Cellular Internalization of Therapeutic Oligonucleotides by Peptide Amphiphile Nanofibers and Nanospheres.
Oligonucleotides are promising drug candidates due to the exceptionally high specificity they exhibit toward their target DNA and RNA sequences. However, their poor pharmacokinetic and pharmacodynamic properties, in conjunction with problems associated with their internalization by cells, necessitates their delivery through specialized carrier systems for efficient therapy. Here, we investigate the effects of carrier morphology on the cellular internalization mechanisms of oligonucleotides by using self-assembled fibrous or spherical peptide nanostructures. Size and geometry were both found to be important parameters for the oligonucleotide internalization process; direct penetration was determined to be the major mechanism for the internalization of nanosphere carriers, whereas nanofibers were internalized by clathrin- and dynamin-dependent endocytosis pathways. We further showed that glucose conjugation to carrier nanosystems improved cellular internalization in cancer cells due to the enhanced glucose metabolism associated with oncogenesis, and the internalization of the glucose-conjugated peptide/oligonucleotide complexes was found to be dependent on glucose transporters present on the surface of the cell membrane.
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University , Ankara 06800, Turkey.
Didem
D
Mumcuoglu
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University , Ankara 06800, Turkey.
Melis
M
Sardan Ekiz
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University , Ankara 06800, Turkey.
Gokhan
G
Gunay
Turgay
T
Tekinay
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University , Ankara 06800, Turkey.
Ayse B
AB
Tekinay
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University , Ankara 06800, Turkey.
Mustafa O
MO
Guler
D002966:Clathrin; D004705:Endocytosis; D006801:Humans; D057139:Nanofibers; D054118:Nanospheres; D009841:Oligonucleotides; D010455:Peptides
D002966:Clathrin; D009841:Oligonucleotides; D010455:Peptides
glucose transporters; glycoconjugates; internalization; oligonucleotide delivery; peptide amphiphiles; self-assembly