Ionizable Lipids

Ionizable lipids, also known as ionizable cationic lipids or ionizable lipid-like materials, are a class of lipids used in the formulation of lipid nanoparticles (LNPs) for drug delivery purposes. These lipids are designed to incorporate ionizable functional groups that can undergo pH-dependent charge changes, enabling efficient encapsulation and delivery of nucleic acids or other therapeutics.

The incorporation of ionizable lipids into LNPs is crucial for overcoming the barriers associated with delivering nucleic acids, such as small interfering RNA (siRNA) or messenger RNA (mRNA), to target cells. The pH-dependent charge properties of these lipids allow them to effectively encapsulate negatively charged nucleic acids within the core of LNPs, protect the cargo from degradation, and facilitate cellular uptake and intracellular release.

The ionizable lipids typically have an amine-containing headgroup that can be protonated or deprotonated depending on the pH of the surrounding environment. At physiological pH (around pH 7.4), the lipid is typically in a neutral or slightly cationic state, enabling efficient encapsulation of nucleic acids. However, upon entering the endosomal compartments within the cells (which have a lower pH), the ionizable lipids become positively charged, promoting endosomal escape and release of the cargo into the cytoplasm.

Commonly used ionizable lipids include:

Here is a list of commonly used ionizable lipids in the field of lipid nanoparticle-based drug delivery:

1. 1,2-Dioleoyl-3-dimethylammonium-propane (DODAP)
2. 1,2-Dioleoyl-3-pyridiniumpropane (DOPP)
3. 1,2-Dioleoyl-sn-glycero-3-ethylphosphocholine (EPC)
4. 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP)
5. 1,2-Dioleoyl-sn-glycero-3-histidine (DOGHis)
6. 1,2-Dioleoyl-3-[(11-succinylamino)undecanoyl]-sn-glycerol (DOGSU)
7. 1,2-Dioleoyl-sn-glycero-3-succinyl (sodium salt) (DOGS-Na)
8. 1,2-Dioleoyl-sn-glycero-3-lysine (DOGSLys)
9. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
10. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DOPE-PEG)
11. 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine (DOPS)
12. 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC)
13. 1,2-Dioleoyl-sn-glycero-3-phosphoglycerol (DOPG)
14. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (DOPE-Rhodamine)
15. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine-N-(carboxyfluorescein) (DOPE-CF)

Please note that this is not an exhaustive list, and there may be other ionizable lipids or variations of the listed lipids used in research and development for lipid nanoparticle-based drug delivery systems. Additionally, the specific properties and applications of these lipids may vary based on the context and formulation requirements.

These ionizable lipids, in combination with other lipids such as phospholipids and cholesterol, are used to formulate LNPs for efficient delivery of nucleic acids to target cells. The ratio and composition of the lipids can be optimized to achieve desired properties such as stability, encapsulation efficiency, and release kinetics.

It is important to note that the field of ionizable lipids and lipid nanoparticle-based drug delivery is rapidly evolving, and new lipid materials and formulations are continuously being developed to enhance the efficacy and safety of nucleic acid delivery systems.