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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 20, 2008; DOI: 10.1124/jpet.107.133298

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Received for publication October 22, 2007.
Revised February 15, 2008.
Accepted for publication February 15, 2008.

Delivery of acid sphingomyelinase in normal and Niemann-Pick disease mice using ICAM-1-targeted polymer nanocarriers

Carmen Garnacho 1, Rajwinder Dhami 2, Eric Simone 3, Thomas Dziubla 4, John Leferovich 5, Edward H. Schuchman 2, Vladimir Muzykantov 6, Silvia Muro 6*

1 Dept. of Pharmacology, IFEM, University of Pennsylvania Medical School 2 Dept. of Genetic and Genomic Sciences, Mount Sinai School of Medicine 3 Dept. of Bioengineering, University of Pennsylvania School of Engineering and Applied Sciences 4 Dept. of Chemical and Materials Engineering, University of Kentucky 5 IFEM, University of Pennsylvania Medical School 6 Dept. of Pharmacology, IFEM, ITMAT, University of Pennsylvania Medical School

* Address correspondence to: E-mail: silvia{at}mail.med.upenn.edu

Abstract

Type B Niemann-Pick disease (NPD) is a multi-organ system disorder caused by a genetic deficiency of acid sphingomyelinase (ASM), for which lungs are an important and challenging therapeutic target. In this study we designed and evaluated new delivery vehicles for enzyme replacement therapy (ERT) of type B NPD, consisting of polystyrene and poly(lactic co-glycolic) acid polymer nanocarriers targeted to Intercellular Adhesion Molecule-1 (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 intravenous 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 non-targeted, 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.


Key words: Acid sphingomyelinase, Enzyme replacement therapy, Enzyme targeting, ICAM-1, Niemann-Pick disease, Polymer nanocarriers




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