title: Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.
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.
authors.affiliation: Department of Pharmacology, John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garnacho
authors.forename: Rajwinder
authors.initials: R
authors.lastname: Dhami
authors.forename: Eric
authors.initials: E
authors.lastname: Simone
authors.forename: Thomas
authors.initials: T
authors.lastname: Dziubla
authors.forename: John
authors.initials: J
authors.lastname: Leferovich
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Vladimir
authors.initials: V
authors.lastname: Muzykantov
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
mesh_terms: D000009:Abdominal Muscles / Q000378:metabolism; D000818:Animals; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004730:Endothelium, Vascular / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D049329:Nanostructures / Q000008:administration & dosage*; D052537:Niemann-Pick Disease, Type B / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics; D011137:Polystyrenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D013154:Spleen / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D011108:Polymers; D011137:Polystyrenes; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D013108:Sphingomyelin Phosphodiesterase