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Gaucher Disease (GD) is a genetic disorder with defective activity of the lysosomal enzyme glucocerebrosidase. Velaglucerasa alfa is a recombinant glucocerebrosidase used for enzyme replacement therapy (ERT) of GD. Due to its limited stability and bioavailability, the use of nanosized systems carrying Velaglucerase alfa is proposed as a novel strategy to improve ERT for GD. Highly stable and low-dispersed Velaglucerase-loaded Eudragit nanoparticles (NPs) (NPs: Vela); 150-160 nm mean size, polydispersity index <0. 15, zeta potential around -32 mV, and 95 % Velaglucerase alfa encapsulation efficiency were obtained. Crystallographic structural analysis by Small Angle X-ray Scattering, confirmed that Velaglucerase alfa was incorporated into the nanoparticle matrix. In vitro studies revealed that NPs: Vela preferentially interact with immunoglobulins and fibrinogen, and a positive enzyme release from NPs:Vela was observed at acidic pH; while no release was observed in neutral conditions. A positive internalization of NPs:Vela in GD mesenchymal stem cells (MSC) was also verified, increasing enzyme cellular activity compared to non-treated cells. Confocal microscopy verified that NPs:Vela colocalized with lysosomes, but no effect of NPs: Vela in the mineralization of MSC was observed. Finally, the viability of GD cell lines is not affected by NPs: Vela, in comparison with Velaglucerase alone, that negatively affects the viability of the target cells. This nanocarrier system for Velaglucerase alfa delivery in lysosomes, initially proposed to improve ERT for GD, may also serve as a starting point to address pathophysiological mechanisms in GD and other lysosomal disorders.
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http://dx.doi.org/10.1016/j.ijbiomac.2024.138248 | DOI Listing |
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