As they grow, solid tumors surround themselves with a thick, hard-to-penetrate wall of molecular defenses. Getting drugs past that barricade is notoriously difficult. Now, scientists at UT Southwestern have developed nanoparticles that can break the physical barriers around tumors to reach cancer cells. Once inside, the nanoparticles release their payload: a gene-editing system that changes the DNA in the tumor, blocks its growth and activates the immune system.
The new nanoparticles, described in Nature Nanotechnology, effectively stopped the growth and spread of ovarian and liver tumors in mice. The system opens up a new avenue for using the gene-editing tool known as CRISPR-Cas9 in cancer treatment, said study leader Daniel Siegwart, Ph.D., an associate professor of biochemistry at UT Southwestern.
“While CRISPR offers a new approach to cancer treatment, the technology is severely hampered by its low efficiency in delivering payloads into tumors,” said Dr. Siegwart, a member of the Harold C. Simmons Comprehensive Cancer Center.
In recent years, CRISPR-Cas9 technology has given researchers a way to selectively edit the DNA in living cells. While the gene editing system has the potential to alter genes that stimulate cancer growth, delivering CRISPR-Cas9 to solid tumors has been challenging.
For over ten years, Dr. Siegwart and his colleagues lipid nanoparticles (LNPs), small spheres of fat molecules that can carry molecular cargo (including recent mRNA COVID-19 vaccines) in the human body. In 2020, Dr. Siegwart sees how to target nanoparticles to specific tissues, which has been a challenge to limit the field.
In the new work, to fight cancer, the researchers started with the nanoparticles they had already optimized to travel to the liver. They added a small piece of RNA (called interfering RNA or siRNA for short) that could turn off focal adhesion kinase (FAK), a gene that plays a central role in keeping the physical defenses of some tumors together.
“Targeting FAK not only weakens the barricade around tumors and makes it easier for the nanoparticles themselves to find their way to the tumor, but also clears the way for immune cells to enter,” said Di Zhang, Ph.D. , a postgraduate study. fellow at UTSW and lead author of the paper.
In the newly designed nanoparticles, the researchers encapsulated CRISPR-Cas9 machines that can edit the gene PD-L1† Many cancers use this gene to produce high levels of the PD-L1 protein, which inhibits the immune system’s ability to attack tumors. Scientists have previously shown that disrupting the PD-L1 gene, in some cancers, can override those brakes and allow a person’s immune system to kill cancer cells.
drs. Siegwart, Zhang and their colleagues tested the new nanoparticles in four mouse models of ovarian and liver cancer. They first showed that by adding siRNA to cap FAK, the matrix of molecules surrounding the tumors was less rigid and easier to penetrate than normal. They then analyzed the tumor cells and found that many more nanoparticles had reached the cells, making the PD-L1 gene.
Finally, they found that tumors in mice treated with the nanoparticles targeting both FAK and PD-L1 shrank to about one-eighth the size of tumors treated with empty nanoparticles alone. In addition, more immune cells invaded the tumors and the treated mice survived on average about twice as long.
More work is needed to demonstrate the safety and efficacy of the nanoparticles in different tumor types. The researchers said the therapy may be useful in combination with existing cancer immunotherapies that aim to use the immune system to attack tumors.
“After the global success of the COVID-19 LNP vaccines, we are all wondering what else LNPs can do. Here we have developed new LNPs capable of delivering multiple types of genetic drugs simultaneously to improve the therapeutic results in There is clearly great potential for LNP drugs to treat different types of diseases,” said Dr. siegwart.
dr. Siegwart is a co-founder and advisor to ReCode Therapeutics, which is licensed for intellectual property from UT Southwestern.