title: Development of surface modified biodegradable polymeric nanoparticles to deliver GSE24.2 peptide to cells: a promising approach for the treatment of defective telomerase disorders.
abstract: The aim of the present study was to develop a novel strategy to deliver intracellularly the peptide GSE24.2 for the treatment of Dyskeratosis congenita (DC) and other defective telomerase disorders. For this purpose, biodegradable polymeric nanoparticles using poly(lactic-co-glycolic acid) (PLGA NPs) or poly(lactic-co-glycolic acid)-poly ethylene glycol (PLGA-PEG NPs) attached to either polycations or cell-penetrating peptides (CPPs) were prepared in order to increase their cellular uptake. The particles exhibited an adequate size and zeta potential, with good peptide loading and a biphasic pattern obtained in the in vitro release assay, showing an initial burst release and a later sustained release. GSE24.2 structural integrity after encapsulation was assessed using SDS-PAGE, revealing an unaltered peptide after the NPs elaboration. According to the cytotoxicity results, cell viability was not affected by uncoated polymeric NPs, but the incorporation of surface modifiers slightly decreased the viability of cells. The intracellular uptake exhibited a remarkable improvement of the internalization, when the NPs were conjugated to the CPPs. Finally, the bioactivity, addressed by measuring DNA damage rescue and telomerase reactivation, showed that some formulations had the lowest cytotoxicity and highest biological activity. These results proved that GSE24.2-loaded NPs could be delivered to cells, and therefore, become an effective approach for the treatment of DC and other defective telomerase syndromes.
authors: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
authors: Susana P
authors: SP
authors: Egusquiaguirre
authors: Instituto de Investigaciones Biomédicas CSIC/UAM, IDIPaz and CIBER de Enfermedades Raras CIBERER, Madrid, Spain.
authors: Cristina
authors: C
authors: Manguán-García
authors: Instituto de Investigaciones Biomédicas CSIC/UAM, IDIPaz and CIBER de Enfermedades Raras CIBERER, Madrid, Spain.
authors: Laura
authors: L
authors: Pintado-Berninches
authors: Instituto de Investigaciones Biomédicas CSIC/UAM, IDIPaz and CIBER de Enfermedades Raras CIBERER, Madrid, Spain; Advanced Medical Projects, Madrid, Spain.
authors: Laura
authors: L
authors: Iarriccio
authors: Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain; Institut de Recerca Biomédica, Barcelona, Spain; Unitat de Química Combinatòria, Parc Científic de Barcelona, Barcelona, Spain.
authors: Daniel
authors: D
authors: Carbajo
authors: Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain; Institut de Recerca Biomédica, Barcelona, Spain.
authors: Fernando
authors: F
authors: Albericio
authors: Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain; Unitat de Química Combinatòria, Parc Científic de Barcelona, Barcelona, Spain.
authors: Miriam
authors: M
authors: Royo
authors: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
authors: José Luís
authors: JL
authors: Pedraz
authors: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
authors: Rosa M
authors: RM
authors: Hernández
authors: Instituto de Investigaciones Biomédicas CSIC/UAM, IDIPaz and CIBER de Enfermedades Raras CIBERER, Madrid, Spain. Electronic address: rperona@iib.uam.es.
authors: Rosario
authors: R
authors: Perona
authors: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain. Electronic address: manoli.igartua@ehu.es.
authors: Manuela
authors: M
authors: Igartua
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects / Q000737:chemistry*; D001692:Biological Transport; D018797:Cell Cycle Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000009:adverse effects / Q000737:chemistry; D002478:Cells, Cultured; D055598:Chemical Phenomena; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000009:adverse effects; D065546:Drug Liberation; D004355:Drug Stability; D019871:Dyskeratosis Congenita / Q000188:drug therapy; D004793:Enzyme Reactivators / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D019344:Lactic Acid / Q000009:adverse effects / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D009687:Nuclear Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000235:genetics; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000235:genetics; D011073:Polyamines / Q000009:adverse effects / Q000737:chemistry; D000071228:Polyelectrolytes; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry; D011098:Polyglactin 910 / Q000009:adverse effects / Q000737:chemistry; D011100:Polyglycolic Acid / Q000009:adverse effects / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D055550:Protein Stability; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D019098:Telomerase / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D018797:Cell Cycle Proteins; D057846:Cell-Penetrating Peptides; D003692:Delayed-Action Preparations; D004793:Enzyme Reactivators; D019344:Lactic Acid; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011073:Polyamines; D000071228:Polyelectrolytes; D011092:Polyethylene Glycols; D011098:Polyglactin 910; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011994:Recombinant Proteins; D019098:Telomerase; C000603663:GSE24.2 peptide; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer
keywords: Biodegradable nanoparticles; Cell-penetrating peptides; Dyskeratosis congenita; GSE24.2 peptide; Polycations; Telomerase reactivation