Highly Versatile Polyelectrolyte Complexes for Improving the Enzyme Replacement Therapy of Lysosomal Storage Disorders.
Lysosomal storage disorders are currently treated by enzyme replacement therapy (ERT) through the direct administration of the unprotected recombinant protein to the patients. Herein we present an ionically cross-linked polyelectrolyte complex (PEC) composed of trimethyl chitosan (TMC) and α-galactosidase A (GLA), the defective enzyme in Fabry disease, with the capability of directly targeting endothelial cells by incorporating peptide ligands containing the RGD sequence. We assessed the physicochemical properties, cytotoxicity, and hemocompatibility of RGD-targeted and untargeted PECs, the uptake by endothelial cells and the intracellular activity of PECs in cell culture models of Fabry disease. Moreover, we also explored the effect of different freeze-drying procedures in the overall activity of the PECs. Our results indicate that the use of integrin-binding RGD moiety within the PEC increases their uptake and the efficacy of the GLA enzyme, while the freeze-drying allows the activity of the therapeutic protein to remain intact. Overall, these results highlight the potential of TMC-based PECs as a highly versatile and feasible drug delivery system for improving the ERT of lysosomal storage disorders.
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Nanoprobes & Nanoswitches, Institute for Bioengineering of Catalonia (IBEC) , Baldiri Reixac 10, 08028 Barcelona, Spain.|Physical Chemistry Department, Universitat de Barcelona , 08028 Barcelona, Spain.
Marina I
MI
Giannotti
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona , 08035 Barcelona, Spain.
Ibane
I
Abasolo
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Nanoprobes & Nanoswitches, Institute for Bioengineering of Catalonia (IBEC) , Baldiri Reixac 10, 08028 Barcelona, Spain.|Pharmacy and Pharmaceutical Technology Department, Universitat de Barcelona , 08028 Barcelona, Spain.
Mireia
M
Oliva
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Nanoprobes & Nanoswitches, Institute for Bioengineering of Catalonia (IBEC) , Baldiri Reixac 10, 08028 Barcelona, Spain.|Pharmacy and Pharmaceutical Technology Department, Universitat de Barcelona , 08028 Barcelona, Spain.|Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.
Fernanda
F
Andrade
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona , 08035 Barcelona, Spain.
Natalia
N
García-Aranda
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Combinatorial Chemistry Unit, Barcelona Science Park , Baldiri Reixac 10, 08028 Barcelona, Spain.
Marta
M
Melgarejo
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Combinatorial Chemistry Unit, Barcelona Science Park , Baldiri Reixac 10, 08028 Barcelona, Spain.
Daniel
D
Pulido
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Institut de Biotecnologia i de Biomedicina and Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona , Bellaterra, 08193 Cerdanyola del Vallès, Spain.
José L
JL
Corchero
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona , 08035 Barcelona, Spain.
Yolanda
Y
Fernández
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Institut de Biotecnologia i de Biomedicina and Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona , Bellaterra, 08193 Cerdanyola del Vallès, Spain.
Antonio
A
Villaverde
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Combinatorial Chemistry Unit, Barcelona Science Park , Baldiri Reixac 10, 08028 Barcelona, Spain.
Miriam
M
Royo
Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology , ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
María F
MF
García-Parajo
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|Nanoprobes & Nanoswitches, Institute for Bioengineering of Catalonia (IBEC) , Baldiri Reixac 10, 08028 Barcelona, Spain.|Physical Chemistry Department, Universitat de Barcelona , 08028 Barcelona, Spain.
Fausto
F
Sanz
Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) , 28029 Madrid, Spain.|CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona , 08035 Barcelona, Spain.
Simó
S
Schwartz
D048271:Chitosan; D016503:Drug Delivery Systems; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease; D006801:Humans; D008247:Lysosomes; D000071228:Polyelectrolytes / Q000737:chemistry*
D000071228:Polyelectrolytes; D048271:Chitosan
Fabry disease; enzyme replacement therapy; lysosomal delivery; nanomedicine; polyelectrolyte complexes; trimethyl chitosan; α-galactosidase A