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Methionine Functionalized Biocompatible Block Copolymers for Targeted Plasmid DNA Delivery
Published on: August 6, 2019
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Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery.
M Rachèl Elzes1, Niels Akeroyd2, Johan F J Engbersen3
1Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
Summary
Researchers developed new polymers for gene therapy by controlling disulfide bond stability. The PAA2m polymer showed high transfection efficiency and stability, making it promising for future gene delivery applications.
Area of Science:
- Biomaterials Science
- Polymer Chemistry
- Gene Therapy
Background:
- Controlled release of genetic material from polymeric carriers is crucial for effective gene therapy.
- Disulfide bonds are often used in polymeric carriers for intracellular payload release, but premature extracellular release is a challenge.
- Tuning the stability of disulfide linkages is key to optimizing polymeric carrier performance.
Purpose of the Study:
- To synthesize and evaluate bioreducible poly(amido amine)s (PAAs) with varying steric hindrance around disulfide bonds for controlled stability.
- To assess the degradation behavior, in vitro toxicity, and transfection efficiency of these novel PAA polymers.
- To identify a PAA-based polymer with optimal stability and gene delivery capabilities.
Main Methods:
- Synthesis of PAAs with 0, 2, or 4 methyl groups (PAA0m, PAA2m, PAA4m) adjacent to disulfide bonds.
- Evaluation of polymer degradation under varying reducing conditions (glutathione concentrations).
- Assessment of in vitro toxicity and transfection efficiency in cellular models.
Main Results:
- Increased steric hindrance around disulfide bonds enhanced polymer stability against reduction.
- PAA2m demonstrated stability in extracellular conditions and rapid degradation intracellularly.
- PAA2m achieved high transfection efficiencies (up to 90%), while PAA0m showed reduced efficiency and PAA4m exhibited increased toxicity and lower efficiency.
Conclusions:
- Steric hindrance effectively tunes the stability of disulfide-containing polyplexes against bioreduction.
- PAA2m offers a promising balance of stability and transfection efficiency for gene therapy applications.
- This strategy provides a method for developing optimized polymeric carriers for targeted gene delivery.
