Nano-mupirocin: enabling the parenteral activity of mupirocin

Ahuva Cern, Ayelet Michael-Gayego 3 , Yaelle Bavli 1 , Erez Koren, Amiram Goldblum 2 , Allon E. Moses 4 , Yan Q. Xiong 5  and Yechezkel Barenholz 6
  • 1 Laboratory of Membrane and Liposome Research, Department of Biochemistry
  • 2 Molecular Modeling and Drug Design Laboratory
  • 3 Microbial Molecular Diagnostics Laboratory, Department of Clinical Microbiology and Infectious Diseases
  • 4 Department of Clinical Microbiology and Infectious Diseases
  • 5 Geffen School of Medicine at UCLA, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
  • 6 Laboratory of Membrane and Liposome Research, Department of Biochemistry
Ahuva Cern
  • Laboratory of Membrane and Liposome Research, Department of Biochemistry
  • Molecular Modeling and Drug Design Laboratory
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  • Ahuva Cern is a researcher at the Laboratory of Membrane and Liposome Research at the Hebrew University of Jerusalem. She is a pharmacist (Hebrew University) with MSc degree in Biomedical Engineering (Ben-Gurion University). Her PhD thesis was focused on computational models of liposome-based drugs. Her research interests are in the field of formulation development, drug delivery systems and their role in improving drug performance. Prior to this position, Ahuva was the director of the formulation development lab at Nextar Chempharma Solutions, where she managed many formulation development projects for pharma and biotech companies.
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, Ayelet Michael-Gayego
  • Microbial Molecular Diagnostics Laboratory, Department of Clinical Microbiology and Infectious Diseases
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  • Ayelet Michael-Gayego is responsible for the microbial molecular diagnostic laboratory at the Department of Clinical Microbiology and Infectious Diseases, Hadassah University Medical Center, Jerusalem. Her research interests focused on gene therapy using viral vectors and virulence mechanisms of group A and group G streptococci. During her PhD studies, she worked on characterization of the necrotizing fasciitis model in mice. She received the Dean’s award of excellence.
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, Yaelle Bavli
  • Laboratory of Membrane and Liposome Research, Department of Biochemistry
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  • Yaelle Bavli is a PhD student at the Laboratory of Membrane and Liposome Research at the Hebrew University of Jerusalem. She has an MSc in Pharmacology with a specialization in pre-clinical models from the Louis Pasteur University of Strasbourg, France. Her PhD research interests include procedures to evaluate in animal models the adverse effects of local and systemic injection of nano-liposomal drugs (including complement activation, CARPA, macrophage depletion and accelerated blood clearance).
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, Erez Koren
  • Laboratory of Membrane and Liposome Research, Department of Biochemistry
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  • Erez Koren is currently employed at Teva Pharmaceuticals in Israel. As a team leader in the Innovative R&D discovery and product development group, the main focus of his team is oral dosage forms and novel injectable formulations and technologies. Prior to this position, he was working for 3 years at Lipocure Ltd as a project manager where he was focused on developing a number of highly-potent therapeutics utilizing proprietary liposome-based nano-drugs with novel drug-loading-capabilities and drug-release mechanisms. Erez is a graduate of the School of Pharmacy, The Hebrew University of Jerusalem, Israel, with a PhD in Pharmaceutical Sciences. He also completed a post-doctoral fellowship in pharmaceutical sciences with special focus on liposomal and micellar drug delivery at Prof. Vladimir Torchilin’s lab, Northeastern University, Boston, MA.
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, Amiram Goldblum
  • Molecular Modeling and Drug Design Laboratory
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  • Amiram Goldblum is Head of Molecular Modeling and Drug Design unit at the Institute for Drug Research of the Hebrew University of Jerusalem. Studied Chemistry and Physics and continued Postdoctoral Studies on Quantum Biochemistry (Paris), Quantitative Structure-Activity Relations and Quantum Mechanics of reaction pathways (California). Developed a prize winning computer algorithm that has been applied to problems in structural biology, protein-ligand and protein-protein interactions, molecular design of small molecules, of peptides and of proteins, and more recently, to cheminformatics and informatics. Amiram Goldblum is a board Member of The Lisa Meitner Minerva Center for Computational Quantum Chemistry, Served as the Chairperson of the 1996 conference of The World Organization of Theoretically Oriented Chemists.
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, Allon E. Moses
  • Department of Clinical Microbiology and Infectious Diseases
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  • Allon E. Moses Allon Moses is a physician-scientist. He studied medicine at the Beer Sheva University Medical School and specialized in Internal Medicine at the Hadassah Hebrew University Medical Center and in Infectious Diseases at the Harvard Combined Infectious Diseases Program. He is currently Chairman of the Department of Clinical Microbiology and Infectious Diseases at the Hadassah Hebrew University Medical Center in Jerusalem. He was previous Chairman of the Israel Society of infectious diseases. His main interests are pathogenesis of infectious diseases at the molecular level especially group A and G hemolytic streptococci. He is also intensely involved in infection control and prevention of bacterial resistance and nosocomial infections.
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, Yan Q. Xiong
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  • Yan Q. Xiong is a Professor of Research at the David Geffen School of Medicine at UCLA, a senior investigator at Harbor-UCLA Medical Center and a key faculty member in the Division of Infectious Diseases at LABioMed at Harbor-UCLA. After her medical degree from Tongji Medical University, China, she earned a PhD from the Universite of Nantes, France, and then she completed a post-doctoral fellowship in infectious diseases at Harbor-UCLA. Her research program focuses on the role of Staphylococcus aureus virulence factors (global regulons and structural genes) that contribute to the ability of this pathogen to cause human disease and resist antibiotics. Her area of intensive interest includes bacterial pathogenesis and antibiotic resistance in endovascular infections. Her long-term goal is to discover novel antimicrobial strategies for the prevention and therapy of serious infections caused by virulent microbes, including MRSA. She has published more than 100 research articles in peer-reviewed journals, and has served as the Principal Investigator on NIH and American Heart Association grant awards.
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and Yechezkel Barenholz
  • Corresponding author
  • Laboratory of Membrane and Liposome Research, Department of Biochemistry
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  • Yechezkel Barenholz (Daniel G. Miller Professor in Cancer Research), the head of Liposome and Membrane Research Lab has been on the faculty of Hebrew University Jerusalem Israel since 1968 and has been a Professor there since 1981, a visiting Professor at the University of Virginia School of Medicine, Charlottesville VA, USA (1973 to 2005); a Donder’s Chair Professor at The Faculty of Pharmacy, University of Utrecht, The Netherlands on 1992; the University Kyoto University (Kyoto, Japan, 1998), La Sapeinza University (Roma, Italy, 2006) Jaiotung University (Shanghai, China, 2006), Kings College (London, UK, 2006), the Technical University Of Denmark (Copenhagen 2010). His current research focuses on the development of drugs based on drug delivery systems (DDS) best exemplified by the anticancer DOXILTM the first nano liposomal and the first FDA approved (1995) nano-drug used world-wide. Professor Barenholz is an author of more than 380 scientific publications having altogether more than 10,000 citations. He is a co-inventor of more than 30 approved patent families. He was an executive editor of Progress in Lipid Research, an editor of four Special Issues, and is on the editorial board of five scientific journals. Professor Barenholz is a founder of Mobeius Medical LTD, Lipocure LTD, and Doxocure LTD all are in advanced stage of development of liposomal drugs based on Professor Barenholz inventions and knowhow. Professor Barenholz was awarded: the Donder’s Chair, the Kaye award twice (1995 and 1997), the Alec D. Bangham (the Liposome research “father”) award (1998), the Teva Founders Prize (2001), an Honorary Doctor degree from the Technical University of Denmark (DTU) in 2012, and the international Controlled Release Society’s (CRS) CRS Founders Award for 2012. In 2003 Professor Barenholz founded (from DOXIL royalties) the “Barenholz Prize” to encourage excellence and innovation in applied science of PhD students in Israel.
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Abstract

Mupirocin is an antibiotic having a unique mode of action, not shared by any other therapeutically available antibiotic. However, due to its rapid elimination following injection and high protein binding, current therapeutic use is limited to topical administration. Computational methods have identified mupirocin as a good candidate for delivery via long-circulating nano-liposomes. Formulating mupirocin in such liposomes to form Nano-mupirocin protects the drug in the circulation, enabling therapeutic efficacy. This was demonstrated using two different animal models that served as a proof of concept: the mice necrotizing fasciitis and rabbit endocarditis models. In both animal models, mupirocin administered intravenously (IV) lacked therapeutic efficacy, while the Nano-mupirocin administered IV was efficacious. In both mice and rabbits the pharmacokinetic (PK) profile following IV injection of Nano-mupirocin showed significantly greater AUC and elimination half-life of Nano-mupirocin compared to the free drug. In addition, in mice we also demonstrated significant drug distribution into the disease site. These PK profiles may explain Nano-mupirocin’s superior therapeutic efficacy. To the best of our knowledge, this is the first study demonstrating that systemic activity of mupirocin is feasible. Therefore, Nano-mupirocin can be considered a novel and unique parenteral antibiotic candidate drug.

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The European Journal of Nanomedicine is dedicated to basic and clinical research in Nanomedicine. Its focus lies on the clinical application of nanoscience tools, methods and materials and on the exploration of the implications of Nanomedicine. EJNM covers topics from nano(bio)technological engineering and characterization to clinically translatable innovative prevention, diagnostics, and therapies of major as well as neglected human diseases.

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