Proton-actuated membrane-destabilizing polyion complex micelles.
The efficiency of nucleic acid-based drugs is usually hampered by the fact that, following their uptake by the cell, these drugs end up in acidic organelles (i.e., endosomes/lysosomes) from which they barely escape. This work relates to the preparation and characterization of polyion complex micelles (PICM) formed by the self-assembly of three polyelectrolytes: a diblock cationic copolymer; a membranolytic, methacrylic acid copolymer; and an oligonucleotide. It is demonstrated that a synthetic membrane-active polyanion can be successfully integrated within the structure of PICM to yield well-defined, narrowly distributed micelles (30 nm) with a core/shell architecture. Besides their ability to protect the oligonucleotide against nuclease degradation, PICM partly dissociate under mildly acidic conditions, releasing chain clusters that destabilize bilayer membranes. This association/dissociation behavior illustrates the potential of these pH-sensitive PICM for the transport and efficient delivery of polyionic drugs.
Yessine
Marie-Andrée
MA
Canada Research Chair in Drug Delivery, Faculty of Pharmacy, Université de Montréal, C.P. 6128 Succ. Centre-Ville, Montreal, Quebec, H3C 3J7, Canada.
Dufresne
Marie-Hélène
MH
Meier
Christian
C
Petereit
Hans-Ulrich
HU
Leroux
Jean-Christophe
JC
D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008823:Micelles; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism; D011109:Polymethacrylic Acids / Q000737:chemistry* / Q000494:pharmacology; D011522:Protons
D008823:Micelles; D009838:Oligodeoxyribonucleotides; D011109:Polymethacrylic Acids; D011522:Protons