The potential treatment has shown efficacy in isolated cells and in animal models using a combination of nanotechnology, chemotherapy and a monoclonal antibody.
Nanostructured lipid carriers containing docetaxel and functionalized with bevacizumab at 100,000x zoom (credit: Leonardo Di Filippo/Unesp)
A transporter that can reach the brain, attach to an aggressive type of tumor known as glioblastoma multiforme and release a chemotherapy drug has been tested for the first time by Brazilian researchers. Second article published outside the journal International Journal of Pharmacy the potential treatment has shown efficacy in isolated cells and in animal models using a combination of nanotechnology, chemotherapy and a monoclonal antibody.
Glioblastoma multiforme, in addition to representing 60% of all brain cancers, is also the most aggressive type. Even with surgery, radiotherapy and conventional chemotherapy, the average patient survival is around 14 months. One reason is that this tumor creates its own blood vessels in an accelerated way to grow – a process known as angiogenesis.
“And because it’s located in the brain, there’s an additional difficulty: getting the drugs across the blood-brain barrier. [estrutura que filtra a passagem de substâncias para o sistema nervoso central] and go see it,” he adds. Leonardo DiFilippo pharmacist-biochemist in the Graduate Program in Pharmaceutical Sciences of the Faculty of Pharmaceutical Sciences of the Universidade Estadual Paulista (Unesp), in Araraquara.
To overcome these challenges, Di Filippo and other researchers from Unesp, the State University of Campinas (Unicamp) and the University of São Paulo (USP) in Ribeirão Preto incorporated docetaxel, a powerful chemotherapy drug, in a nanostructured lipid carrier – a lipid base. that can cross the blood-brain barrier. “We have developed a formulation in which the substances combine in a stable way”, comments Di Filippo.
The professionals also added bevacizumab, a monoclonal antibody already approved for other purposes, which targets endothelial growth factor (VEGF) to this carrier. “It’s the cancerous protein that stimulates angiogenesis and tends to be overexpressed in glioblastoma multiforme,” says Di Filippo. In other words, the proposal was to create a formulation capable of entering the brain, specifically targeting the tumor, and then releasing a chemotherapy drug to destroy it.
“The development of this system, with this app, is an innovation,” says Marlus Chorili professor at Unesp and coordinator of the project, who had Support of FAPESP.
quality testing
Once the nanostructured lipid carrier was created with docetaxel and bevacizumab, researchers began to verify that it met the basic criteria. In the lab, it was found to be 128 nanometers long, enough to cross the blood-brain barrier.
The product was also able to trap 90% of docetaxel and retain 62% of bevacizumab attached to its structure. “These are positive numbers. Within these thresholds, we were able to guarantee adequate therapeutic concentrations,” Di Filippo points out.
The next step was to evaluate the effect of the compound on two glioblastoma cell lines and on healthy cells. Compared to docetaxel alone, the nanocarrier killed five times more cancer cells, without affecting healthy cells.
Among glioblastoma strains, the compound was particularly effective against U87MG, which overexpresses VEGF. Its effect was reduced on A172, which contains less of this protein. “This is a fact that reinforces the ability of our nanocarrier to selectively attack cells with high expression of this protein”, says Di Filippo.
The researchers also verified that the potential drug was able to enter diseased cells and release docetaxel continuously for about 84 hours, suggesting prolonged availability of chemotherapy in the body.
Good results in animals
Using techniques developed by the Unicamp team, mice were inoculated with glioma cells (a type of cancer similar to glioblastoma). After five days, they were divided into six groups: placebo treatment; treatment with docetaxel alone; treatment with the nanocarrier alone, without bevacizumab or docetaxel; nanocarrier treatment with bevacizumab, but without docetaxel; nanocarrier therapy with docetaxel, but without bevacizumab; and nanocarrier therapy with docetaxel and bevacizumab.
After 15 days of therapy, it was noted that the first four groups did not reap the benefits of the therapy. The nanocarrier with docetaxel promoted a 40% reduction in cancer volume in the brain. And, when the compound still contained bevacizumab, this reduction reached 70%. “It’s a very important number for works of this type”, rejoices Chorilli.
The formulation also did not show worse indices of biomarkers such as albumin and creatinine, compared to the use of docetaxel alone. “This indicates that the toxicity has not intensified”, contextualizes Di Filippo.
proceedings
Chorilli points out that, while encouraging, these are the first experiences with the nanostructured lipid carrier in question with this application. “We need to keep moving forward with more studies in single cells and animals,” he reflects. “If research continues to show positive results against glioblastoma multiforme, we could try to find partnerships to carry out clinical trials with volunteers,” he concludes.
The professional adds that this article reinforces the potential of lipid nanocarriers in the fight against malignant tumors. “We can use different combinations, with other monoclonal and chemotherapeutic antibodies, against other strains of cancer”, illustrates Chorilli. “It’s a line of research that probably has many years ahead of it,” he points out.
Chorilli, by the way, is studying similar methods against infections, such as bacteria Helicobacter pylori, which causes gastritis. work has also Support of FAPESP.
The article Targeted delivery of docetaxel in glioblastoma multiforme using bevacizumab-modified nanostructured lipid carriers impairs cell growth in vitro and tumor progression in vivo by Leonardo Delello Di Filippo, Jonatas Lobato Duarte, Juliana Hofstätter Azambuja, Rubia Isler Mancuso, Marcela Tavares Luiz, Victor Hugo Sousa Araújo, Ingrid Delbone Figueiredo, Lucas Barretto-de-Souza, Rafael Miguel Sábio, Estela Sasso-Cerri, Amanda Martins Baviera , Carlos Crestani, Sara Teresinha Ollala Saad and Marlus Chorilli. The text is available here.