Scientists Develop Lipid Nanoparticles That Can Transport Drugs Past Tumor Defenses

Researchers from UT Southwestern have announced their development of nanoparticles that can help to penetrate barriers around tumors and carry gene-editing drugs to cancer cells.

Genetic Engineering

Tumors are usually hard to get rid of as a result of solid walls around them. They protect themselves with molecular defenses as they increase in size, making it hard for drugs to penetrate.

The nanoparticles in this study can get around the physical barriers and discharge their payload inside tumors. Essentially, they offload gene-editing drugs that specifically edit DNA inside cancer cells, block the growth of tumors, and set off the immune system.

In the study published in the journal Nature Nanotechnology, the novel nanoparticles halted the enlargement and spread of liver and ovarian tumors in mice. Scientists say these offer a better way to make the CRISPR-Cas9 gene-editing technology more effective for cancer treatment.

Challenge of gene editing

CRISPR-Cas9 gene editing has proven to offer a radical approach to the treatment of cancer in recent times. It enables scientists to edit the DNA within living cells selectively.

In spite of how promising this gene-editing tool is for fighting cancer growth, it has proven difficult to deliver a gene-altering payload inside cancer cells. This is a result of the thick molecular shields they protect themselves with.

“Although CRISPR offers a new approach for treating cancer, the technology has been severely hindered by the low efficiency of delivering payloads into tumors,” explained Dr. Daniel Siegwart, an associate biochemistry professor at UT Southwestern who led the study.

The lipid nanoparticles (LNPs) developed in this study offers a means of overcoming that delivery hurdle.

Recruiting nanoparticles

Dr. Siegwart’s team has been exploring and developing LNPs for more than 10 years. These are tiny fatty molecule spheres that can help ferry molecular payloads into the human body. They were used in the highly successful mRNA vaccines for COVID-19.

Two years ago, Dr. Siegwart and his fellow researchers revealed how to guide nanoparticles precisely to defined tissues in the body. This had been a major obstacle to their use until then.

Researchers in this current study designed nanoparticles that would go to the liver. They attached to them short interfering RNA (siRNA) that could switch off the gene called focal adhesion kinase (FAK), which is critical for supporting molecular defenses that protect tumors.

“Targeting FAK not only weakens the barricade around tumors and makes it easier for the nanoparticles themselves to make their way into the tumor, but also paves the way to allow immune cells in,” said Dr. Di Zhang, who is the study’s first author.

The research team put CRISPR-Cas9 inside the novel nanoparticles to target the gene PD-L1. Research has shown that impeding this gene can enable the immune system to deal with some cancer cells. In many cancer forms, the gene is used to drive elevated PD-L1 protein levels and, thus, block the immune system from fighting tumors.

The engineered LNPs were tested in ovarian and liver cancer models in mice. Researchers found that siRNA made tumors more penetrable than usual. As a result, many more nanoparticles found their way to cancer cells to edit the PD-L1 gene.

Results showed that the sizes of tumors in mice that received the modified LNPs reduced to roughly one-eighth of those in mice treated with just placebo nanoparticles. Treated animals lived around two times as long, on average, as more immune cells made their way into tumors.

“After the worldwide success of the COVID-19 LNP vaccines, we are all wondering what else LNPs can do,” Dr. Siegwart said. “Here, we developed new LNPs capable of delivering multiple kinds of generic drugs simultaneously to improve therapeutic outcomes in cancer.”

The Harold C. Simmons Comprehensive Cancer Center member added that LNPs offer a great promise for the treatment of diverse disorders.

However, the team stated that more research is necessary to demonstrate the LNPs’ safety and effectiveness for different tumor types.