Lipid Conjugate-Based Delivery Systems

In recent years, oligonucleotide therapeutics have gained a lot of attention, as they can drug the un-druggable targets from the conventional small-molecule perspective. However, poor cellular permeability and susceptibility to nuclease degradation remain a major challenge for the development of oligonucleotide therapeutics. Therefore, efficient delivery system development is necessary for turning oligonucleotides into clinically acceptable therapeutic drugs.

Neutral lipid-oligonucleotide conjugates have become a subject of considerable interest to reduce the risk of immunogenesis while maintaining tolerance to a high dose in vivo^[1]. Oligonucleotides can be chemically conjugated to hydrophobic moieties such as cholesterol, squalene, or fatty acids for enhancing their pharmacokinetic behavior and trans-membrane delivery. With a dedicated technology platform, Alfa Chemistry provides customers with lipid conjugate-based delivery systems for delivering siRNA, ASO, and other oligonucleotide therapeutics.

Synthetic Approaches of Lipid-Oligonucleotide Conjugates

At Alfa Chemistry, there are two major synthetic approaches to lipid-oligonucleotide conjugates: the post-synthetic conjugation approach (or solution-phase approach) and the pre-synthetic conjugation approach (or stepwise solid-phase synthesis approach).

Post-synthetic conjugation approach

When using the post-synthetic conjugation approach, it is necessary to attach specific reactive groups to both oligonucleotides and lipids. The assembly of the oligonucleotides and lipid groups is then obtained after independent synthesis and purification. Generally, to achieve high coupling efficiency, the conjugate group is used in considerable excess which complicates the purification when conjugation is carried out in solution.

Pre-synthetic conjugation approach

When using the pre-synthetic conjugation approach, the lipid-oligonucleotide conjugates are prepared on a single support by assembling the conjugate group through a stepwise process before or after oligonucleotide synthesis and using suitable protecting groups or functional moieties which minimize side reactions. The advantage of the pre-synthetic conjugation approach compared to the post-synthetic conjugation approach is that the purification is more labor-saving. By contrast, on a solid support, the unreacted conjugated group and the possible side products may be removed by simple washing, which markedly facilitates the chromatographic purification after the conjugate is released from the support. The use of a solid support may also help to avoid other problems arising from the limited solubility of one of the reactants.

Example of Lipid Conjugates

At Alfa Chemistry, cholesterol-oligonucleotide conjugates and fatty acid-oligonucleotide conjugates are often used for enhancing the delivery efficiency of oligonucleotide therapeutics.

Cholesterol-Oligonucleotide Conjugates

Most studies have demonstrated that cholesterol-oligonucleotide conjugates were particularly effective at delivering oligonucleotide therapeutics to liver tissue. Hence, hepatic-related disorders would be its ideal target. Some cholesterol-oligonucleotide conjugates were successfully introduced to clinical trials. For example, ARC-520-HBV was the first RNA interference therapeutic for treating hepatitis B virus (HBV).

Fatty Acid-Oligonucleotide Conjugates

Fatty acid is an attractive entity for bioconjugation since it offers hydrophobicity customization and mimics the uncanny composition of the phosphor-lipid membrane. It can be used as an ideal conjugate with the potential to deliver oligonucleotide therapeutics to muscle tissue.

How We Do?

Alfa Chemistry is proficient in the drug delivery technology of oligonucleotide therapeutics and provides solutions to improve the delivery efficiency and security of oligonucleotide therapeutics. You can also order raw materials directly from us for delivery technology research, such as phospholipids, pegylated lipids, cationic lipids, and fluorescent lipids.

Our products and services are for research use only and cannot be used for any clinical purposes.

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