Monomolecular DNA nanoparticles for intravenous delivery of genes.
Delivery is the major obstacle to success of nucleic-acid-based therapies. We have neutralized DNA with a cationic detergent (C12CCP) obtained by amide bond formation between dodecanoic acid, cysteinyl-cysteine, and diaminopropane. Subsequent detergent polymerization by formation of intermolecular disulfide bonds within the condensed plasmid DNA leads to 32-nm-large neutral particles. (C12CCP)n/DNA complexes are more stable than those formed with other gene delivery agents toward exchange with extracellular polyanions such as glycosaminoglycans. Yet exposure to phosphatidylserine, an ubiquitous intracellular anionic lipid, still releases DNA from the complexes for transcription of the carried gene. Pharmacokinetics and biodistribution in mice showed that 25% of the complexes were still circulating after 30 min (2% for other cationic lipid vectors) in a form essentially not bound to blood cells. Altogether, straightforward control over size and surface charge, stability toward aggregation or exchange, and favorable pharmacokinetics make these complexes attractive vehicles for reaching tumor metastases after injection in the blood circulation.
Chittimalla
Chandrashekhar
C
Université Louis Pasteur de Strasbourg, Laboratoire de Chimie Génétique associé au CNRS, Faculté de Pharmacie, BP24, 67401 Illkirch, France.
Zammut-Italiano
Liliane
L
Zuber
Guy
G
Behr
Jean-Paul
JP
D000818:Animals; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003902:Detergents / Q000737:chemistry; D018014:Gene Transfer Techniques; D007275:Injections, Intravenous; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D014018:Tissue Distribution
D003902:Detergents; D004247:DNA