Home > Faculty > Primary > Muro Galindo

Department of Pharmacology
Silvia Muro Galindo, Ph.D.

Education:

1995	B.S. (Biology)	University of Granada. Spain
1999	Ph.D. (Molecular Biology)	Center for Molecular Biology "Severo Ochoa"- University Autonomous of Madrid, Spain

Research Summary:
Dr. Muro’s research interest is on intracellular delivery of enzyme therapeutics by targeting specific cell surface determinants. Subcellular destination and metabolism of targeted nanocarriers, protein conjugates and fusion proteins containing therapeutic enzymes can be controlled by a variety of parameters. These include both features pertinent to the delivery vehicle utilized and those intrinsic to the cell surface target to which such vehicles are directed. The ability of a given molecular target to be internalized by the cell of interest (either naturally or upon induction by the delivery vehicle) will determine its suitability for intracellular drug delivery applications. This parameter can be further modulated by controlling the precise contact site between the delivery vehicle and the cell surface target (e.g., an epitope on the target inducing internalization), and may additionally be modulated depending on the size, shape, and valency of the delivery vehicle utilized. Understanding such interactions between drug delivery vehicles and the target cells brings crucial information towards the optimization of intracellular delivery of therapeutics and the duration of their effects. Methodology utilized in these studies includes molecular and cell biology, morphology and imaging techniques, nano-technologies, cell culture and animal models.

Particularly, Dr. Muro identified a non-classical endocytic pathway (namely cell adhesion molecule -CAM- mediated endocytosis) induced by clustering Ig-like surface determinants such as ICAM-1 by polymer nanocarriers bearing anti-ICAM antibodies as targeting motifs. ICAM-1 up-regulation during pathology by a variety of cell types makes this a potentially suitable target for therapeutic delivery to various tissues and a particularly effective target for vascular endothelium in the case of vehicles administered systemically. This pathway is currently being explored for intracellular delivery of antioxidant enzymes (e.g., catalase) for containment of vascular oxidative stress, in collaboration with Dr. Muzykantov at UPenn.

In addition to intracellular delivery, multivalent polymer nanocarriers targeted to ICAM-1 efficiently traffic to lysosomes within the target cells. Hence they represent potentially suitable delivery vehicles for enzyme therapeutics destined to treatment of lysosomal storage disorders. Classical enzyme replacement therapy for these genetic disorders depends on cell receptors that recognize sugar residues present in the recombinant lysosomal enzymes administered intravenously. Such receptors then lead to clathrin-mediated uptake of the recombinant enzymes and trafficking to lysosomes. However, suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in affected cells limit enzyme delivery and compromises the efficacy of this strategy. A main direction of Dr. Muro’s research is the application of targeted nanocarriers (e.g., ICAM-1-directed polymer nanoparticles) as a means to surpass such obstacles, hence providing more effective therapies for lysosomal storage diseases. In collaboration with Dr. Schuchman (Mount Sinai School of Medicine, New York), Dr. Muro is developing ICAM-1-targeted nanocarriers for delivery of recombinant acid sphingomyelinase, the lysosomal enzyme deficient in Types A and B Niemann-Pick disease.