Lipids
in Drug Delivery
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
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
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
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.
Lipid Supplier
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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