Positive Charge Leads to Positive Results: DOTAP and MC3 in Lipid-Polymer Hybrid Nanoparticles

Posted on February 28, 2022


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mRNA therapeutics are being investigated for various diseases such as cancer immunotherapy, protein replacement, and infectious diseases. One of the key benefits of using mRNA compared to non-viral DNA or adeno-associated virus (AAV) gene delivery systems is that mRNA does not have to gain access to the nucleus to undergo transcription. This usually means that protein production is more robust and much faster. mRNA therapy also has a lower risk of mutagenesis and thus has a safer genotoxic profile. Many of our previous articles have described the challenges associated with protecting mRNA in extracellular environments. And, I’m sure you know that lipids have emerged as a highly attractive delivery vehicle for mRNA.

Another attractive delivery system for mRNA is a polymer-based system. Polymer-based systems present certain benefits compared to lipid-based systems most notably their ability to break down into less-toxic constituents. The current drawback to polymer-based systems is their lack of translational efficacy compared to lipid-based systems. So, without further ado, let’s take a look at how Avanti’s DOTAP is being used to deliver mRNA!

How is DOTAP being used?

So, you can use lipids or you can use polymers to deliver mRNA to cells. Why not combine these two systems into a lipid-polymer hybrid (LPH) system and take advantage of the benefits that each provide? That’s exactly what researchers at AstraZeneca did when they created an LPH by using ester terminated poly (lactic-co-glycolic acid) (PLGA), DSPE, DMG-PEG, and either DOTAP, MC3, or DOTAP:MC3 to encapsulate and adsorb mRNA.

This study determined that 1:1 and 3:1 blends of DOTAP:MC3 were most effective for transfection in vivo. In this study, they also found that using either DOTAP or MC3 alone resulted in no transfection. Increasing the amount of DOTAP compared to MC3 resulted in altering the primary organ of expression from liver to spleen. Transgene protein expression in the lung and spleen were detected in significant levels when administered intravenously. When injected intramuscularly, the formulation led to rapid mRNA expression that continued for 9-12 days. The route of administration was also found to affect which type of formulation, adsorbed or encapsulated mRNA, was most effective. In the case of intramuscular administration, encapsulated mRNA formulations outperformed adsorbed mRNA formulations.

There is a long way to go before LPH nanoparticle systems can be used for mRNA therapeutics. This research not only provides key insights for using cationic lipids and ionizable lipids in combination for LPH nanoparticle formulations but also provides a robust and scalable microfluidics processing method that can be translated to the clinical level. We are excited to see our lipids being used in new, innovative ways, and we hope that they continue to improve the lives of people in the future.

To read the full research article, click HERE!

To learn more or buy Avanti’s cationic lipid, DOTAP, just click on it!