Scientists test a library of lipid-based compounds to empower safe RNA drug delivery to Lungs

Scientists test a library of lipid-based compounds to empower safe RNA drug delivery to Lungs


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  • Source: Hokkaido University

  • Date: 30 Jul,2021

Japan’s Hokkaido University researchers created and tested a collection of lipid-based compounds in order to deliver RNA drugs safely and effectively to the lungs. The findings were published in Materials Horizons.

The COVID-19 pandemic response made it all more familiar with RNA vaccines. These vaccines carry genetic code into the cells, which triggers the production of virus protein that triggers our protective immunity. The potential of RNA drugs is great for many other diseases. They can also be used to control the production of protein inside cells. This can be done without inserting or deleting any DNA. Scientists face many challenges when delivering RNA drugs to the right cells. The most successful, but complicated, approach is to carry the RNA codes in nanoparticles that are coated with compounds called targeting ligands. These compounds can bind specific cells. This method has been successful in targeting liver cells.

Hideyoshi Harashima, a Hokkaido University pharmacist, and Toshifumi Satoh, a polymer chemist, led a team of researchers who developed and tested a library of edecalactone-based lipids. These lipids could bypass the liver which degrades foreign substances and toxins. They also deliver RNA code to the lungs. Harashima was recently awarded the Host Madsen Medal by the International Pharmaceutical Federation (FIP), the highest scientific honour.

Two closely related rings-shaped compounds were used by the scientists: e–caprolactone (or e–decalactone). These lactone-containing lipid nanoparticles (NPs), have been shown to accumulate in the lungs. They were then subjected to ring opening reactions with one of 11 amino alcohols. The molecular weights of the resulting products were used to further classify the products. To form mRNA-carrying nuclei, the products were combined with DMG-PEG and mRNA. The team decided to use e-decalactone NPs as they were stable.

The team first tested the ability to deliver RNA-carrying e–decalactone NPs intravenously into mice and into lab cancer cells. To identify the destination of NPs, they used mRNA encoding enhanced light fluorescence protein (EGFP). They found that edecalactone and a linear amino acid called AA03 gave the best results. These investigations revealed that NPs containing this lipomer could largely bypass liver to carry the RNA material directly into the lungs. The NPs were engulfed in the cell membrane, and the RNA was released into the cytoplasmic cells of the lung cells.

We showed that expanding the chemical space of smart materials could enable the fabrication of nanoparticles for hard-to-reach targets without the need for targeting ligands. Designing combinatorial libraries that provide diverse ε-decalactone lipomers could be an easy and scalable strategy for the development of next-generation gene therapies for organs beyond the liver.”

Hideyoshi Harashima, Pharmaceutical Scientist, Hokkaido University

Journal reference:

Abd Elwakil, M.M., et al. (2021) Engineered ε-decalactone lipomers bypass the liver to selectively in vivo deliver mRNA to the lungs without targeting ligands. Materials Horizons.

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