Comparison between Nanoparticle Encapsulation and Surface Loading for Lysosomal Enzyme Replacement Therapy

International Journal of Molecular Sciences

Guillem Vives¹  Maximilian Loeck¹  Maria del Moral¹  Marcelle Silva-Abreu¹  Silvia Muro²  Vy Pham²  Eameema Muntimadugu²  Melani Solomon² 

[1] Institute for Bioengineering of Catalonia, Barcelona Institute for Science and Technology, 08028 Barcelona, Spain;Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, MD 20742, USA;

关键词: enzyme therapeutics;    poly(lactic-co-glycolic acid) nanoparticles;    encapsulation;    surface loading;    ICAM-1 targeting;    lysosomal delivery;   

DOI  :  10.3390/ijms23074034

来源: DOAJ

【 摘 要 】

Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) enhance the delivery of therapeutic enzymes for replacement therapy of lysosomal storage disorders. Previous studies examined NPs encapsulating or coated with enzymes, but these formulations have never been compared. We examined this using hyaluronidase (HAse), deficient in mucopolysaccharidosis IX, and acid sphingomyelinase (ASM), deficient in types A–B Niemann–Pick disease. Initial screening of size, PDI, ζ potential, and loading resulted in the selection of the Lactel II co-polymer vs. Lactel I or Resomer, and Pluronic F68 surfactant vs. PVA or DMAB. Enzyme input and addition of carrier protein were evaluated, rendering NPs having, e.g., 181 nm diameter, 0.15 PDI, −36 mV ζ potential, and 538 HAse molecules encapsulated per NP. Similar NPs were coated with enzyme, which reduced loading (e.g., 292 HAse molecules/NP). NPs were coated with targeting antibodies (> 122 molecules/NP), lyophilized for storage without alterations, and acceptably stable at physiological conditions. NPs were internalized, trafficked to lysosomes, released active enzyme at lysosomal conditions, and targeted both peripheral organs and the brain after i.v. administration in mice. While both formulations enhanced enzyme delivery compared to free enzyme, encapsulating NPs surpassed coated counterparts (18.4- vs. 4.3-fold enhancement in cells and 6.2- vs. 3-fold enhancement in brains), providing guidance for future applications.

【 授权许可】

Unknown