This specialized gel could improve cancer therapy

Researchers are now developing a new tool in cancer therapy: a specialized gel that is capable of delivering combination drugs straight to the tumor.

One key problem facing cancer research is how to deliver therapies in the most efficient way, as well as how to target tumors directly, minimize invasiveness, and maximize success.

Chemotherapy uses chemical agents to target and destroy cancer cells — or at least prevent them from multiplying — and it is one of the most widespread treatments for cancer.

Researchers acknowledge that chemotherapy could act more effectively in some cases if it is delivered alongside immunotherapy — a type of treatment focused on boosting the body's own immune system, so that it might reinforce a person's natural barriers against cancer.

Now, scientists based at the University of North Carolina School of Medicine in Chapel Hill and the North Carolina State University in Raleigh have been experimenting with a new injectable medium.

Senior study author Zhen Gu and his colleagues have developed a "bioresponsive scaffold system" — a polymer network, similar to a gel, that when injected delivers a combination of chemotherapy and immunotherapy drugs directly to the cancer tumors.

In the new study, Gu and team tested their injectable gel-like medium on particular types of cancer tumors: B16F10 melanoma and 4T1 breast cancer. However, the researchers are confident that the medium could be used just as successfully on other types of cancer tumors, as well.

The researchers report the results of their study — conducted on a mouse model — in the journal Science Translational Medicine.

Innovative medium for combination therapy

The team started from the premise that, in certain cases, chemotherapy and immunotherapy work better together — particularly if the cancer tumors are exposed to chemotherapy first and then to immunotherapy.

This is because although immunotherapy can be very effective at boosting the immune system response so that it starts to attack cancer cells, the immune system might then also mistakenly target healthy cells.

One type of immunotherapy, for instance, uses drugs called immune checkpoint inhibitors, which "block certain proteins" that are sometimes used by cancer cells as a "shield" against the body's immune response.

When those proteins are blocked, the immune system can once more trigger cell death, killing certain cancer cells.

Immune checkpoint inhibitors deliver improved results when paired with chemotherapy, so Gu and his team developed their bioresponsive scaffolding to be able to hold a combination of chemotherapy and immunotherapy drugs and deliver it straight to primary tumors.

Through its directness, this approach will be more efficient and may help to reduce the impact of the drugs on healthy tissue elsewhere in the body.

A smart therapeutic approach

"We've created a simple method," says Gu, "to use chemotherapy while leveraging the biology of the tumor and our natural defense against foreign invaders to beat back tumor development with limited side effects."

The medium amalgamates into a gel-like substance once injected into the body, delivering the therapeutic agents straight to the targeted tumor.

"The trick is that the gel can be formed quickly inside the body once a biocompatible polymer and its crosslinker are mixed together," explains co-lead study author Jinqiang Wang.

"We made sure that one of these agents can be cleaved apart by reactive oxygen species, or ROS — a natural chemical byproduct of cell metabolism," he adds.

High ROS levels are characteristic of most cancer types, and they are known to play an important role in tumor growth and metastasis.

Therefore, since ROS is abundant in cancer tumors, the gel-like medium — which is designed to fall apart when coming into contact with ROS — would disintegrate, allowing the therapeutic agents to do their work.

Experiments yield promising results

Before injecting it into tumors, the team filled the bioreactive scaffolding with the chemotherapy drug gemcitabine and anti-PD-L1 antibody, which is an immunotherapy agent that blocks the checkpoint protein PD-L1.

This protein is capable of deterring the immune response from triggering the death of cancer cells. When "meeting" the ROS in cancer tumors, the gel would then begin to disintegrate gradually, releasing the chemotherapy agent first, and then the immune checkpoint inhibitor.

"The cytotoxic chemotherapy can first kill some cancer cells and enhance the sensitivity of the tumor toward ICB [immune checkpoint blockade] therapy, which then stimulates the effectiveness of the ICB therapy."

Study co-author Gianpietro Dotti

"With degradation of the gel," he adds, "the ROS level in the tumor site can be reduced, which also helps inhibit tumor growth."

So far, the study's results have shown much promise. When injected at the site of a primary tumor, the gel rendered the tumor's microenvironment more vulnerable to the therapeutic agents.

Moreover, if injected at the site from which a primary tumor had been surgically removed, the drug-loaded gel also seemed to effectively prevent the cancer from recurring.

"Regarding the potential of this approach, scientists should further investigate the biocompatibility of using the gel scaffold for clinical benefit," explains Gu, adding, "Meanwhile, we will optimize the dosages of combination drugs as well as treatment frequencies."