Synthetic lipids: Paving the path for better drug delivery systems

In a world where ‘natural’ and ‘organic’ have become synonymous with sustainability, labelling a product ‘synthetic’ seems antithetical. From a pharma perspective, however, synthetic chemistry has been transformative for the healthcare of humanity. It has powered new drug discovery for years, preventing epidemics and saving lives.

Pharma breakthroughs today are coming from targeted drug delivery systems based on synthetic lipids. The technology is opening a wide medicinal platform with the potential to deliver a whole range of therapeutics, encompassing genes, RNAs, peptides and diagnostic imaging agents. It is offering hope for improving the therapeutic index, pharmacokinetics, and pharmacodynamics of several drugs.

How do synthetic lipids help with drug delivery?

Lipid-based drug delivery systems possess great potential to deliver drugs, biologics and nutrients through various administration routes due to their biocompatibility, slow-release rate, high stability, and low toxicity. Some of them like Solid Lipid Carriers (SLC) and Nanostructured Lipid Carriers (NLC) are among the most widely studied. These systems are based on phospholipids. Working with phospholipids extracted from natural sources is, however, not easy. Due to the presence of a wide range of unsaturated fatty acids in natural phospholipids, they produce a variety of components in mixed ratios that could vary from batch to batch. The resulting differences in physical, chemical, and biological properties make it difficult to develop robust, reproducible, controlled-release drug delivery systems.

Modern synthetic phospholipids can help overcome this hurdle.

They are easier to standardise, being single, well-defined molecules. Under suitable conditions, they permit a controlled adjustment of physical, chemical, and biological properties especially where more physically stable liposomes with increased stability in blood plasma or phospholipids with more powder-like properties are desired. Since they lack antigenic properties, they can also be metabolised easily in the body. They are less toxic and have a higher degree of solubility, thus making them better candidates for liposomal-based drug delivery systems, especially for parenteral administration and inhalation dosage forms.

Synthetic phospholipids like DOPC (Dioleoyl Phosphatidylcholine), DMPC (Dimyristoyl Phosphatidylcholine), DSPC (Distearoyl Phosphatidylcholine) and DSPG (Distearoyl Phosphatidylglycerol) among others are usually preferred in lipid-based drug delivery systems.

Synthetic lipids can help build improved drug delivery systems

Progress in synthetic lipid nanoparticle-based delivery systems has led to the development of robust drug delivery systems. As seen in the new mRNA-based COVID-19 vaccine delivery systems, synthetic lipid nanoparticles are providing stability throughout the delivery process and helping generate a stronger immunogenic response. The mRNA strand is extremely fragile and susceptible to degradation but when this strand encoded with the key protein is encapsulated in synthetic lipid nanoparticles and used in the vaccine, it is delivered much more efficiently.

Nucleic acid drugs encapsulated in synthetic LNP (Lipid Nano Particles) are being extensively researched for their potential to be used for replicon-based therapeutics in oncology, protein replacement therapy, and to aid gene-editing techniques. The use of ionizable lipids which is the critical component of the LNP helps in determining the potency of the LNP towards target sites and allows for enhanced penetration in the target tissues such as the liver and solid tumours.

The use of synthetic cationic lipids like oxime ether lipids containing hydroxylated head groups is known to be superior siRNA delivery agents and offers hope in the treatment of breast cancer using Small Interfering RNA (siRNA) based gene silencing therapy. Due to their small size, they can easily penetrate the tumour and release the drug in the intracellular space. This target cell site delivery mechanism using LNPs helps in reducing side effects to the surrounding healthy tissues. As the optimum size ranges from 80 nm to 100 nm, these nanoparticles can tide through several bioavailability barriers that are encountered during the treatment phase.

Few of the cationic lipids used in the delivery of solid lipid nanoparticles have no long-term toxicity, biodegradation or biocompatibility data and induce a proinflammatory response.

Why isn’t everyone making synthetic lipids?

Synthetic phospholipids with different polar head groups, fatty acid compositions can be manufactured using various synthesis routes. By varying fatty acids incorporated in the phospholipid, differences in the liposome’s physical properties can be studied but it involves complicated chemistry, complex characterisation as well as elaborate manufacturing techniques. However, the advantage of using synthetic phospholipids which have relatively high purity is that the delivery system is relatively more stable with a predictable release pattern. It also allows targeting. A lot of research is being carried out and it is likely that online libraries will be available soon. This will help to advance the LNP targeting and delivery.

Research and government support will help fully unlock the potential of synthetic lipids

Modifications to liposomal drug delivery systems are constantly investigated to minimise toxicity, increase efficacy, and reduce rapid clearance from the bloodstream. Experimental studies focused on complex multi-functional liposomal formulations are in progress to develop more efficient drug delivery systems.

There currently exist bottlenecks in the clinical translation of synthetic lipid-based drug delivery systems owing to pharmaceutical manufacturing, government regulations, and IP. Quality assurance and costs remain a major challenge. This complex system can be affected by the scalability of the process, the reliability and reproducibility of the final product, the stability of the product and the lack of in-house expertise. IP of liposomal-based drug delivery systems is quite a perplexing challenge and expensive. Clinical trials of liposomal formulations are more complex and time-consuming than chemical formulations.

In India, the government has now introduced schemes and incentives for companies that manufacture synthetic lipid nanocarriers by allocating budgets for the research and development activities of such manufacturers. State-funded research on the effectiveness of liposomal nanotechnology will go a long way in positively providing support to industry and academia as well. With proper support and awareness, there is no doubt that the pharma industry’s use of synthetic lipids will grow rapidly in the next decade worldwide.