Assistant Professor Silvia Muro
Joint appointment with the Center for Biosystems Research, part of the University of Maryland Biotechnology Institute (UMBI)
Ph.D., Autonomous University of Madrid, Spain, 1999
Room 5115 Plant Sciences Building
E-mail: muro@umbi.umd.edu
Phone: (301) 405-4777
Fax: (301) 314-9075
Research Interests
Mechanisms of endocytic vesicular transport: their role in physiology and disease, and their translational application for the controlled delivery of nano-scale therapeutics to precise targets at the sub-cellular level (targeting, intracellular drug delivery, endocytosis, cell culture, animal models, pharmacokinetics, microscope imaging).
TopCurrent Research
Site-specific delivery of therapeutic compounds to sites of pathology is an important goal that would permit us to optimize the efficiency of such agents and minimize their potential toxicity. However, most therapeutic agents do not present intrinsic affinity to any particular tissue, cell type, or sub-cellular compartment, which results in rapid clearance, inefficient transport to the target sites, and suboptimal effects.
This obstacle can be surmounted by coupling the agents to be delivered to targeting carriers in the nano-scale size-range (natural ligands, antibodies, affinity peptides, nanoparticles, etc.) that recognize determinants expressed by cells at the sites where the intervention is required. Targeting of such carriers to cell surface molecules involved in endocytic vesicular transport may help improve delivery of therapeutic agents both intracellularly (e.g., to the cytosol, vesicular compartments such as lysosomes, the nucleus, etc.) and across cell layers into a given tissue.
Parameters under investigation include those intrinsic to the cell targets and endocytic mechanisms utilized (selection of accessible cell surface receptors and mechanisms which shall remain operative during the disease condition, role of signaling molecules, the cytoskeleton and membrane lipid domains in the endocytic event and subsequent intracellular transport and metabolism), as well as parameters pertinent to the design of the delivery carriers utilized (chemical properties, size, shape, affinity to the target, specificity, etc.). Our goal is to understand how cells interact with and react to these nano-scale drug delivery carriers, to optimize their transport within and across cells and, hence, their therapeutic potential.
Particular applications under development in our group include the design and validation of biodegradable amphiphilic dendrimers targeted to receptors of endocytosis, to provide transport of cargoes from endosomal vesicles to the cytosol and the nucleus of the target cells. This platform is being tested for safe and efficient delivery of probes, drugs, enzymes, and nucleic acids (plasmids, siRNA, AONs, etc.) as analytical, diagnostic and therapeutic tools.
Another translational application under investigation employs targeted nanocarriers for the delivery of enzyme replacement therapies. As an example, polymer nanocarriers targeted to certain cell surface molecules involved in endocytosis can be transported to lysosomes within the cells. These carriers are useful for the delivery of recombinant lysosomal enzymes which are known to be deficient in particular genetic diseases (the lysosomal storage disorders).
Finally, due to their design versatility, the targeting carriers and nano-structure devices employed for site-specific drug delivery can themselves be utilized as analytical tools in the study of the basic parameters governing endocytosis in cells, including pathways: regulating transport of molecules, activated during pathology, exploited by pathogens, involved in immune responses, etc. For instance, using polymer carriers targeted to ICAM-1 (an endothelial cell adhesion molecule involved in inflammation and thrombosis), our group identified a new endocytic pathway in vascular endothelial cells (Cell Adhesion Molecule—or CAM-mediated endocytosis), distinct from the classical pathways mediated by clathrin, caveoli, macropinocytosis, or phagocytosis. We are currently studying the physiological role of this new mechanism of vesicular transport and its potential contribution to vascular disease.
Selected Honors and Awards
- 2007: Communication Award, Nanomedicine and Drug Delivery Symposium, Boston, MA.
- 2005: Communication Award, Spanish Society for Inborn Errors of Metabolism, Spain
- 2000: Communication Award, Society for the Study of Inborn Errors of Metabolism, UK.
- 2000-2002: Ramón Areces Foundation Postdoctoral Fellowship, Spain
- 2000: NATO Postdoctoral Fellowship
Selected Refereed Publications
(* denotes senior corresponding author)
Garnacho C., Albelda S., Muzykantov V., Muro S.* (2008) Differential intra-endothelial delivery of polymer nanocarriers targeted to distinct PECAM-1 epitopes. J Control Rel. In press. Ahead of print July 18, PMID: 18606202.
Muro S.*, Garnacho C., Champion J., Leferovich J., Gajewski C., Schuchman E., Mitragotri S., Muzykantov M. (2008) Controlled endothelial targeting and intracellular delivery of therapeutics by modulating size and shape of ICAM-1-targeted carriers. Mol Ther. In press. Ahead of print June 17, PMID: 18560419.
Garnacho C., Dhami R, Simone E., Dziubla T., Leferovich J., Schuchman E., Muzykantov V., Muro S.* (2008) Delivery of acid sphingomyelinase in normal and Niemann-Pick disease mice using ICAM-1-targeted polymer nanocarriers. J Pharm Exp Ther. 325(2):400-408.
Garnacho C., Shuvaev V., Thomas A., MacKenna L., Sun J., Koval M., Albelda S., Muzykantov V., Muro S.* (2008) RhoA activation and actin reorganization involved in endothelial CAM-mediated endocytosis of anti-PECAM carriers: critical role for tyrosine 686 in the cytoplasmic tail of PECAM-1. Blood. 111(6):3024-3033.
Muro S.*, Schuchman E., Muzykantov V. (2006) Lysosomal enzyme delivery by ICAM-1 targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis. Mol Ther. 13(1):135-141.
Muro S.*, Gajewski C.M., Koval M., Muzykantov V. (2005) ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs. Blood. 105(2):650-658.
Muro S., Wiewrodt R., Thomas A., Koniaris L., Albelda S.M., Muzykantov V.R, Koval M. (2003) A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. J Cell Sci, 116(8): 1599-1609.
Selected Book Chapters and Review Publications
Muro S. (2007) ICAM-1 and VCAM-1. In: Aird, W., editor. Endothelial Biomedicine. Cambridge University Press. New York, NY. Chapter 117:1058-1070.
Schuchman E., Muro S. (2006) The development of enzyme replacement therapy for lysosomal diseases: Gaucher disease and beyond. In: Futerman T. and Zimran A., editors. Gaucher Disease: Lessons Learned About Therapy of Lysosomal Diseases. CRC Press. Chapter 8: 125-140.
Muro S., Muzykantov V. (2005) Targeting of antioxidant and anti-thrombotic drugs to endothelial cell adhesion molecules. Current Pharm Design. 11(18):2383-2401.
Muro S., Koval M., Muzykantov V. (2004) Endothelial endocytic pathways: gates for vascular drug delivery. Current Vasc Pharm. 2(3):281-299.
Selected Presentations
"Optimizing intracellular delivery of drug carriers by targeting receptors of vesicular transport" Meng M., Garnacho C., and Muro S. BioMedical Engineering Society, St Louis, MO. October 2008.
"Control of subcellular delivery of targeted polymer therapeutics by endothelial vesicular transport" Muro S. International Symposium on Polymer Therapeutics. Valencia, Spain. May 2008
"In vivo intracellular delivery of ICAM-1-targeted nanocarriers for enzyme replacement therapies of lysosomal disorders". Garnacho C., Dhami R., Schuchman E., Muzykantov V., Muro S. Conference on Controlled Drug Delivery. Pamplona, Spain. October 2006
"Nanocarriers targeted to clathrin-independent pathways for lysosomal enzyme replacement therapy" Muro S., Dhami R., Muzykantov V., Schuchman E. Society for Inborn Errors of Metabolism. Palma de Mallorca, Spain. October 2005
"Immunotargeting to ICAM-1 provides binding, internalization and lysosomal delivery of acid sphingomyelinase" Muro S., Schuchman E., Muzykantov V. American Society of Human Genetics. Toronto, ON, Canada. October 2004
Professional Affiliations
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American Heart Association
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American Society for Cell Biology
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BioMedical Engineering Society
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Controlled Release Society
