Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice.
Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Here, using polystyrene and poly(lactic-co-glycolic acid) nanocarriers, we optimized lung delivery by varying enzyme dose and nanocarrier concentration, verified endocytosis and lysosomal trafficking in vivo, and evaluated delivered activity and effects. Raising the enzyme load of nanocarriers progressively increased absolute enzyme delivery to all lung, liver, and spleen, over the naked enzyme. Varying nanocarrier concentration inversely impacted lung versus liver and spleen uptake. Mouse intravital and postmortem examination verified endocytosis, transcytosis, and lysosomal trafficking using nanocarriers. Compared to naked enzyme, nanocarriers increased enzyme activity in organs and reduced lung sphingomyelin storage and macrophage infiltration. Although old mice with advanced disease showed reactivity (pulmonary leukocyte infiltration) to injections, including buffer without carriers, antibody, or enzyme, younger mice with mild disease did not. We conclude that anti-ICAM nanocarriers may result in effective lung enzyme therapy using low enzyme doses.
['Garnacho|Carmen|C|', 'Dhami|Rajwinder|R|', 'Solomon|Melani|M|', 'Schuchman|Edward H|EH|', 'Muro|Silvia|S|']
D000818:Animals D000911:Antibodies, Monoclonal D001692:Biological Transport D004337:Drug Carriers D004339:Drug Compounding D004705:Endocytosis D006801:Humans D018799:Intercellular Adhesion Molecule-1 D019344:Lactic Acid D008099:Liver D008168:Lung D051379:Mice D008810:Mice, Inbred C57BL D058990:Molecular Targeted Therapy D053758:Nanoparticles D052537:Niemann-Pick Disease, Type B D011100:Polyglycolic Acid D000077182:Polylactic Acid-Polyglycolic Acid Copolymer D011137:Polystyrenes D013108:Sphingomyelin Phosphodiesterase D013109:Sphingomyelins D013154:Spleen
type B Niemann-Pick disease acid sphingomyelinase deficiency ICAM-1 targeting enzyme replacement therapy polymer nanocarriers pulmonary effects