Poly(sarcosine) Lipid Synthesis From CO₂-Based Sarcosine-N-Carboxyanhydride

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Nanotechnology

Background:

• Polymer lipids (PLs) are crucial for the stability of lipid nanoparticles (LNPs) used in gene delivery.
• Poly(ethylene glycol) (PEG)-based lipids are standard but linked to rare adverse reactions in LNP vaccines.
• Alternative PLs, such as poly(sarcosine) (PSar)-based lipids, are under investigation.

Purpose of the Study:

• To develop a phosgene-free synthesis route for sarcosine-N-carboxyanhydride (Sar-NCA).
• To enable the production of PSar lipids for LNP applications.
• To provide a safer and more accessible method for PSar-based biomaterial synthesis.

Main Methods:

• A novel synthesis pathway utilizing carbon dioxide (CO2) to produce Sar-NCA from sarcosine.
• Gram-scale synthesis of Sar-NCA with high purity.
• Subsequent living polymerization of Sar-NCA to yield PSar.
• Synthesis of PSar lipids for LNP preparation.

Main Results:

• Successful gram-scale synthesis of Sar-NCA using a phosgene-free, CO2-based method.
• High purity of the synthesized Sar-NCA monomer.
• Demonstrated utility of the synthesized PSar for creating functional PSar lipids for LNPs.

Conclusions:

• The CO2-based Sar-NCA synthesis is a safe, efficient, and scalable alternative to current toxic methods.
• This method facilitates the production of PSar lipids, offering a promising alternative to PEG-based lipids in LNP formulations.
• The developed process has significant potential for advancing biomaterial synthesis for gene delivery applications.