Enhancing biodistribution of therapeutic enzymes in vivo by modulating surface coating and concentration of ICAM-1-targeted nanocarriers.

[fabry disease]

Coupling therapeutic proteins to targeted nanocarriers can enhance their biodistribution . This is the case for enzyme replacement therapies where intravenously injected enzymes must avoid prolonged blood exposure while reaching body organs . We have shown enhanced tissue targeting of various lysosomal enzymes by coupling to nanocarriers targeted to intercellular adhesion molecule-1 (ICAM-1 ). Here , we varied design parameters to modify tissue enzyme levels without affecting specific targeting and relative biodistribution . We coupled a-galactosidase (aGal ; affected in Fabry disease ) to model polymer nanocarriers and varied enzyme load (50 vs . 500 molecules /particle ), anti-ICAM surface density (80 vs . 180 molecules /particle ), and nanocarrier concentration (1 .6 x 1013 vs . 2 .4 x 1013 carriers /kg ) to render three formulations (45 , 449 , 555 microg alphaGal /kg ). Naked alpha Gal preferentially distributed in blood vs . organs , while nanocarriers shifted biodistribution from blood to tissues . Accumulation in brain , kidneys , heart , liver , lungs , and spleen did not vary among nanocarrier formulations , with enhanced specific tissue accumulation compared to naked aGal . The highest specificity was associated with lowest antibody density and nanocarrier concentration , but highest enzyme load ; possibly because of synergistic enzyme affinity toward cell-surface markers . Variation of these parameters significantly increased absolute enzyme accumulation . This strategy may help optimize delivery of lysosomal enzyme replacement and , likely , other protein delivery approaches .

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fabry disease

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