Prediction of the Apparent pKa Value of Lipid Nanoparticles by Density Functional Theory

One of the most important parameters for the development of novel ionizable lipids (ILs) for use in lipid nanoparticle (LNP) drug carriers is their pK_a value. Ideally, the LNP should be deprotonated outside the cell to prevent cytotoxicity and protonated inside the endosome, where pH is lower. To achieve this switch, the LNP’s pK_a value, the so-called “apparent pK_a value”, should range generally between 5.5 and 7. For specific applications, the range is narrower. We present a straightforward approach to computationally estimate this apparent pK_a value of LNPs using density functional theory (DFT). This method uses “surrogates” of the ILs, which are hypothetical derivatives featuring an N,N-dimethylethylaminium side group attached to the lipid’s nitrogen atom.