigation by
expert psychiatrists for 5 consecutive years in the literature. Moreover, significant alleviation
is seen in cognition scores assessed by double-blinded physicians in healthy elderly people
given capsules of powdered high-quality green tea compared to those with normal-grade green
tea capsules after daily oral ingestion for 7 to 12 consecutive months. High-quality green tea is
well-known to contain more theanine than normal grade green tea. In a flow of our sustained
studies on endogenous analogous amino acids such as glutamic acid and GABA in the brain,
an attempt was made to evaluate pharmacological profiles of this exogenous green tea amino
acid in neural progenitor cells (NPCs). In cultured NPCs isolated from neocortex from
embryonic rats and mice, theanine invariably promoted both proliferation and neuronal
differentiation, along with suppressed astroglial differentiation. In cultured NPCs isolated from
the hippocampus of adult mice, a significant theanine increased the size of neurospheres
composed of clustered proliferating cells. In murine embryonic carcinoma P19 cells with
theanine, similarly significant promotion was seen in both proliferation and neuronal
differentiation. Theanine up-regulated the glutamine transporter Slc38a1 transcript in
neurospheres prepared from embryonic rats and mice. Stable overexpression of Slc38a1 led to
drastic facilitation of both proliferation and neuronal differentiation in P19 cells, whereas
theanine failed to stimulate additionally both proliferation and neuronal differentiation
activities already facilitated in stable transfectants of Slc38a1. Taken together, the green tea
amino acid theanine would promote embryonic and adult neurogenesis through activation of
NPCs in a manner relevant to upregulation of the glutamine transporter Slc38a1 in rodent
brains. We have made dietary supplements enriched of theanine to expect benefits for the
cognition improvement during embryonic to senile neurogenesis toward human brain
Dr Joachim Loo is currently Associate Professor in the School of Materials Science and Engineering (MSE), Nanyang Technological University (NTU), Singapore. He holds a joint appointment at the Singapore Centre on Environmental Life Sciences Engineering (SCELSE), and is a Visiting Scientist at the Harvard School of Public Health (HSPH), USA. He is also an international member of the Association of Pacific Rim Universities (APRU) for Sustainable Waste Management, and a member of the Coordinated Research Project (CRP) under the International Atomic Energy Agency (IAEA), United Nations (UN). He has published more than 190 international journal papers (h-index: 47 – Web of Science), three book chapters and filed more than 15 patents in these research areas. Recently, he was also awarded a grant from the Bill and Melinda Gates Foundation to develop delivery systems for nutraceuticals. He is currently a co-convenor of the ISO/TC 229 Nanotechnology National Working Group (WG3), under the Singapore Chemical Industry Council.
Delivery systems find their uses in a broad range of applications – as a protective carrier for bioimaging agents, drugs, fertilizers, fragrances, flavours, nutrients, and pesticides, i.e. agro-food and biomedical applications. By altering the properties of these particulate systems, triggered, controlled and sustained release of the encapsulated agents can be achieved. Such systems are therefore highly versatile and robust, and can be exploited for agro-food and pharmaceutical applications. For agrofood and pharmaceutical purposes, oral delivery systems are designed to elicit targeted and controlled release of the encapsulates, i.e. nutrients or drugs, respectively. Amongst the many agro-food applications, the delivery of nutraceuticals is one key aspect that is of interests to the agro-food industry. In this presentation, we will discuss the use of food-based entericcoated, nano-carriers for targeted delivery of nutraceuticals to specific parts of the gastro-intestinal tract (GIT), with the aim of increasing bioavailability and enhancing efficacy. In addition, we will also look at other oral encapsulation technologies that have been designed for Parkinson’s disease, and how this oral delivery system is envisaged to overcome clinical problems of current Parkinson’s disease drugs by sustaining the release of levodopa in the GIT.
Dr. Jyh-Ping Chen has been a professor in Chemical and Materials Engineering at Chang Gung University since 1997. He is currently a researcher in Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital and holds joint appointments as Professor in Department of Materials Engineering, Ming Chi University of Technology, and Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taiwan, ROC. He received his BS degree in Chemical Engineering from National Taiwan University in 1981 and PhD in Chemical Engineering from Pennsylvania State University in 1988. Professor Chen has published over 150 papers in SCI journals with more than 3500 citations. He is a guest editor or editorial board member for 13 international journals and a peer reviewer for more than 50 reputed SCI journals.
Time: 09:30 - 10:15
Mohamed Abbas Ibrahim is a professor of Pharmaceutics, Kayyali Chair for Pharmaceutical Industries, Department of Pharmaceutics, King Saud University, KSA. He gained a Ph.D. in Pharmaceutical Technology from the University of Regensburg, Germany, in collaboration with Al-Azhar University, Cairo Egypt. His Research interests include biomaterials as drug delivery systems, pelletisation nanotechnology and tablet technology. He supervised more than 10 master and Ph.D. students in Egypt and Saudi Arabia. Dr. Ibrahim has a good experience in the tablet and pelletisation technology, biomaterials, nanotechnology and polymeric drug delivery systems. He published more than 75 research and review articles in these areas.
William J. Rowe M.D. FBIS (Fellow British Interplanetary Society), FACN (Fellow American College of Nutrition, Retired Fellow Royal Society of Medicine), is a board certified specialist in Internal Medicine. He received his M.D. at the University of Cincinnati and was in private practice in Toledo, Ohio for 34 years. During that time he supervised over 5000 symptom - limited maximum hospital-based treadmill stress tests. He studied 3 world class extraordinary endurance athletes and published their exercise-related magnesium deficiencies. This triggered a 20 year pursuit of the cardiovascular complications of Space flight. All his publications are posted on his website www.femsinspace.com).
Time: 11:10 - 11:55
Our lab has been using phage display and targeting peptides to explore novel biomarkers and cellular processes. First, with phage screening, we identified a peptide that can selectively recognize macrophages associated with lung infection and solid tumors, but not normal organs (1, 2). We further isolated the peptide receptor as Retinoid X Receptor Beta (RXRB) (2). Intriguingly, RXRB belongs to a nuclear receptor family which is present in virtually all cell types. Our study not only demonstrates the cell surface presence of RXRB for the first time, but also defines its correlation with disease-associated macrophages. Last, we showed that this peptide can lead more drug carriers to disease sites, and improve their therapeutic efficacy in vivo.
Second, we have studied the endocytic pathways to engulf peptide-functionalized nanoparticles (NPs). Here, we discovered that the endocytic pathway engulfing NPs coupled to TAT peptide can also internalize bystander NPs, which are unable to enter the cells themselves (3). This bystander uptake process uses a macropinocytic machinery and relies on TAT binding to its receptor. Moreover, we discovered two properties of this bystander uptake: first, it is specific to NPs but not other types of bystander cargo (cargo selectivity); second, its activity is greatly stimulated by Cysteine in the surrounding environment, but not any other 19 amino acids (Cysteine regulation). Overall, we unveil a novel endocytic pathway, and this study may open up a new avenue for the interplay among extracellular nutrients, endocytosis and nanomaterial delivery.
Andrea Danani received the Dipl-Ing degree in Physics from ETH in Zuerich in 1987. After the Ph.D. degree at SISSA/ISAS in Trieste in 1992, he worked as postdoc for many years at several Physics Departments (Politecnico di Torino, Università Statale of Milano and Università di Genova) and as scientific collaborator by the Swiss National Supercomputing Center (CSCS). His scientific activity was first centered on the modelization of many-electron systems and their phase transitions and the description of surface diffusion of adatoms in metals using analytical models and several numerical simulation methods. Since 2000, Prof. Danani works at SUPSI, where he received the Professor title in 2006. He has been project leader of many industrial and academic projects related to the numerical simulation and modelization of systems mainly at the molecular level:
Dr. Seungpyo Hong is Professor of Pharmaceutics in the Pharmaceutical Sciences Division, School of Pharmacy at the University of Wisconsin-Madison (UW-Madison). He also serves as Associate Editor for Nanomedicine: Nanotechnology, Biology and Medicine of Elsevier. He graduated from Hanyang University in Seoul, Korea with BS and MS degrees in polymer engineering in 1999 and 2001, respectively. After working as a researcher at Korea Institute of Science and Technology (KIST), he started his PhD study at the University of Michigan working with his advisors Profs. Mark Banaszak Holl and James Baker, Jr. Dr. Hong graduated with his PhD in Macromolecular Science and Engineering in 2006 and joined Massachusetts Institute of Technology (MIT) as a postdoctoral associate in the laboratory of Prof. Robert Langer. From 2008 to 2014, Seungpyo was Assistant Professor in the College of Pharmacy at the University of Illinois at Chicago (UIC) where he was promoted to Associate Professor with tenure in 2014, and subsequently joined the UW-Madison faculty as full Professor in 2016. Since 2008, he has led a research group under the major research theme of “Biomimetic Nanotechnology” for cancer diagnosis and treatment. To date, Prof. Hong’s research has culminated in over 70 peer-reviewed articles that have a combined total number of citations over 10,000 times with an h-index of 32, 7 book chapters, and 15 issued or pending patents, while delivering over 110 invited talks worldwide and over 150 conference proceedings. His academic/research achievements have been recognized by the related scientific communities, resulting in him receiving a number of awards including 2012 AAPS New Investigator Award in Pharmaceutics and Pharmaceutical Technologies and 2012 UIC Researcher of the Year - Rising Star Award.
Time: 10:00- 10:45
In recent decades, there has been growing interest in applying nanomaterials to cancer treatment due to their appealing features for drug delivery, diagnosis and imaging. However, there have been only a few successful translations of nanomaterials into clinical applications so far, namely a handful of liposomes, polymeric micelles and albumim nanoparticles (NPs). In the meanwhile, we have also gradually realized the challenges that frustrate the clinical translation, typically low biocompatibility and biodegradability of nanomaterials, and the relatively complex scale-up of the manufacturing process. In our research, we managed to employ biocompatible and biodegradable proteins to fabricate NPs for applications in drug delivery systems in order to tackle the problems mentioned above. Using a straightforward and scalable self-assembly method, human serum albumin (HSA) could form hydrophobic drugloaded NPs. HSA-paclitaxel NPs greatly increased the in vivo and in vitro antitumor efficacy of paclitaxel, which earned the patents granted in U.S., China and Japan, as well as the approval of clinical trials in China. Moreover, we made use of suckerins, recently discovered proteins from squid sucker ring teeth in nanomedicine. By tuning the parameters in salting-out of suckerins including the protein concentrations and temperature, we achieved tailorable particle size from ~2 µm to 200 nm. Doxorubicin-loaded suckerin NPs displayed significant in vivo tumor-targeting and inhibition with the absence of systematic toxicity. In conclusion, our findings in protein-based nanomedicine open promising avenues for cancer therapy, which provide both facile and scalable industrial manufacturing, and good biocompatibility, biodegradability due to the merits of proteins.