The Heads and Tails of Lipid-Based
Lipid-based drug delivery (LBDD) systems, such as liposomes, lipid nanoparticles (LNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), are customizable platforms for the targeted delivery of pharmaceuticals and other therapeutic agents, for instance, vaccine components or oligonucleotides, to cells and tissues. LBDD overcomes obstacles associated with conventional therapeutic formulations by encapsulating bioactive molecules in a lipid vesicle, which increases their bioavailability, distribution, and plasma half-life, and decreases systemic toxicity induced by off-target activity. The versatility of LBDD formulations is achievable in part through the diversity of lipids available for these applications.
Structural Differences Between Glycerophospholipids and Sphingomyelin
LBDD systems are composed of mixtures of lipids, especially phospholipids (PLs), which contain a hydrophilic head group and a hydrophobic tail. PLs include glycerophospholipids (GPLs) and sphingomyelin (SM), which is also categorized as a sphingolipid (SL). GPLs contain a polar head group and two fatty acyl tails attached to a glycerol backbone. Differences in the polar head group give rise to various members, including phosphatidylcholine (PC), phosphatidylethanolamine (PE),phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidic acid (PA). SM is composed of a phosphocholine polar head group and a fatty acyl tail attached to a sphingosine backbone. The biophysical properties of these PLs are defined by variations in their polar head groups and fatty acyl tails, each possessing unique biophysical properties that can be leveraged in LBDD. By leveraging the biophysical properties of lipids, researchers can achieve an assortment of LBDD systems that encapsulate and deliver a wide variety of biomolecules.
Biophysical Properties of PLs in LBDD Systems
The structural and functional properties of an LBDD system depend on the physiochemical characteristics of its constituent lipids. PLs with various head group properties can be harnessed to mediate effective delivery of encapsulated cargo to cells. The hydrophilic head of PLs determines the surface charge of the particle, which can be neutral, negative, or positive (Figure 2).1 PC, PE, and SM are zwitterionic at pH 7 and have a neutral overall charge. Neutral PLs have an important role in membrane fusion of the LBDD particle, and they can also be used to distribute or modify its net surface charge. Anionic PLs, including PG, PI, PS, and PA, are typically used for the delivery of small molecules and are incorporated into neutral LBDD systems to prevent aggregation during storage. Cationic lipids, such as the ionizable cationic lipids SM-102 and ALC-0315 at low pH, are superior for the encapsulation and delivery of anionic nucleic acids and have been used to formulate LNPs in mRNA-based COVID-19 vaccines.
Lipid-Based Drug Delivery Tools
Matreya offers highly purified natural PLs available from a variety of sources. These PLs contain a heterogenous mixture of fatty acids attached to the glycerol, which is dependent on several factors, including species, diet, and environmental conditions. Normal variations in the fatty acids include chain length, saturation, and hydroxylation. A breakdown of the typical fatty acid composition of PLs obtained from natural sources by Matreya is available on the Technical Information page of the Matreya website.
Matreya has developed fluorescent standards that can be detected in cultures and in biological systems, making them ideal for studies involving the metabolism of sphingolipids. These lipid analogs are useful for determining the localization of various sphingolipids in membranes and organelles. The NBD fluorescent group attached to hexanoic acid has been shown to be readily taken up by cells and used in the biosynthesis of more complex sphingolipids.
Semi-synthetic PLs contain well-defined fatty acids attached to the glycerol, eliminating the variability of natural PLs. They are useful in the preparation of various LBDD systems. Matreya offers an extensive list of semi-synthetic PLs, including several species of PC, the most commonly used lipid in LBDD formulations, as well as SM.
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