Binary Copolymer Blending Enhances pDNA Delivery Performance and Colloidal Shelf Stability of Quinine-Based...

Area of Science:

• Biomaterials Science
• Gene Therapy
• Polymer Chemistry

Background:

• Efficient nucleic acid delivery is crucial for gene therapy success.
• Quinine-based polymers show promise as nucleic acid carriers but suffer from hydrophobicity-induced aggregation.
• Large polyplexes (>1000 nm) exhibit poor in vivo performance, hindering clinical translation.

Purpose of the Study:

• To overcome hydrophobicity-induced aggregation in quinine-based polymer-nucleic acid complexes (polyplexes).
• To develop colloidally stable, small polyplexes (<300 nm) with enhanced gene delivery performance.
• To explore polymer blending as a strategy for optimizing polyplex characteristics.

Main Methods:

• A facile blending approach was employed using quinine-based copolymers (HQ-X) and a polyethylene glycol-containing quinine-based diblock copolymer (PHQ).
• Extensive screening of 66 formulations, varying polymer pairs, mixing ratios, and sequences, was performed.
• Polyplex characteristics including particle size, colloidal stability (up to 7 days at 4 °C), and transfection efficiency were evaluated.

Main Results:

• 37 out of 66 formulations yielded non-aggregating small polyplexes (<300 nm) with demonstrated colloidal stability.
• 18 stable formulations exhibited transfection performance comparable to or better than the commercial control (jetPEI).
• Optimal balance of transfection efficiency, toxicity, and colloidal stability was achieved at moderate PHQ percentages without compromising payload binding.

Conclusions:

• Polymer blending is an effective strategy to mitigate hydrophobicity-induced aggregation in quinine-based polyplexes.
• This approach enables the creation of small, colloidally stable polyplexes suitable for gene therapy applications.
• The findings highlight polymer blending as a versatile method for tailoring polyplex characteristics, analogous to lipid-based systems.