Researchers at Tel Aviv University led by Prof. Ronit Satchi-Fainaro, Department of Physiology and Pharmacology, have developed a new platform using polymer nanoparticles to deliver drug pairs to certain types of cancer tumors, particularly those of the skin and breast. According to the researchers, the fact that the two drugs reach the tumor site together significantly amplifies their therapeutic effect.
The study was carried out by doctoral student Shani Koshrovski-Michael, in collaboration with Dr. Pradip Dey, Dr. Yana Epshtein, Dr. Marina Green Buzhor, Dr. Sabina Pozzi, Dr. Eilam Yeini, Dr. . Rachel Blau, Daniel Rodriguez Ajamil, Ron Kleiner, Rami Khoury, Gal Shenbach-Koltin, from the laboratory of Prof. Satchi-Fainaro; Prof. Iris Barshack from the Department of Pathology, Prof. Roey Amir and Shahar Tevet from the Faculty of Chemistry, as well as researchers from the Israel Institute for Biological Research, Italy, Portugal and the Netherlands. It was published in the prestigious journal Science Advances.
Deliver two medications simultaneously
“Currently, cancer treatment often involves a combination of several drugs that act synergistically to enhance their mutual anticancer effect,” explains Prof. Satchi-Fainaro. “However, these drugs differ in their chemical and physical properties, such as their rate of degradation, their rate of circulation in the bloodstream, and their ability to enter and accumulate in the tumor. Therefore, even if they are administered to the patient simultaneously, they do not reach the tumor together and therefore their combined effect does not find its full expression. To ensure maximum effectiveness, we sought a way to deliver two drugs simultaneously and precisely and selectively to the tumor site, without damaging healthy cells.”
Researchers have developed biodegradable polymer nanoparticles (which break down into water and carbon dioxide within a month) capable of encapsulating two different drugs that enhance each other, with the aim of guiding them together in a precise manner to the cancer site. To do this, these nanoparticles were aggregated with groups of sulfates which have the property of binding to a protein called P-selectin, expressed at high levels in cancer cells, as well as on the new blood vessels that they produce to provide them with nutrients and oxygen.
They then loaded the platform with two pairs of drugs approved by the FDA: inhibitors of the BRAF and MEK genes, used for the treatment of melanoma (skin cancer), containing a mutation in the BRAF gene (present in 50% of cases). melanoma); and inhibitors of PARP and PD-L1 enzymes, intended for the treatment of breast cancer, characterized by a mutation or deficiency of the BRCA gene. The new treatment was tested in two different environments: in 3D cancer cell models in the laboratory, and in animal models presenting both the two types of primary tumors (melanoma and breast cancer), as well as their brain metastases.
A potential improvement in the treatment of a range of cancers
The results showed that the nanoparticles, targeted to the P-selectin protein, accumulated, mainly in primary tumors, without harming healthy tissues. Additionally, they successfully penetrated the blood-brain barrier, reaching metastases in the brain precisely without damaging healthy brain tissue.
In addition, the combination of drugs delivered simultaneously directly to the tumor proved to be much more effective than administering these same drugs separately by conventional injection, even at doses 30 times lower than those in previous pre-clinical trials. Treatment with nanoparticles considerably reduced the size of the tumor, slowing its rate of progression by 2.5 times compared to standard treatments, and extended the lifespan of treated mice: those treated with nanoparticles had a longer survival. median 2 times higher than those who received the drugs independently, and 3 times longer than the untreated control group.
“In our study, we developed an innovative platform using biodegradable polymer nanoparticles to deliver drug pairs to primary tumors and metastases. We found that this way of administering these pairs of drugs considerably improved their therapeutic effect in skin cancers carrying a BRAF mutation and in breast cancers carrying a BRCA mutation, and their brain metastases. Because our platform is versatile by design, it can be used to carry numerous pairs of drugs that enhance each other's effects, thus having the potential to improve the treatment of a range of primary tumors and metastases expressing the P-selectin protein, such as glioblastoma (brain cancer), pancreatic ductal adenocarcinoma and renal cell carcinoma,” concludes Prof. Satchi-Fainaro.
The project won research grants from the Spanish La Caixa Foundation, the Melanoma Research Alliance (MRA), the Israel Science Foundation (ISF) and the Israel Cancer Research Fund (ICRF). It is also part of a larger research project carried out in the laboratory of Prof. Satchi-Fainaro, and funded by Advanced Grant, Proof of Concept and Innovative Training Networks grants from the European Research Council (ERC), and by the Kahn Foundation.
