The emergence of mRNA as a new therapeutic agent to prevent and treat diseases such as cancer, has been made possible by advancements in lipid nanoparticle (LNP) technologies. To be an effective therapeutic, mRNA must remain stable and reach its target in vivo. To have a large therapeutic window - mRNA must reach its target and produce adequate amounts of an encoded protein. Lipid nanoparticles have been particularly successful and authorized for numerous therapeutics in mRNA delivery. These LNPs offer advantages over other drug delivery methods due to their stability and ability to manufacture at a large scale at a low cost. LNPs have also shown less cytotoxicity and immunogenicity compared to liposomes.
Lipids are anamorphic and composed of three domains: a polar head, a hydrophobic tail, and a domain linking the two. The lipids investigated for drug delivery are cationic, ionizable, and PEG lipid.
Ionizable lipids are protonated at low pH - giving them a positive charge but remaining neutral at physiological pH. This feature has many in vivo benefits because neutral lipids have fewer interactions with the anionic membranes of blood cells' thus improving biocompatibility. A noteworthy ionizable lipid is DLin-MC3-DMA, used in the FDA-approved siRNA drug Onpattro as a treatment for polyneuropathy. Additional fine-tuning of MC3 through adding esters to the tails of DLin-MC3-DMA, the new lipid L319 was created, with the benefit of having better delivery efficacy and faster elimination from the liver and plasma in vivo. The progressive structural changes of these lipids are in Figure 1. The Ionizable lipids that have gained the most notoriety are SM-102 and ALC-0315, used in COVID-19 vaccines mRNA-1273 and BNT162b. Both these lipids are biodegradable and made of ester motifs.
Figure 1. Diagram showing the structural changes to the ionizable lipids DLin-MC3-DMA and L319.
Cationic lipids' defining feature is having a head group with a permanent positive charge. As an example, the biodegradable analog of DOTMA called DOTAP is in the formulation of MegaFectin seen in Figure 2. DOTAP-based cationic nanoemulsions can deliver antigen mRNA to treat viral, bacterial, and parasitic infections. DOTAP-polymer hybrid nanoparticles can deliver mRNA molecules to treat cancers, infections, and genetic disorders.
Figure 2. Structural changes and characteristics of cationic lipids DOTMA and DOTAP.
Peg-lipids have several different effects on the properties of the LNPs. PEG-lipids in the drug formulations affect the particle size and zeta potential. They also have the potential to increase particle stability and prolonged circulation times. There is also the possibility of conjugation of ligands to the delivery particle. The PEG-lipid PEG-DSG 2,000 can promote stability, delivery, efficacy, tolerability, and biodistribution.
Figure 3. Shows the PEGylated lipid DSG-PEG2, MW 2000.
As a worldwide leading lipid supplier, BroadPharm offers a wide variety of lipids for drug delivery. Including ionizable, cationic, and PEG lipid. We pride ourselves on empowering your research in lipids for drug delivery.
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