Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy.

Abstract

PURPOSE:

This study demonstrates the nasal administration (NA) of nanoemulsions complexed with the plasmid encoding for IDUA protein (pIDUA) as an attempt to reach the brain aiming at MPS I gene therapy.

METHODS:

Formulations composed of DOPE, DOTAP, MCT (NE), and DSPE-PEG (NE-PEG) were prepared by high-pressure homogenization, and assessed in vitro on human fibroblasts from MPS I patients and in vivo on MPS I mice for IDUA production and gene expression.

RESULTS:

The physicochemical results showed that the presence of DSPE-PEG in the formulations led to smaller and more stable droplets even when submitted to dilution in simulated nasal medium (SNM). In vitro assays showed that pIDUA/NE-PEG complexes were internalized by cells, and led to a 5% significant increase in IDUA activity, besides promoting a two-fold increase in IDUA expression. The NA of pIDUA/NE-PEG complexes to MPS I mice demonstrated the ability to reach the brain, promoting increased IDUA activity and expression in this tissue, as well as in kidney and spleen tissues after treatment. An increase in serum IL-6 was observed after treatment, although with no signs of tissue inflammatory infiltrate according to histopathology and CD68 assessments.

CONCLUSIONS:

These findings demonstrated that pIDUA/NE-PEG complexes could efficiently increase IDUA activity in vitro and in vivo after NA, and represent a potential treatment for the neurological impairment present in MPS I patients.

• Authors: Roselena Silvestri Schuh, Juliana Bidone, Edina Poletto, Camila Vieira Pinheiro, Gabriela Pasqualim, Talita Giacomet de Carvalho, Mirian Farinon, Dirnete da Silva Diel, Ricardo Machado Xavier, Guilherme Baldo, Ursula Matte, Helder Ferreira Teixeira
• Journal: Pharmaceutical research (Pharm Res) Vol. 35 Issue 11 Pg. 221 (Sep 26 2018) ISSN: 1573-904X [Electronic] United States
• PMID: 30259180 (Publication Type: Journal Article)

Chemical References

• Cations
• Emulsions
• Fatty Acids, Monounsaturated
• Nucleic Acids
• Phosphatidylethanolamines
• Quaternary Ammonium Compounds
• polyethylene glycol-distearoylphosphatidylethanolamine
• dioleoyl phosphatidylethanolamine
• Polyethylene Glycols
• IDUA protein, human
• Iduronidase
• 1,2-dioleoyloxy-3-(trimethylammonium)propane

Topics

• Administration, Intranasal
• Animals
• Brain (metabolism)
• Cations
• Cell Survival (drug effects)
• Emulsions
• Fatty Acids, Monounsaturated (chemistry)
• Fibroblasts (pathology)
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors
• Humans
• Iduronidase (biosynthesis, genetics)
• Mice
• Mice, Inbred C57BL
• Mucopolysaccharidosis I (genetics, pathology, therapy)
• Nanoparticles (chemistry)
• Nucleic Acids (administration & dosage)
• Particle Size
• Phosphatidylethanolamines (chemistry)
• Polyethylene Glycols (chemistry)
• Quaternary Ammonium Compounds (chemistry)
• Spleen (metabolism)
• Transfection