Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA

Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a p...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2021-05, Vol.26 (11), p.3238
Main Authors: Liu, Shuang, Deng, Shaohui, Li, Xiaoxia, Cheng, Du
Format: Article
Language:English
Subjects:
Anions
Antibodies
Block copolymers
Blood circulation
Cationic polymerization
Cations
Cell Survival
Copolymers
Cross-Linking Reagents - chemistry
Crosslinking
Cytoplasm - metabolism
Diethylene triamine
disulfide bond-crosslinking
Disulfides
Drug Delivery Systems
Efficiency
Fourier transforms
Humans
Hydrogen-Ion Concentration
Interlayers
Lauric acid
Lauric Acids - chemistry
Ligands
Magnetic Resonance Spectroscopy
Molecular weight
Nanoparticles
Oxygen - chemistry
Particle Size
pH-sensitive PEG shedding
Polyethylene glycol
Polyethylene Glycols - chemistry
Polymerization
Polymers
Polymers - chemistry
RNA, Small Interfering - metabolism
Shedding
siRNA
siRNA delivery
small polyplex
Spectroscopy, Fourier Transform Infrared
targeting delivery
THP-1 Cells
Transfection
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Summary:Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a poly(l-cysteine) block with a thiol group (PCys block), and a cationic poly(aspartate) block grafted with diethylenetriamine (PAsp(DETA) block). The cationic polymers efficiently complexed siRNA into polyplexes, showing a sandwich-like structure with a PAsp(-N=C-PEG) out-layer, a crosslinked PCys interlayer, and a complexing core of siRNA and PAsp(DETA). Low pH-triggered breakage of pH-sensitive imine bonds caused PEG shedding. The disulfide bond-crosslinking and pH-triggered PEG shedding synergistically decreased the polyplexes' size from 75 nm to 26 nm. To neutralize excessive positive charges and introduce the targeting ligand, the polyplexes without a PEG layer were coated with an anionic copolymer modified with the targeting ligand lauric acid. The resulting polyplexes exhibited high transfection efficiency and lysosomal escape capacity. This study provides a promising strategy to engineer the size and surface of polyplexes, allowing long blood circulation and targeted delivery of siRNA.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26113238