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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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Universitat de Barcelona. Departament de Biomedicina

# metadata.dc.description.abstract[].value
[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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Tesis Doctorals - Departament - Biomedicina

# metadata.dc.title[].value
Comparative study of nanocarriers targeted to different transport pathways into and across the endothelium for brain delivery of therapeutic enzymes