Abstract
Targeted delivery remains the major limitation in the development of small interfering RNA (siRNA) therapeutics. The successful siRNA multistep delivery requires precise carriers of substantial complexity. To achieve this, a monodisperse carrier is presented, synthesized by solid-phase supported chemistry. The sequence-defined assembly contains two oleic acids attached to a cationizable oligoaminoamide backbone in T-shape configuration, and a terminal azide functionality for coupling to the atherosclerotic plaque-specific peptide-1 (AP-1) as the cell targeting ligand for interleukin-4 receptor (IL-4R) which is overexpressed in a variety of solid cancers. For combined cytosolic delivery with siRNA, different apoptotic peptides (KLK, BAK, and BAD) are covalently conjugated via bioreversible disulfide linkage to the 5 '-end of the siRNA sense strand. siRNA-KLK conjugates provide the highest antitumoral potency. The optimized targeted carrier is complexed with dual antitumoral siEG5-KLK conjugates. The functionality of each subdomain is individually confirmed. The lipo-oligomer confers stable assembly of siRNA conjugates into spherical 150-250 nm sized nanoparticles. Click-shielding with dibenzocyclootyne-PEG-AP-1 (DBCO-PEG-AP-1) mediates an IL-4R-specific cell targeting and gene silencing in tumor cells. Most importantly, formulation of the siEG5-KLK conjugate displays enhanced apoptotic tumor cell killing due to the combined effect of mitotic arrest by EG5 gene silencing and mitochondrial membrane disruption by KLK.
| Item Type: | Journal article |
|---|---|
| Faculties: | Chemistry and Pharmacy > Department of Pharmacy |
| Research Centers: | Center for NanoScience (CENS) |
| Subjects: | 500 Science > 540 Chemistry 500 Science > 500 Science |
| ISSN: | 1616-301X |
| Language: | English |
| Item ID: | 83575 |
| Date Deposited: | 15. Dec 2021, 15:08 |
| Last Modified: | 15. Dec 2021, 15:08 |
Actions (login required)
- View Item
