Lipid-based Drug Delivery Development with Cayman – Part 1

Lipid-based drug delivery systems (LBDDS) have been studied and developed since the 1960s. The main objective is to develop formulations that increase the bioavailability of drugs while reducing undesirable side effects. In 2020, this technology received a lot of attention due to its application in SARS-CoV-2 vaccination. In this first part of our LBDDS two-parter, we will focus on the structure and composition of lipid-based drug delivery systems and the different types of LBDDS. In addition to their application in mRNA vaccines, there are other possible uses for LBDDS, some of which we would like to introduce here.

These topics await you:

1) What are LBDD systems?

2) Which LBDD systems are available?

3) What components can LBDD systems be composed of?

What are LBDD systems?

In 1964, the research group around Alec Douglas Bangham discovered the so-called liposome [1]. Liposomes are vesicles consisting of a lipid bilayer (e.g. phospholipids or fatty acids) and enclosing an aqueous phase inside (Fig. 1). The lipids are amphiphilic, meaning that the molecules have a lipophilic and a hydrophilic part. Within the lipid bilayer, the hydrophilic portions each face outward and the lipophilic portions face inward, allowing an aqueous phase to exist inside the liposome (Fig. 1). If the lipid structure of the liposome is reversed (when the lipophilic portions point outward), it is a so-called reverse-phase liposome, in which a lipophilic phase can be introduced inside [2]. The liposome represents the first commercially used LBDD system. Examples of approved drugs using liposomes as a drug delivery system include:

- Epaxal: Hepatitis A vaccine

- Influvac: influenza virus vaccine

- Amphotericin B: antifungal agent against systemic fungal infections

- Verteporfin: age-related macular degeneration, myopia

- Perflutren: contrast agent for ultrasound examination

Figure 1: Schematic representation of the liposome (source: Cayman Chemical). The envelope of liposomes consists of a lipid bilayer (e.g. phospholipids). The lipids have a lipophilic and a hydrophilic part. In classical liposomes, the lipophilic parts point to the inside of the lipid bilayer and the hydrophilic parts point to the outside, so that an aqueous phase can exist in the core of the liposome. Here, hydrophilic drugs can be encapsulated, whereas hydrophobic drugs can be packaged inside the lipid shell.

LBDD systems are highly versatile and allow for the delivery of diverse, bioactive molecules (such as small molecule inhibitors and vaccine components) into target cells and tissues. LBDDS have several advantages over conventional delivery methods. These include improved stability, higher bioavailability and better distribution of the drug. Poorly water-soluble drugs, in particular, pose challenges during delivery, which causes problems for the development of such drugs. Lipid-based drug delivery systems therefore lend themselves especially well to the administration of such agents. The delivery of drugs packaged via LBDD systems can generally be oral, parenteral, ocular, intranasal, and also dermal/transdermal. However, oral drug administration is generally preferred as it is both easiest and most cost-effective for the patient, especially with regard to the treatment of chronic diseases [3]. In addition to "the classic" liposome, a variety of other, different packaging units have been developed in the field of LBDD systems to meet different needs.

Which LBDD systems are available?

LBDD systems are generally differentiated according to their structure and the chemical nature of their core. Depending on their structure, they are suitable for the transport of different substances (Fig. 2).

1. Lipid nanoparticles (LNPs) consist of a lipid shell surrounding an inner core of reverse micelles. Oligonucleotides, such as siRNA, mRNA and plasmid DNA (pDNA), are encapsulated in these micelles.

2. Liposomes, mentioned earlier, consist of one or more lipid bilayers and an aqueous core. They are differentiated according to their lamellarity and size. Depending on the orientation of the lipid bilayer, liposomes can be used for the delivery of hydrophobic and/or hydrophilic small molecules (see also Fig. 1).

3. Solid lipid nanoparticles (SLNs) are composed of a surfactant shell surrounding a core matrix of solid lipids. They are used for the encapsulation of hydrophobic and/or hydrophilic active ingredients.

4. Nanostructured lipid carriers (NLCs) are also built up from a surfactant shell surrounding a core matrix of solid and liquid lipids. They are used for the encapsulation of hydrophobic and/or hydrophilic substances.

5. Micelles are a self-assembly of lipid monolayers in aqueous solutions. They have a hydrophobic core with the phospholipid tails facing inward. They can be used for encapsulation of small hydrophobic charges.

6. Reverse micelles are an inverted structure compared to traditional micelles. They form a hydrophilic core with the phospholipid tails facing outward. They can be used for encapsulation of small hydrophilic cargoes, such as oligonucleotides in LNPs.

Figure 2: Overview of different LBDD systems (source: Cayman Chemical).