Utilizing Novel Reaction Setups to Develop Lipid Nanoparticles for mRNA Delivery

Abstract

Challenges associated with mRNA vaccines include adverse reactions, poor organ targeting upon injection, and mRNA viability in the cell. The solution lies in optimizing the vaccine’s delivery mechanism using lipid nanoparticles (LNPs) to effectively transport mRNA into cells and express immunogens post-injection while enhancing adjuvant activity. Several lipid molecules were designed and synthesized through standard procedures based on lipids such as Moderna (SM-102), Pfizer-BioNTech (ALC-0315), and Onpattro (MC3). Novel lipid molecules with polyamine heads (cyclic, acyclic, or both) and linkers (donating alcohols and withdrawing esters) were designed and synthesized to understand the chelating effect on mRNA encapsulation and stability. Their functionality was predicted and compared to the lipid MC3. Physico-chemical properties such as size, Z-average, and PDI are measured by Dynamic light scattering (DLS). The lipids that were tested and synthesized, 666 through 670, had particularly low pKa values, whereas epoxide-opening lipids had a pKa of around 5.5-6.2. To increase the pKa, reactions with epoxide tails and lower equivalence ratios were implemented to obtain pKa values between 6.3-6.7. This research found that using epoxide-based and lower-equivalence reactions could allow for lipid synthesis at a higher pKa, enabling appropriate adjuvant allocation with similar efficacy.