Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.

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TitleDelivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.
Publication TypeJournal Article
Year of Publication2008
AuthorsGarnacho, C, Dhami, R, Simone, E, Dziubla, T, Leferovich, J, Schuchman, EH, Muzykantov, V, Muro, S
JournalJ Pharmacol Exp Ther
Volume325
Issue2
Pagination400-8
Date Published2008 May
ISSN1521-0103
KeywordsAbdominal Muscles, Animals, Drug Carriers, Endothelium, Vascular, Intercellular Adhesion Molecule-1, Kidney, Lactic Acid, Liver, Lung, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium, Nanostructures, Niemann-Pick Disease, Type B, Polyglycolic Acid, Polymers, Polystyrenes, Recombinant Proteins, Sphingomyelin Phosphodiesterase, Spleen
Abstract

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.

DOI10.1124/jpet.107.133298
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID18287213
Grant ListHD 28607 / HD / NICHD NIH HHS / United States
HL/GM 71175 / GM / NIGMS NIH HHS / United States
HL85533 / HL / NHLBI NIH HHS / United States
P30 DK47757-14 / DK / NIDDK NIH HHS / United States