Browsing by Subject "Oligonucleotide delivery"

Now showing 1 - 2 of 2

Open Access
Cellular internalization of therapeutic oligonucleotides by peptide amphiphile nanofibers and nanospheres
(American Chemical Society, 2016-04) Mumcuoglu, D.; S. Ekiz, M.; Gunay, G.; Tekinay, T.; Tekinay, A. B.; Güler, Mustafa O.
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.
Open Access
Self-assembled peptide nanostructure delivery sytems for oligonucleotide therapy
(2014-06) Mumcuoğlu, Zahide Didem
Oligonucleotides are potent therapeutic agents in the treatment of cancer, metabolic, cardiovascular and various hereditary diseases. Despite their great potential, oligonucleotide-based drugs have failed in clinical and pre-clinical studies due to their low cell penetration capacities, short plasma half-lives and rapid clearances. As such, development of delivery systems for oligonucleotide drugs is necessary to protect oligonucleotide based-drugs from renal and reticulo-endothelial system (RES) clearance and as well as to facilitate their delivery within target sites. In this thesis, a peptide nanostructure delivery system was developed to improve these deficiencies and to create an effective carrier for oligonucleotide therapy. Cell penetration capacity and silencing efficiency of a model oligonucleotide drug, Bcl-2 antisense oligonucleotide, was shown to be increased following encapsulation within cell penetrating peptides. In addition, the importance of the geometry of the delivery system in cellular internalization was investigated. The geometry of the nanostructure was shown to be critical in cellular internalization, where nanofibers were observed to be internalized to a greater extent compared to nanospheres. Their cellular uptake mechanisms were also studied and internalization of nanofibers was found to depend on an endocytic pathway whereas nanospheres were internalized via a non-endocytic pathway.