Associate Professor Silvia Muro
Joint, Institute for Bioscience and Biotechnology Research (IBBR)
Ph.D., Universidad Autonoma de Madrid (Spain) 1999
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).
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.
- Outstanding Invention of the Year, Life Sciences, University of Maryland, College Park, Md. (2011) (Silvia Muro)
- Outstanding paper, American Society of Nanomedicine (2011) (Rasa Ghaffarian)
- Outstanding paper, Controlled Release Society (2011) (Tridib Bhowmick)
- Outstanding paper, AIChE Mid-America (2010) (Laura Northrop)
- Outstanding paper, Nanomedicine and Drug Delivery Symposium (2011 and 2007) (Daniel Serrano and Carmen Garncho, respectively)
- Outstanding paper, Spanish Society for Inborn Errors of Metabolism, Spain (2005) (Silvia Muro)
- Outstanding paper, Society for the Study of Inborn Errors of Metabolism, UK. (2000) (Silvia Muro)
- Ramón Areces Foundation Postdoctoral Fellowship, Spain (2000-2002) (Silvia Muro)
- NATO International Postdoctoral Fellowship (2000) (Silvia Muro)
- Scientist Development, American Heart Association (2004-2008) (Silvia Muro)
- Howard Hughes Medical Institute Undergraduate Research Fellowship (2012 and 2010) (Rasa Ghaffarian and Maria Ansar, respectively)
- National Science Foundation Graduate Research Fellowship Program (2010-2013) & (2011-2014) (Daniel Serrano and Rasa Ghaffarian & Rachel Manthe, respectively)
(* denotes senior corresponding author)
Mane V, Muro S. (2012) Biodistribution and endocytosis of ICAM-1-targeting antibodies and nanocarriers in the gastrointestinal tract in mice. Int J Nanomed. In press.
Ghaffarian R, Bhowmick T, Muro S. (2012) Transport of nanocarriers across gastrointestinal epithelial cells by a new transcellular route induced by targeting ICAM-1. J Control Rel. In Press.
Garnacho C, Serrano D, Muro S. (2012) A fibrinogen-derived peptide provides ICAM-1-specific vascular targeting and intra-endothelial transport of polymers nanocarriers in cell cultures and mice. J Pharm Exp Ther, 340(3):638-647.
Serrano D, Bhowmick T, Chadha R, Garnacho C, Muro S. (2012) Intercellular adhesion molecule 1 engagement modulates sphingomyelinase and ceramide, supporting uptake of drug carriers by the vascular endothelium. Arterioscler Thromb Vasc Biol. 32(5):1178-85. Highlighted in the editorial.
Bhowmick T, Berk E, Cui X, Muzykantov V*, Muro S. (2012) Effect of flow on endothelial endocytosis of nanocarriers targeted to ICAM-1. J Control Rel, 157(3):485-492.
Hsu J, Northrup L, Bhowmick T, Muro S. (2011) Delivery of a-glucosidase for Pompe disease by ICAM-1-targeted polymer nanocarriers. Nanomedicine. In press.
Hsu J, Serrano D, Bhowmick T, Kumar K, Kuo YC, Shen Y, Muro S. (2011) Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease. J Control Rel, 10;149(3):323-31. Highlighted on the cover and in the editorial.
Calderon A, Bhowmick T, Leferovich J, Burmann B, Pichette B, Muzykantov V, Eckmann D*, Muro S. (2011) Optimizing endothelial targeting by modulating the antibody density and particle concentration of anti-ICAM coated carriers. J Control Rel, 150(1):37-44.
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.* (2012) Strategies for delivery of therapeutics into the central nervous system for treatment of lysosomal storage disorders. Drug Deliv Transl Res. In press.
Muro S.* (2012) Challenges in designs and characterization of ligand-targeted drug delivery systems. J. Controlled Release. In Press.
Hsu J, Muro S. (2011) Nanomedicine and drug delivery strategies for treatment of genetic diseases. In: Plaseska-Karanfilska D, ed. Genetic Disease. InTech, Rijeka, Croatia. Chapter 14:241-266.
Muro S.* (2007) ICAM-1 and VCAM-1. In: Aird, W., editor. Endothelial Biomedicine. Cambridge University Press. New York, NY. Chapter 117:1058-1070.
"Sub-cellular transport of drug delivery systems: an intricate road." Muro S. Annual Meeting of the Controlled Release Society. Quebec City, QC, Canada, July 2012.
"Targeted drug delivery systems: achievements and challenges." Muro S. International conference of Nanotechnology and Nanomedicine. Philadelphia, Pa., August 2012. (Invited)
"ICAM-1 targeting of nanocarriers to the central nervous system." Muro S. International Brains for Brain Workshop. Waterville Valley, N.H., August 2012. (Invited)
"Transport of enzymes coupled to ICAM-1-targeted nanocarriers across gastrointestinal epithelial cells." Muro S. World Organization for Research on Rare Disorders. San Diego, Ca., February 2012.
"Delivery of lysosomal enzyme replacement therapies by targeted nanocarriers." Muro S.International Nanomedicine and Drug Delivery Symposium. Salt Lake City, Utah, October 2012. (Invited)
"Targeting therapeutic carriers across the blood-brain barrier." Muro S.Annual Meeting of the Controlled Release Society. National Harbor, Baltimore, Md., July 2011.
"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.
American Heart Association
American Society for Cell Biology
BioMedical Engineering Society
Controlled Release Society