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Cross-Linkable Polyion Complex Micelles from Polypept(o)ide-Based ABC-Triblock Copolymers for siRNA Delivery
Leon Capelôa1,2, Mina Yazdi3, Heyang Zhang4
1Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einstein weg 55, Leiden, 2333CC, The Netherlands.
Macromolecular Rapid Communications
|December 30, 2021
Summary
New ABC-type triblock copolymers offer advanced functionality for oligonucleotide delivery. These polypept(o)ide-based polymers form stable polyion complex micelles for effective small interfering RNA delivery and gene knockdown.
Area of Science:
- Polymer Chemistry
- Biomaterials Science
- Nanotechnology
Background:
- ABC-type triblock copolymers are emerging as versatile platforms for oligonucleotide delivery.
- Existing systems require effective shielding, complexation, and additional functionalities for enhanced performance.
Purpose of the Study:
- To develop and characterize novel polypept(o)ide-based ABC-type triblock copolymers for small interfering RNA (siRNA) delivery.
- To investigate the self-assembly behavior of these copolymers and their resulting polyion complex (PIC) micelle structure.
- To evaluate the efficacy of these PIC micelles in cellular delivery and gene knockdown.
Main Methods:
- Synthesis of ABC-type triblock copolymers via amine-initiated ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs).
- Characterization of copolymer self-assembly and PIC micelle formation, correlating block lengths with micelle structure.
- Introduction of disulfide cross-links using multifunctional thiols to enhance micelle stability.
- Assessment of siRNA loading capacity and cellular delivery in Neuro2A and KB cells.
Main Results:
- Polypept(o)ide-based ABC-type triblock copolymers self-assemble into PIC micelles.
- The poly(S-ethylsulfonyl-l-cystein) (pCys(SO2Et)) block significantly influences micelle structure and enables disulfide cross-linking.
- Well-defined, cross-linked PIC micelles (50-60 nm) with determinable siRNA loading were achieved.
- Effective cellular uptake and specific gene knockdown were demonstrated in cellular assays.
Conclusions:
- ABC-type triblock copolymers provide a tunable platform for creating functional PIC micelles for siRNA delivery.
- The incorporation of a cross-linkable block enhances micelle stability and control over structure.
- These novel polymeric micelles show promise for efficient and targeted gene silencing applications.
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