Multifunctional Poly(amine-co-ester-co-ortho ester) for Efficient and Safe Gene Delivery

Area of Science:

• Biomaterials Science
• Gene Therapy
• Polymer Chemistry

Background:

• Current cationic polymers for non-viral gene delivery face challenges in overcoming biological barriers.
• Existing materials often lack the necessary multifunctionality for efficient and safe gene transfer.

Purpose of the Study:

• To design and synthesize a novel family of quaterpolymers with enhanced functionalities for gene delivery.
• To investigate the acid sensitivity, charge, hydrophobicity, and biodegradability of these new polymers.
• To evaluate the efficiency of these polymers in delivering genetic material to various cell types.

Main Methods:

• Lipase-catalyzed polymerization of ortho ester diester, lactone, dialkyl diester, and amino diol monomers.
• Synthesis of quaterpolymers incorporating acid-sensitive ortho ester groups.
• Evaluation of polymer-mediated gene delivery in HEK293 cells, human glioma cells, primary mouse melanoma cells, and HUVECs.
• Development of a lyophilized nanoparticle formulation.

Main Results:

• The synthesized quaterpolymers demonstrated acid-sensitive degradation at endosomal pH (4-5).
• Polymers facilitated efficient endosomal escape and gene unpackaging.
• High gene delivery efficiency was observed across multiple cell lines, including cancer and endothelial cells.
• A stable, lyophilized nanoparticle formulation maintained efficiency for at least one month.

Conclusions:

• The rationally designed quaterpolymers offer a multifunctional platform for advanced non-viral gene delivery.
• Acid sensitivity and optimized physicochemical properties contribute to efficient endosomal escape and gene transfection.
• The developed lyophilized formulation provides a practical and stable solution for gene delivery applications.