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Comparative study of nanocarriers targeted to different transport pathways into and across the endothelium for brain delivery of therapeutic enzymes
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[eng] The blood-brain barrier (BBB) is a major obstacle for the treatment of neurological
diseases such as common Parkinson’s disease or rare lysosomal storage disorders
(LSDs). LSDs are characterised by deficiency of lysosomal components, mainly
enzymes, resulting in lysosomes accumulation of macromolecules affecting the CNS
and peripheral organs. Examples are Niemann-Pick disease (NPD) and Gaucher disease
(GD), characterised by deficiency in acid sphingomyelinase (ASM) and
glucocerebrosidase (GBA), respectively. Additionally, GBA alterations are involved in
Parkinson’s. Currently, enzyme replacement therapy (ERT) fails to treat neuropathic
symptoms due to the BBB. Targeting enzymes across the BBB using nanocarriers
capable to transcytosis in this interface offers an interesting approach to improve ERT.
This project studied the transport of differently targeted therapeutic nanocarriers
across the BBB to identify the most suitable formulations, using polymer nanocarriers
targeted to different routes, BBB cell models and in vivo animal models, as well as
physicochemical measurements of colloidal properties, radioactive tracing, and
confocal fluorescence microscopy. Four aims were addressed. First, biodegradable
PLGA nanocarriers and non-degradable polystyrene models were produced, which had
similar physicochemical properties, were functionalized for targeting, loaded with a
enzyme and increased enzyme delivery in cell cultures, also providing in vivo targeting.
Non degradable nanocarriers were thereafter used to focus on transport solely
avoiding degradation artifacts. Second, transport across a cellular BBB was examined
for formulations targeting intercellular adhesion molecule 1 (ICAM-1), identifying a
dual simultaneous transport to endothelial lysosomes and BBB transcytosis with
additional basolateral re-uptake of nanocarriers, intertwined and dependent on the
targeting valency of nanocarriers. Third, the effects of NPD on this transport was
examined for ICAM-1 targeting nanocarriers along with formulations targeting the
transferrin receptor (TfR) or plasmalemma vesicle associated protein 1 (PV1). Disease
altered all pathways in different ways, with ICAM-1 targeting nanocarriers being the
most efficient formulation for BBB transport in this disease model. Fourth, a similar
study was conducted in GD, where different alterations were also found, yet again
ICAM-1 targeting nanocarrier were the most suitable candidate for trans BBB delivery.
Thus, this study, encompassing multidisciplinary basic and applicable research, found
relevant findings for a better understanding of the pathological alterations associated
to these neuropathies and the practical design of therapeutic nanocarriers.
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LOECK, Maximilian. Comparative study of nanocarriers targeted to different transport pathways into and across the endothelium for brain delivery of therapeutic enzymes. [consulta: 26 de febrer de 2026]. [Disponible a: https://hdl.handle.net/2445/201043]