期刊
ADVANCED FUNCTIONAL MATERIALS
卷 29, 期 25, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201900697
关键词
atherosclerotic plaque-specific peptide-1; click chemistry; gene silencing; lipo-oligomer; mitochondrial membrane disruption; siRNA-apoptotic peptide conjugate; targeted cancer therapy
类别
资金
- China Scholarship Council
- DFG Excellence Cluster 'Nanosystems Initiative Munich' (NIM) [SFB1032]
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.
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