Combination of three technologies makes potential treatment effective against aggressive brain tumors

A drug carrier capable of reaching the brain, attaching to an aggressive type of tumor called glioblastoma multiforme and releasing a chemotherapeutic agent has been tested for the first time by Brazilian researchers.

According to an article published in the International Journal of Pharmacythe potential treatment has been shown to be effective in isolated cells and animal models through a combination of nanotechnology, chemotherapy and a monoclonal antibody.

Glioblastoma multiforme accounts for 60% of all brain tumors in adults and is also the most aggressive type of brain cancer. Even after surgery, radiotherapy and conventional chemotherapy, patient survival averages about 14 months. One of the reasons is angiogenesis, a process by which the tumor rapidly creates its own blood vessels in order to grow.

Another difficulty is the blood-brain barrier, which prevents drugs from reaching the tumor.”


Leonardo Di Filippo, PhD student and researcher, Araraquara School of Pharmaceutical Sciences, São Paulo State University

To address these challenges, Di Filippo worked with fellow researchers from UNESP and two other Brazilian institutions, the University of Campinas (UNICAMP) and the University of São Paulo (USP) in Ribeirão Preto, to combine docetaxel , a potent chemotherapeutic agent, with a nanostructured lipid carrier designed to cross the blood-brain barrier. “We developed a formulation in which the substances were stably combined,” he said.

The researchers also paired the transporter with bevacizumab, a monoclonal antibody developed against vascular endothelial growth factor (VEGF) and approved for other uses. “VEGF is the cancer protein that stimulates angiogenesis and tends to be overexpressed in glioblastoma multiforme,” Di Filippo explained. The goal was to create a formulation capable of entering the brain and releasing a chemotherapy drug to destroy the tumor.

“Developing this system with this app is an innovation,” said Marlus Chorili, a UNESP professor and principal investigator of the FAPESP-supported project.

Quality testing

After creating the nanostructured lipid carrier with docetaxel and bevacizumab, the researchers set out to ensure that it met certain basic criteria. Laboratory tests showed its size to be 128 nanometers, small enough to cross the blood-brain barrier. In addition, the entrapment of docetaxel was 90% and the coupling efficiency of bevacizumab was 62%. “These are positive numbers, sufficient to ensure adequate therapeutic concentrations,” Di Filippo said.

The next step was to evaluate the effects of the compound on two glioblastoma cell lines and healthy cells. The nanocarrier eliminated five times more cancer cells than docetaxel alone without affecting healthy cells. It was particularly effective against U87MG, a glioblastoma cell that overexpresses VEGF, but less so against A172, which expresses relatively little VEGF. “These results show that our nanocarrier selectively attacks cells that express a lot of VEGF,” Di Filippo said.

The researchers also found that the potential drug was able to enter cancer cells and release docetaxel continuously for around 84 hours, suggesting prolonged availability of the chemotherapy drug in the body.

Good results in animals

Using techniques developed by the UNICAMP team, rats were inoculated with glioma cells (glioma is a type of cancer similar to glioblastoma). Five days later, they were divided into six groups: treatment with placebo; docetaxel alone; nanocarrier alone, without bevacizumab or docetaxel; nanocarrier and bevacizumab, without docetaxel; nanocarrier and docetaxel, without bevacizumab; nanocarrier with docetaxel and bevacizumab.

After 15 days, the first four groups turned out not to have benefited from the treatment. In the fifth group (nanocarrier with docetaxel) and the sixth group (nanocarrier with docetaxel and bevacizumab), the tumor volume was reduced by 40% and 70% respectively. “These are significant numbers for trials of this type,” Chorilli said.

The researchers also found that the formulation did not cause any deterioration in levels of biomarkers such as albumin and creatinine compared to using docetaxel alone. “It shows that the toxicity has not been intensified,” Di Filippo explained.

Next steps

According to Chorilli, the results were positive but these were the first experiences with the nanostructured lipid carrier for this specific application. “We need to conduct more studies using isolated cells and animals. If the results against glioblastoma multiforme remain good, we could try to find partners for clinical trials with human volunteers,” he said. .

The study reported in the article highlighted the potential of lipid nanocarriers in the treatment of brain cancer, he added: “We can use different combinations with other monoclonal antibodies and chemotherapy drugs against other types of cancer. Many years will undoubtedly be needed to complete this research. .”

Chorilli is studying similar methods for treating infections, such as gastritis and other illnesses caused by the bacteria Helicobacter pyloriin research also supported by FAPESP.

Source:

Journal reference:

DiFilippo, L, D., et al. (2022) Targeted delivery of docetaxel glioblastoma multiforme using bevacizumab-modified nanostructured lipid transporters alters in vitro cell growth and tumor progression in vivo. International Journal of Pharmacy. doi.org/10.1016/j.ijpharm.2022.121682

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