Lipid is a class of organic molecules that are fatty acids or their derivatives. Lipids are insoluble in aqueous solution but soluble in organic solvents. Most common lipids include fats, waxes, oils, certain vitamins, phospholipids, and steroids. In the cells, the functions of lipids include storing energy, signaling, and acting as structural components of cell membranes.
Lipids have become widely used in the cosmetic and food industries as well as in nanoparticle drug technology. The amphiphilic nature of some lipids allows them to form structures such as vesicles, multilamellar/unilamellar liposomes, or membranes in an aqueous environment.
A variety of lipid molecules have been developed for mRNA delivery and that are one of key elements leading to the success of two of the Covid-19 vaccines, mRNA-1273 and BNT162. More and more lipid nanoparticle-mRNA formulations have been developed and are under clinical evaluation for the prevention and treatment of virus infections, cancer and genetic diseases.
There are a variety of lipids used in lipid nanoparticle (LNP) drug delivery vehicles. These lipids include Cationic Lipid, Ionizable Lipid, Helper Lipid, PEG lipid, Phospholipid & Cholesterol as described below.
Cationic lipids such as DOTAP (Figure 1) have a head group with permanent positive charges. Cationic lipids neutralize negative charges and facilitate encapsulation and cell uptake in lipid nanoparticles (LNP).
Ionizable lipids such as ALC-0315 (Figure 2) are protonated at low pH, which makes them positively charged, but they remain neutral at physiological pH. The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells which improves the biocompatibility of lipid nanoparticles. Trapped in endosomes, in which the pH is lower than the pH in the extracellular environment, ionizable lipids are protonated and become positively charged, which may promote membrane destabilization and facilitate endosomal escape of the nanoparticles. Ionizable Lipids promote endosome escape and reduce toxicity of lipid nanoparticles (LNP).
Helper Lipids is a class of lipid molecules that increase particle stability and fluidity of lipid nanoparticles (LNP). For example, lipid components, such as phospholipids DSPC (Figure 3) can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerability and biodistribution.
Cholesterol can enhance particle stability by modulating membrane integrity and rigidity. The molecular geometry of cholesterol derivatives can further affect delivery efficacy and biodistribution of lipid nanoparticles. For example, cholesterol analogues with C-24 alkyl phytosterols increase the in vivo delivery efficacy of lipid nanoparticle-mRNA formulations.
Phospholipid or phosphatide is an amphipathic molecule containing two hydrophobic fatty acid tails and one phosphate hydrophilic head connected by glycerol as shown in Figure 4. The phosphate group can be attached with various moieties, such as serine, ethanolamine, choline, glycerol, inositol, and polyethylene glycol (PEG). In aqueous solution, phospholipids can self-assemble spontaneously to form lipid bilayers. Phospholipids can be used as vehicles or excipients for delivering therapeutics via parenteral, topical, and oral administration.
PEG lipids, also known as PEGylated lipid is a class of PEG derivatives that is attached with a lipid moiety such as DMG or DSPE. PEG lipid has been used extensively to improve circulation times for liposome encapsulated (LNP) drugs and reduce non-specific uptakes.
PEG lipids such as PEG2000-DMG (Figure 5) can have multiple effects on the properties of lipid nanoparticles. The amount of PEG lipids can affect particle size. PEG lipids can further contribute to particle stability by decreasing particle aggregation, and the optimization of PEG prolong the blood circulation time of nanoparticles by reducing clearance mediated by the kidneys and the mononuclear phagocyte system. Finally, PEG lipids can also be used to conjugate specific ligands to the particle for targeted delivery. The extent of these effects depend on the proportions and properties of the PEG lipids (such as PEG molar mass and lipid length). Lipid nanoparticle-siRNA formulations containing PEG2000-DMG have shorter circulation times and higher delivery efficacy in vivo than formulations containing PEG2000-DSG. This difference may be attributed to the faster dissociation of PEG2000-DMG from lipid nanoparticles, compared with PEG2000-DSG, which may benefit cellular uptake and endosomal escape of lipid nanoparticles.
As a leading biochemical supplier worldwide, BroadPharm offer 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.