Role of the Lactide : Glycolide Ratio in PLGA Nanoparticle Stability and Release under Lysosomal Conditions for Enzyme Replacement Therapy of Lysosomal Storage Disorders
del Moral, Maria (Universitat de Barcelona)
Loeck, Maximilian (Universitat de Barcelona)
Muntimadugu, Eameema (University of Maryland)
Vives, Guillem (Universitat Autònoma de Barcelona)
Pham, Vy (University of Maryland)
Pfeifer, Peter (Institut de Bioenginyeria de Catalunya)
Battaglia, Giuseppe (Institució Catalana de Recerca i Estudis Avançats)
Muro, Silvia (Institució Catalana de Recerca i Estudis Avançats)

Date:	2023
Abstract:	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 ζ-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.
Grants:	Agencia Estatal de Investigación RTI2018-101034-B-I00 European Commission 713673 Agencia Estatal de Investigación CEX2018-000789-S European Commission 769798 Agencia Estatal de Investigación PID2020-119914RB-I00 "la Caixa" Foundation 11660018
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Lysosomal storage disorder ; Enzyme replacement therapy ; Hyaluronidase ; Poly(lactide-co-glycolide) nanoparticles ; Copolymer ratio ; Nanoparticle stability ; Enzyme release
Published in:	Journal of Functional Biomaterials, Vol. 14, Num 9 (August 2023) , art. 440, ISSN 2079-4983

DOI: 10.3390/jfb14090440
PMID: 37754854

16 p, 2.4 MB

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