Journal
JOURNAL OF FUNCTIONAL BIOMATERIALS
Volume 14, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/jfb14090440
Keywords
lysosomal storage disorder; enzyme replacement therapy; hyaluronidase; poly(lactide-co-glycolide) nanoparticles; copolymer ratio; nanoparticle stability; enzyme release
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This study investigated the impact of lactide:glycolide ratio on the encapsulation, characteristics, stability, and release of enzymes in PLGA nanoparticles. The results showed that PLGA nanoparticles with a lactide:glycolide ratio of 60:40 had the highest encapsulation efficiency and stability. These findings provide guidance for future studies on using PLGA nanoparticles for enzyme replacement therapy in lysosomal storage disorders.
Prior studies demonstrated that encapsulation in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) enhanced the delivery of enzymes used for replacement therapy (ERT) of lysosomal storage disorders (LSDs). This study examined how the copolymer lactide:glycolide ratio impacts encapsulation, physicochemical characteristics, stability, and release under lysosomal conditions. Hyaluronidase, deficient in mucopolysaccharidosis IX, was encapsulated in NPs synthesized using 50:50, 60:40, or 75:25 lactide:glycolide copolymers. All NPs had diameters compatible with cellular transport (<= 168 nm) and polydispersity indexes (<= 0.16) and zeta-potentials (<=-35 mV) compatible with colloidal stability. Yet, their encapsulation efficiency varied, with 75:25 NPs and 60:40 NPs having the lowest and highest EE, respectively (15% vs. 28%). Under lysosomal conditions, the 50:50 copolymer degraded fastest (41% in 1 week), as expected, and the presence of a targeting antibody coat did not alter this result. Additionally, 60:40 NPs destabilized fastest (<1 week) because of their smaller diameter, and 75:25 NPs did not destabilize in 4 weeks. All formulations presented burst release under lysosomal conditions (56-78% of the original load within 30 min), with 50:50 and 60:40 NPs releasing an additional small fraction after week 1. This provided 4 weeks of sustained catalytic activity, sufficient to fully degrade a substrate. Altogether, the 60:40 NP formulation is preferred given its higher EE, and 50:50 NPs represent a valid alternative, while the highest stability of 75:25 NPs may impair lysosomes. These results can guide future studies aiming to translate PLGA NP-based ERT for this and other LSDs.
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