Lysosomal Storage Disorders (LSDs) are a group of more than 50 different hereditary diseases, mostly due the deficit of activity of one or more acid hydrolases in lysosomes. About 70% of LSD patients present a neurological impairment which is still untreatable, since recombinant corrective lysosomal enzymes, where available, cannot cross the blood-brain barrier (BBB). Among LSDs, Mucopolysaccharidosis type I (MPS I, Hurler Disease) and type II (MPS II, Hunter Disease) are both characterized by a totally or partially defective activity of lysosomal enzymes involved in the catabolism of the mucopolysaccharides (or glycosaminoglycans, GAGs) heparan- and dermatan-sulfate which, therefore, heavily accumulate within cellular compartment and in the extracellular matrix. Enzyme Replacement Therapy (ERT), applied to both diseases in the last few years, has shown to determine some clinical improvements, but it has also shown some limitations. In addition to the elevated costs and to the weekly administration in a day-hospital regimen, the low level of the BBB transport system for acid hydrolases and the high molecular weight of these enzymes make any paracellular or transcellular diffusion of these proteins across the BBB almost non-existent. Therefore, alternative methods to achieve transcytosis into the CNS need to be explored. Thus, we combined the experience of clinical-based skills with pharmaceutical nanotechnology-based skills in order to create nanocarriers, biodegradable and biocompatible, able to deliver the recombinant enzymes across the BBB and to both assure a prolonged drug circulation and release, and a protection from metabolic drug inactivation. With this aim, we produced polymeric nanoparticles (PLGA-NPs) modified with 7-aminoacid glycopeptides (g7), able to drive the NPs across the BBB after administration in rodents. Before going into functional and efficacy study, we studied the ability of PLGS-NPs in carrying across the BBB the FITC-albumin, as a model drug with a high molecular weight, comparable to that of the enzymes using in ERT. In vivo experiments on both WT and knock-out (KO) mouse models for MPS I and MPS II were performed by i.v.-injecting g7-NPs loaded with FICT-albumin together with a plethora of control samples (i.e. un-modified NPs, FITC-albumin solution) in order to have a broad preliminary view. The results clearly showed that g7-NPs are able to deliver FITC-albumin to the brain, crossing the BBB, in all treated mice (WT and KO models); interestingly, we found qualitative and semi-quantitative evidences of a higher grade of brain accumulation of g7-NPs loaded with Albumin in the KO-brains with respect to WT ones. These results lay the basis for a possible successful set of pilot experiments on the ability of enzyme-loaded g7-NPs to deliver sufficient amount of the drug to the brain district, hopefully exerting a corrective effect on the cellular pathological GAG deposits.

A Nanoparticle-based approach for drug delivery to the brain in Lysosomal Storage Disorders / M., Salvalaio; Tosi, Giovanni; L., Rigon; Belletti, Daniela; F., D’Avanzo; Ruozi, Barbara; Vandelli, Maria Angela; Forni, Flavio; M., Scarpa; R., Tomanin. - STAMPA. - 1:(2013), pp. 1-1. ((Intervento presentato al convegno 19th ESGLD Workshop tenutosi a Seggau Castle (www.seggau.com), near Graz, Austria nel 26th-29th September 2013.

A Nanoparticle-based approach for drug delivery to the brain in Lysosomal Storage Disorders

TOSI, Giovanni;BELLETTI, Daniela;RUOZI, Barbara;VANDELLI, Maria Angela;FORNI, Flavio;
2013

Abstract

Lysosomal Storage Disorders (LSDs) are a group of more than 50 different hereditary diseases, mostly due the deficit of activity of one or more acid hydrolases in lysosomes. About 70% of LSD patients present a neurological impairment which is still untreatable, since recombinant corrective lysosomal enzymes, where available, cannot cross the blood-brain barrier (BBB). Among LSDs, Mucopolysaccharidosis type I (MPS I, Hurler Disease) and type II (MPS II, Hunter Disease) are both characterized by a totally or partially defective activity of lysosomal enzymes involved in the catabolism of the mucopolysaccharides (or glycosaminoglycans, GAGs) heparan- and dermatan-sulfate which, therefore, heavily accumulate within cellular compartment and in the extracellular matrix. Enzyme Replacement Therapy (ERT), applied to both diseases in the last few years, has shown to determine some clinical improvements, but it has also shown some limitations. In addition to the elevated costs and to the weekly administration in a day-hospital regimen, the low level of the BBB transport system for acid hydrolases and the high molecular weight of these enzymes make any paracellular or transcellular diffusion of these proteins across the BBB almost non-existent. Therefore, alternative methods to achieve transcytosis into the CNS need to be explored. Thus, we combined the experience of clinical-based skills with pharmaceutical nanotechnology-based skills in order to create nanocarriers, biodegradable and biocompatible, able to deliver the recombinant enzymes across the BBB and to both assure a prolonged drug circulation and release, and a protection from metabolic drug inactivation. With this aim, we produced polymeric nanoparticles (PLGA-NPs) modified with 7-aminoacid glycopeptides (g7), able to drive the NPs across the BBB after administration in rodents. Before going into functional and efficacy study, we studied the ability of PLGS-NPs in carrying across the BBB the FITC-albumin, as a model drug with a high molecular weight, comparable to that of the enzymes using in ERT. In vivo experiments on both WT and knock-out (KO) mouse models for MPS I and MPS II were performed by i.v.-injecting g7-NPs loaded with FICT-albumin together with a plethora of control samples (i.e. un-modified NPs, FITC-albumin solution) in order to have a broad preliminary view. The results clearly showed that g7-NPs are able to deliver FITC-albumin to the brain, crossing the BBB, in all treated mice (WT and KO models); interestingly, we found qualitative and semi-quantitative evidences of a higher grade of brain accumulation of g7-NPs loaded with Albumin in the KO-brains with respect to WT ones. These results lay the basis for a possible successful set of pilot experiments on the ability of enzyme-loaded g7-NPs to deliver sufficient amount of the drug to the brain district, hopefully exerting a corrective effect on the cellular pathological GAG deposits.
19th ESGLD Workshop
Seggau Castle (www.seggau.com), near Graz, Austria
26th-29th September 2013
M., Salvalaio; Tosi, Giovanni; L., Rigon; Belletti, Daniela; F., D’Avanzo; Ruozi, Barbara; Vandelli, Maria Angela; Forni, Flavio; M., Scarpa; R., Tomanin
A Nanoparticle-based approach for drug delivery to the brain in Lysosomal Storage Disorders / M., Salvalaio; Tosi, Giovanni; L., Rigon; Belletti, Daniela; F., D’Avanzo; Ruozi, Barbara; Vandelli, Maria Angela; Forni, Flavio; M., Scarpa; R., Tomanin. - STAMPA. - 1:(2013), pp. 1-1. ((Intervento presentato al convegno 19th ESGLD Workshop tenutosi a Seggau Castle (www.seggau.com), near Graz, Austria nel 26th-29th September 2013.
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