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dc.creatorMoreno, PM
dc.creatorSantos, J
dc.creatorGomes, C
dc.creatorVarela-Moreira, A
dc.creatorCosta, A
dc.creatorLeiro, V
dc.creatorMansur, H
dc.creatorPêgo, AP
dc.description.abstractSplice switching oligonucleotides (SSOs) are a class of single-stranded antisense oligonucleotides (ssONs) being used as gene therapeutics and demonstrating great therapeutic potential. The availability of biodegradable and biocompatible delivery vectors that could improve delivery efficiencies, reduce dosage, and, in parallel, reduce toxicity concerns could be advantageous for clinical translation. In this work we explored the use of quaternized amphiphilic chitosan-based vectors in nanocomplex formation and delivery of splice switching oligonucleotides (SSO) into cells, while providing insights regarding cellular uptake of such complexes. Results show that the chitosan amphiphilic character is important when dealing with SSOs, greatly improving colloidal stability under serum conditions, as analyzed by dynamic light scattering, and enhancing cellular association. Nanocomplexes were found to follow an endolysosomal route with a long lysosome residence time. Conjugation of a hydrophobic moiety, stearic acid, to quaternized chitosan was a necessary condition to achieve transfection, as an unmodified quaternary chitosan was completely ineffective. We thus demonstrate that amphiphilic quaternized chitosan is a biomaterial that holds promise and warrants further development as a platform for SSO delivery strategies.
dc.description.sponsorshipThis work was cofinanced by Fundacão para a Ciência e a Tecnologia (FCT, Portugal) within projects HMSP-ICT/0020/2010 and PTDC/CTM-NAN/NAN/115124/2009. Additionally, P.M.D.M.acknowledges the support from the Marie Curie Actions of the European Community’s 7th Framework Program (PIEF-GA-2011-300485); J.C.S. acknowledges the graduate fellowship from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq, Ministry of Science and Technology, Brazil); C.P.G. and V.L. acknowledge FCT for their scholarships (SFRH/BD/79930/2011 and SFRH/BPD/69110/2010). We thank M. Lázaro from the Bioimaging Center for Biomaterials and Regenerative Therapies (b.IMAGE) for help with confocal microscopy. 1H NMR and Cryo-SEM were performed at the Centro de Materiais daUniversidade do Porto (CEMUP).
dc.publisherAmerican Chemical Society
dc.relation.ispartofMolecular Pharmaceutics, vol. 13(2), p. 344-356
dc.subjectsplice switching oligonucleotides
dc.titleDelivery of Splice Switching Oligonucleotides by Amphiphilic Chitosan-Based Nanoparticles
dc.typeArtigo em Revista Científica Internacional
dc.contributor.uportoInstituto de Investigação e Inovação em Saúde
Appears in Collections:I3S - Artigo em Revista Científica Internacional

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