The Categories of Lipids as Pro-Moieties in Lipid Pro-drugs

At present, four types of lipids have been used as pro-moieties in small molecule lipidic pro-drugs, they are:

Fatty Acids (FAs): Lipids enable the free carboxylic acid of the fatty acids to easily conjugate with the free hydroxyl or amine functional groups of other molecules. Such fatty acids are similar to the lipids in biological lipid membranes. In some cases, they are totally the same. As a result, the fatty acids can interact with lipid membranes to enable the drugs to penetrate the membranes and finally get into the cells. The long hydrocarbon chain is another key property of fatty acids, while the hydrocarbon chain is helpful in the formation of nanoparticles and the process of self-assembly.

Glycerides: Triglycerides in high levels are harmful to human health. However, at the same time, triglycerides can be used for small molecule drugs delivery and disease treatment. The backbone of a glyceride is a glycerol which is a three-carbon chain. Each carbon has a free hydroxyl group. Once a fatty acid is conjugated with each of the free hydroxyl groups of a glycerol molecule, a triglyceride is formed. The triglyceride is an excellent energy storage molecule which makes it a good choice for the small molecule lipidic pro-drugs. Compared to many small molecules with short metabolic pathway, the metabolic pathway of the triglyceride molecules is relatively long. After a long period, a triglyceride is completely metabolized to a monoglyceride and then re-acylated and recirculated as lymph lipoproteins. Due to the association with the lymphatic transport pathway, triglyceride mimicking pro-drugs are favorable.

Bile Acids: Bile acids, a promising lipidic pro-drug strategy, can enhance drug pharmacokinetics . With the specific property, bile acids have become another candidate for small molecule lipidic pro-drugs. Bile acids are molecules of amphipathic detergent so that they can be used to solubilize drug and permeate cell membrane. Existing in liversand small intestinrs, bile acids are capable of resisting the environment of the gastrointestinal system and regulating the transportion and absorption of conjugated molecules through transporters.

Phospholipids: Owing to the ability to interact with outer surface of cell membranes and other properties, phospholipids are often used in lipid nanoparticles and liposomes. Phosphatidylcholine (PC) is the main component of cell membranes and a candidate for phospholipid-drug conjugates (PCDs). Drugs can be linked to phospholipids through the group of phosphate or backbone of glycerol. Compared to traditional liposomes, the utilization of PCDs in liposomes are more stable with higher drug loading efficiency and targeting ability.

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