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CARDIOVASCULAR

Delivery of Acid Sphingomyelinase in Normal and Niemann-Pick Disease Mice Using Intercellular Adhesion Molecule-1-Targeted Polymer Nanocarriers

Department of Pharmacology (C.G., V.M., S.M.), Institute for Environmental Medicine (C.G., E.S., J.L., V.M., S.M.), Institute for Translational Medicine and Therapeutics (V.M., S.M.), School of Medicine, and Department of Bioengineering (E.S.), School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky (T.D.); and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York (R.D., E.H.S.)

Type B Niemann-Pick disease (NPD) is a multiorgan system disorder caused by a genetic deficiency of acid sphingomyelinase (ASM), for which lung is an important and challenging therapeutic target. In this study, we designed and evaluated new delivery vehicles for enzyme replacement therapy of type B NPD, consisting of polystyrene and poly(lactic-coglycolic) acid polymer nanocarriers targeted to intercellular adhesion molecule (ICAM)-1, an endothelial surface protein up-regulated in many pathologies, including type B NPD. Real-time vascular imaging using intravital microscopy and postmortem imaging of mouse organs showed rapid, uniform, and efficient binding of fluorescently labeled ICAM-1-targeted ASM nanocarriers (anti-ICAM/ASM nanocarriers) to endothelium after i.v. injection in mice. Fluorescence microscopy of lung alveoli actin, tissue histology, and ¹²⁵I-albumin blood-to-lung transport showed that anti-ICAM nanocarriers cause neither detectable lung injury, nor abnormal vascular permeability in animals. Radioisotope tracing showed rapid disappearance from the circulation and enhanced accumulation of anti-ICAM/¹²⁵I-ASM nanocarriers over the nontargeted naked enzyme in kidney, heart, liver, spleen, and primarily lung, both in wild-type and ASM knockout mice. These data demonstrate that ICAM-1-targeted nanocarriers may enhance enzyme replacement therapy for type B NPD and perhaps other lysosomal storage disorders.

Address correspondence to: Dr. Silvia Muro, Department of Pharmacology, John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068. E-mail: silvia{at}mail.med.upenn.edu