Ionizable lipids are a class of lipid molecules which remain neutral at physiological pH, but are protonated at low pH, making them positively charged (Ref 1). ALC-0315 (Figure 1) is an example of an ionizable lipid with a pKa of 6.09.
Figure 1: Structure of ALC-0315
Ionizable lipids are one key component of lipid nanoparticles (LNPs) which have been widely used for the systemic delivery of RNA therapeutics. Other lipid molecules in LNPs include cationic lipid, helper lipid, cholesterol, and PEG lipid.
SM-102 (pKa 6.68) is known for its use in the FDA-approved Moderna COVID-19 vaccine mRNA-1273. To fine-tune its properties, BroadPharm developed a series of analogs, incorporating alterations between the chargeable tertiary amine head, bridge chain, and hydrophobic fatty tails linked through an ester or amide bond (see Figure 2).
Figure 2: Structure of SM-102
The team at The University of Texas demonstrated that SM-102, ALC-0315 & their analogs, developed from BroadPharm, were key to predicting the impact of small structural changes on mRNA LNP transfection efficiency using machine learning, thus accelerating lipid screening for mRNA therapeutics. Of these new lipids, BP Lipid 142 demonstrated the greatest transfection efficiency as well as significantly higher luminescence in the Calu-3s cell line (Ref 2).
D-Lin-MC3-DMA (pKa 6.44), used in the FDA-approved drug Onpattro, delivers siRNA to the liver. The unique cis-double bonds that promote the hexagonal II (HII) fusogenic phase prevent tight lipid packing, facilitating endosomal fusion cytosolic delivery. To further improve its properties, BroadPharm synthesized a range of MC3 analogs, modifying the head, chemical linkage, bridge chain, and/or tail parts of the lipid (see Figure 3).
Figure 3: Structure of D-Lin-MC3-DMA
LP01 (pKa 6.1) effectively delivers CRISPR/Cas9 components and is well-tolerated in animal studies. It shows advantages in biodegradability and liver clearance (Kazemian). A series of analogs have been developed with alterations to the chargeable amine head (e.g. replacement by an azetidine or other ring), carbonate linkage (replacement by an ester or carbamate bond), and different lipid tails (see Figure 4).
Figure 4: Structure of LP01
As a leading biochemical supplier worldwide, BroadPharm offers a wide array of Lipid molecules, such as Ionizable lipids, cationic lipids, helper lipids, PEG lipids, to our clients worldwide. BroadPharm also provides fast speed custom synthesis of novel lipid molecules to empower your advanced research. Please call 1-858-677-6760 or email to sales@broadpharm.com.