Scientists are working to improve the world’s most powerful cancer drug

Malignant neoplastic disease (cancer) represents a global public health problem, being the third[1] cause of death, after neurological and cardiovascular diseases. Chemotherapy is one of the key modalities of cancer treatment and the first line of therapy for most types of malignancy, supported by clinical and scientific evidence. In the last decades, there was an improvement in the five-year survival of neoplastic patients, from 40% in 1960 to 60% in the 2000s[2]so it can be stated that for some of the patients, cancer has become a curable disease, and for others a chronic disease, which is why the attention of scientists nowadays is directed towards knowing and trying to prevent the adverse effects of treatments antitumor effects, especially those induced by chemotherapy.

Imagine fourteen mice running around in lab cages, eating, sniffing, and running quietly. You’d never guess that a few weeks ago, half of them received five times the lethal dose of a top chemotherapy drug.

Doxorubicin (DOX) is one of the most effective chemotherapies approved for the treatment of solid tumors.

Scientists originally named the drug “adriamycin” after the Adriatic Sea, as doxorubicin-producing bacteria were originally discovered in the soil of Apulia (Italy), located on the Adriatic coast. The compound was then renamed “doxorubicin”.

However, many people know this drug by its nickname, given by patients and nurses who have a love/hate relationship with this life-saving compound: The Red Devil, with increased secondary toxicity that causes cardiotoxicity , liver toxicity and hair loss in patients undergoing this course of chemotherapy.

Unfortunately, because DOX and other chemotherapies are given intravenously, they often accumulate in non-targeted tissues and organs – leading to a variety of serious health problems for cancer survivors.

“Survivors of childhood cancer are a group at high risk for many serious or life-threatening chronic conditions, including the development of another cancer, cardiovascular and endocrine disease, kidney dysfunction and serious musculoskeletal problems,” said Elizabeth Barker, Professor assistant professor in the Department of Mechanical, Aerospace and Biomedical Engineering (MABE) at the University of Tennessee (UT), in a news release.

According to the researcher, the risk continues to increase for years after chemotherapy is completed.

The Jude Lifetime Cohort Study, published by the American Children’s Research Hospital St. Jude (St. Jude) in 2021, found that 99.9% of children whose tumors are treated with chemotherapy develop chronic health conditions later in life.

“What we need is a way to deliver targeted drugs directly to the tumor site and keep them there,” says Barker.

The American researcher began investigating this idea as a master’s student in UT’s materials science and engineering department, where she began developing a new hydrogel: a hydrophobic polymer that retains its structure after absorbing large amounts of water.

After years of development, the final product is Amygel: an injectable and biodegradable starch hydrogel.

Injecting the tissues with a mixture of Amygel and a chemotherapy drug such as DOX not only improves the distribution of the chemotherapy within the tumor – up to 10 mm from the injection site – but prevents the drug from leaving the tumor.

“Amygel is compatible with many types of medicinal compounds,” explains Barker. “It’s a platform technology that can be used to deliver treatments for a lot of different diseases.”

His research team recently demonstrated the efficacy of the Amygel/DOX delivery system in mice implanted with human pediatric medulloblastoma cells, the most common malignant brain tumor in pediatric patients.

Half of the tumors were injected with a single small but therapeutic dose of 10 microliters (μL) of DOX. The other half tested Amygel’s limits, with the animals receiving a huge amount of DOX, one milligram, about five times the lethal dose for an average mouse.

The results were impressive. At the end of the six-week test, not only were all the mice still alive and showing no side effects from the injection, but each of the Amygel/DOX-treated tumors had shrunk by at least 20 percent, Baker notes.

In fact, more than half of the tumors experienced a complete response, with no cancer cells left alive.

Just as significantly, Barker and his team could find no trace of DOX in off-target tissues or organs in any of the mice.

If this result were repeated in humans, it would eliminate the risk of health complications derived from chemotherapy.

“Amygel allowed us to achieve a complete treatment response with a single 10 μL injection—a fraction of a drop—and no systemic side effects,” said Barker.

With these results in hand, the team worked together with the Lead Discovery Informatics Center (LDI) of St. Jude, which focuses on discovering new drugs and developing them into targeted treatments for pediatric cancer patients.

LDI took the opportunity to test the new drug delivery system and completed its first preclinical experiment with Amygel, which resulted in effective drug delivery without systemic side effects.

The team is planning more experiments, but so far tests with Amygel at an outside lab (drug development company Charles River Laboratories) are equally promising.

In the future, the gel could improve chemotherapy with DOX and other chemotherapeutic agents with increased toxicity, alleviating serious side effects for millions of people around the world dealing with cancer.

[1] A recently published analysis by hundreds of researchers under the auspices of the Institute for Health Metrics and Evaluation (IHME), a reference body for health statistics, indicates that neurological pathologies have taken the place of cardiovascular diseases in the ranking of causes of health problems. global health.

[2] The cardiotoxic potential of cytostatics.