Encapsulation of oligonucleotides in stealth Me.PEG-PLA50 nanoparticles by complexation with structured oligopeptides.

Two oligopeptides with alternating hydrophilic-hydrophobic amino acids, H-(leu-lys-lys-leu)10-OH and H-(leu-lys-leu-lys)10-OH, were shown to have higher affinity for a 13-mer oligonucleotide than H-(pro-lys-lys-leu)10-OH used as a control. This increased affinity was correlated to the secondary structure adopted by the oligopeptides (respectively, α-helix and β-sheet for LKKL and LK) when complexed to the oligonucleotide. Tight ion-pairing association between the phosphate groups of the oligonucleotide and the lysines of the oligopeptide led to efficient encapsulation of the resulting oligonucleotide/oligopeptide non-water-soluble complex in hydrophobic Me.PEG-PLA50 nanoparticles, by coprecipitation with the co-polymer.