Peptides containing blocks of different charge densities facilitate cell uptake of oligonucleotides.
Polyelectrolyte complexes (PECs) are of great importance in drug delivery and gene therapy. The density and the distribution of the charges are key parameters of a polyelectrolyte, determining the structure of the complex and the kinetics of the complexation. Using peptides of precisely-controlled charge density as model molecules, we showed that the presence of weakly-charged peptides, (KGGG)5 or (KGKG)5, did not affect the complexation of highly-charged peptides (KKKK)5 with 21 bp oligonucleotides. However, peptide containing blocks of different charge densities, such as (KKKK)5-b-(KGGG)5 or (KKKK)5-b-(KGKG)5, exhibited superior performance during complexation. With a relatively uniform small size, the complex was also stable in serum. More importantly, the cellular uptake of the complex was greatly enhanced by a ratio of 40-60%, compared to that of the complex formed by uniformly-charged peptides. We attributed the improvement to the structure of the complex, in which the highly-charged blocks form the core with the oligonucleotide whilst the weakly-charged blocks dangle outside, preventing the complexes from further aggregation.
Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. dliang@pku.edu.cn quan.du@pku.edu.cn.
Jihan
J
Zhou
Dong
D
Li
Cuicui
C
Su
Hao
H
Wen
Quan
Q
Du
Dehai
D
Liang
D016503:Drug Delivery Systems; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry* / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D055672:Static Electricity; D014018:Tissue Distribution
D009841:Oligonucleotides; D010446:Peptide Fragments; D011108:Polymers