Plant cholesterol – The future of lipid-based drug delivery

Over the years, cholesterol has established itself as a critical component in drug delivery systems. It not only stabilizes lipid-based drug delivery systems such as liposomes, lipid nanoparticles, lipospheres, and self-emulsifying systems but also enhances their intracellular delivery and gene transfection capabilities. Additionally, cholesterol also plays a vital role in the formulation of immune-stimulating complexes (ISCOMs) and liposomal adjuvant systems, further underscoring its versatility and significance in advanced drug delivery technologies.  

While cholesterol is undeniably a key player in lipid formulations, effective across various dosage routes and genetic delivery applications, an important question remains: does the source of cholesterol in these systems matter? 

From a chemical point of view, cholesterol is an amphipathic lipid belonging to the class of sterols and consisting of four hydrophobic rings and a hydrophilic hydroxyl moiety. Cholesterol occurs naturally in both plants and animals. 

In animals, cholesterol plays a vital role as a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D. It is also a fundamental structural component of animal cell membranes, constituting about 30% of their composition. Cholesterol provides strength and stability to cell membranes while reducing their permeability. Given its critical role in stabilizing biological membranes, it’s no surprise that cholesterol serves a similarly important function in synthetic systems. In lipid-based drug delivery systems, cholesterol fills gaps between phospholipids, stabilizing membranes and reducing permeability, which is essential for effective drug delivery. 

In plants, cholesterol exists in the form of phytosterols. These compounds share a similar molecular structure with cholesterol but differ slightly in their side chains. Phytosterols play a comparable role to animal cholesterol, in stabilizing plant cell membranes. Despite their similarities, plant-based cholesterol offers unique advantages over its animal-derived counterpart, particularly in the context of lipid-based drug delivery systems and the optimization of nucleic acid transfection. 

Currently, most cholesterol used in industry is sourced from animal materials, typically extracted from lanolin or animal tissues. However, animal-derived cholesterol presents several challenges, especially in fragile formulations. It carries risks of impurities and potential contaminants, which can compromise formulation effectiveness and lead to issues with batch-to-batch consistency during drug manufacturing. 

In contrast, plant-based cholesterol addresses these concerns. It eliminates the risks associated with impurities and contamination from animal sources, offering a cleaner and more consistent alternative. Additionally, plant-based cholesterol can help mitigate lipid shortages, particularly during vaccine production, by ensuring a more reliable and sustainable supply chain.  

As the pharmaceutical industry advances in developing lipid-based drugs, cholesterol will continue to be an indispensable component. The growing demand for a sustainable alternative to ensure consistency, stability, and a reliable supply chain will become increasingly critical for future pharmaceutical applications. 

What is happening in the world of cholesterol and cholesterol-like molecules development?  

Beyond cholesterol

Researchers have long recognized cholesterol’s importance in drug delivery systems, but new studies are revealing even more innovative ways to leverage cholesterol and its analogs. Enhanced transfection potential of cholesterol analogs and the development of a luminescent cholesterol mimic for real-time visualization in living cells are some of the groundbreaking approaches not only improving our understanding of cholesterol’s functions but also opening new possibilities for medical research and therapeutic applications. 

In a study published by ACS Publications titled The Role of Cholesterol and Structurally Related Molecules in Enhancing Transfection of Cationic Liposome−DNA Complexes, it was shown that some Cholesterol-like molecules, called cholesterol analogs, have demonstrated even greater efficiency in transfection than natural cholesterol, opening up exciting possibilities for further research. 

Additionally, scientists are ever advancing towards novel approaches to study even the most complex cellular processes. For example, published by ACS Publications titled Design, Synthesis, and Evaluation of a Luminescent Cholesterol Mimic, a groundbreaking luminescent cholesterol mimic that allows for safer, more efficient, and dynamic visualization of cholesterol behaviour in living cells is showing promising results. This innovative molecule retains cholesterol's biological activity while incorporating a luminescent group, enabling real-time tracking through fluorescence microscopy. The mimic integrates seamlessly into cellular membranes, mimics cholesterol's functions, and provides unambiguous luminescent signals for study. Looking ahead, this work raises new questions at the crossroads of lipid dynamics and cellular biochemistry. And as researchers improve and extend this approach, our ability to examine how cholesterol affects biological processes will guide new discoveries in health and disease.