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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 325; no. 2; pp. 400 - 408
• Main Authors: Garnacho, Carmen, Dhami, Rajwinder, Simone, Eric, Dziubla, Thomas, Leferovich, John, Schuchman, Edward H, Muzykantov, Vladimir, Muro, Silvia
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.05.2008
• Subjects: Abdominal Muscles - metabolism; Animals; Drug Carriers - administration & dosage; Drug Carriers - pharmacokinetics; Endothelium, Vascular - metabolism; Intercellular Adhesion Molecule-1 - metabolism; Kidney - metabolism; Lactic Acid - administration & dosage; Lactic Acid - pharmacokinetics; Liver - metabolism; Lung - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium - metabolism; Nanostructures - administration & dosage; Niemann-Pick Disease, Type B - metabolism; Polyglycolic Acid - administration & dosage; Polyglycolic Acid - pharmacokinetics; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers - administration & dosage; Polymers - pharmacokinetics; Polystyrenes - administration & dosage; Polystyrenes - pharmacokinetics; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; Recombinant Proteins - pharmacokinetics; Sphingomyelin Phosphodiesterase - administration & dosage; Sphingomyelin Phosphodiesterase - genetics; Sphingomyelin Phosphodiesterase - pharmacokinetics; Spleen - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.133298

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 125 I-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/ 125 I-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.