Harnessing the power of synthetic lipids in drug delivery

May 15, 2022 0 By FM

Arun Kedia

In a world where ‘natural’ and ‘organic’ have become synonymous with sustainability, labelling something as ‘synthetic’ seems antithetical. However, from a pharmaceutical perspective, synthetic chemistry has always been a good thing for humanity. It has powered new drug discovery for years. 

Pharmaceutical 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. 

So how do synthetic lipids help with drug delivery?

Lipid-based drug delivery systems possess great potential to deliver drugs and nutrients through various administrative 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. However, working with phospholipids extracted from natural sources is not easy. Due to the presence 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, controlled release drug delivery systems.

Modern synthetic phospholipids can help overcome this hurdle. They are easier to standardize. 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. Because they lack antigenic properties they can also be metabolized 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) and DSPC (DiStearoyl Phosphatidylcholine) among others are usually preferred in lipid-based drug delivery systems.

Synthetic lipids can help build robust 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, the 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 Nanoparticles) are being extensively researched for their potential to be used for replicon-based therapeutics in oncology, protein replacement therapy, and to aid in 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 liver and solid tumours.

The use of synthetic cationic lipids like oxime ether lipids containing hydroxylated head groups is known to be more 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 100nm, these nanoparticles can tide through several bioavailability barriers that are encountered during the treatment phase. 

So why isn’t everyone making synthetic lipids?

Synthetic phospholipids with different polar head groups, fatty acid composition 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 expensive process. However, the advantages of using synthetic phospholipids which has relatively high purity is that the delivery system is relatively more stable with predictable release pattern, and it also allows targeting.

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

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

In India, the government needs to consider introducing schemes and incentives for companies that manufacture synthetic lipid nanocarriers. 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 pharmaceutical industry’s use of synthetic lipids will grow rapidly in the next decade worldwide.

(The author is Managing Director, VAV Life Sciences)