Nanoparticles deliver drugs to kill cancer cells in mice

Researchers have developed a nanomedicine that increases the penetration and accumulation of chemotherapeutic agents in tumor tissue and effectively kills cancer cells in mice.

The study in Scientific advances addresses a limitation of chemotherapy. Although chemotherapy is the primary treatment option for most cancers, much of the drug is rapidly broken down by enzymes in the body or rapidly excreted by the kidneys before it reaches the tumor tissue.

In addition, a large amount of the drug enters the healthy tissue and causes toxic side effects.

To overcome this challenge, a new approach is to package chemotherapy drugs into nanoparticles. These particles, which are so small that they are invisible even under a microscope, can deliver chemotherapy drugs directly to the tumor. While nanomedicine is promising, its ability to incorporate the drug into tumor cells still needs to be significantly improved.

Wenbin Lin, a professor of chemistry at the University of Chicago, is a pioneer in the development of nanoparticles for medical imaging and drug delivery. The new study from his lab reports a novel approach to enhancing the effects of nanomedicine that has proven effective in mice and that the team now hopes to advance into preclinical testing.

Chemotherapy drugs reach tumor cells by crossing from blood vessels into neighboring tumor tissue. However, cancer cells often use nearby blood vessels to invade other tissues, and these hastily formed vessels are often abnormal—they create irregular blood flow patterns and make it difficult for a drug to effectively penetrate tumor tissue.

The researchers looked at a specific signaling pathway called STING, which stands for stimulator of interferon genes. Activating STING disrupts tumor vasculature – the arrangement of blood vessels – and increases the leakiness of blood vessels near the tumor. However, previous attempts to activate STING had not produced the desired results.

The team found a strong antitumor effect with strong inhibition of tumor growth and high cure rates.

Lin and his team developed a tiny polymer that encapsulates both STING and the chemotherapy drug, taking advantage of the unique property of STING activators by releasing them together with chemotherapy drugs. The idea is that activating STING increases the permeability of the blood vessels around the tumor, thereby enhancing the effect of chemotherapy.

“We have discovered a novel way to use STING activators to disrupt tumor vasculature, thereby fundamentally improving drug delivery to tumors without translocating them to other tissues,” says Lin.

“STING activators have not worked particularly well on their own, but I think that by developing nanomedicine, we could make STING activators work alone or in combination, which I think is an important contribution,” says Ralph Weichselbaum, professor and chair of radiation and cellular oncology at the University of Chicago and senior author of the new study.

The research team investigated the antitumor effect of the therapy on several tumor types in mice and found a strong antitumor effect with strong inhibition of tumor growth and high cure rates.

“We found that radiation activates STING like a pathogen due to the double-strand breaks caused by radiation and, importantly, that STING agonists could be useful in cancer therapy,” says Weichselbaum.

The scientists also point out that STING may have other effects besides blood vessel permeability. The STING pathway is activated by invading pathogens such as bacteria, viruses and abnormal DNA from cancer, and triggers an inflammatory response to eliminate unwanted cells. STING activation also increases T cell infiltration and transforms immunologically “cold” tumors into so-called “hot” or inflamed tumors, making them more responsive to immunotherapy agents such as immune checkpoint inhibitors.

“The next steps are to conduct further validation studies and prepare to scale up the technology and hopefully test it in humans,” says Lin.

The work was funded by the National Institutes of Health.

Source: University of Chicago