A team of researchers from Tel Aviv University has developed a revolutionary nanoparticle platform that delivers drug pairs directly to cancer cells and brain metastases, while minimizing damage to healthy cells and doubling patient survival in laboratory models.
Researchers at Tel Aviv University have developed a new polymer nanoparticle platform designed to deliver drug pairs to certain types of cancerous tumors, including skin cancer and breast cancer. The research team explains that the fact that both drugs reach the tumor together significantly increases the therapeutic effect.
Strengthening each other – cancer treatment drugs
The research was led by Prof. Ronit Sachi-Painero and doctoral student Shani Koshrovsky-Michael. From the Department of Physiology and Pharmacology At the Faculty of Medical and Health Sciences, in collaboration with other researchers in Prof. Sachi-Painero's laboratory: Daniel Rodriguez Ajmil, Dr. Pradeep Day, Ron Kleiner, Dr. Jana Epstein, Dr. Marina Green Bozour, Rami Khoury, Dr. Sabina Pozzi, Gal Schenbach-Koltin, Dr. Eilam Yeni and Dr. Rachel Blau; as well as Prof. Iris Barshak From the Department of Pathology At the Faculty of Medical and Health Sciences, Prof. Roy Amir and Shahar Tevet from the school of chemistry at the Faculty of Exact Sciences by Raymond and Burley Sackler, and researchers from the Institute for Biological Research in Ness Ziona, from Italy, Portugal, and the Netherlands. The article was published in the prestigious journal Science Advances.
"Today, the treatment of cancer patients often consists of several different drugs, designed to work together synergistically to enhance the anti-cancer effect. However, the different drugs differ from each other in their chemical and physical properties, such as decomposition time, speed of movement in the bloodstream, and ability to penetrate the tumor. Therefore, even if they are injected into the patient at the same time, they do not reach the cancerous tumor together, and as a result, their combined effect is not fully expressed. To ensure maximum effectiveness, we looked for a way to deliver two different drugs to the tumor simultaneously and in a precise and selective manner - so that they do not harm healthy cells," explains Prof. Sacchi-Painero.
The researchers developed a platform of biodegradable polymeric nanoparticles (which break down into water and carbon dioxide within a month), within which two different drugs can be trapped that enhance each other's action, in order to deliver them together and selectively to the cancerous tumor. To precisely target them to the cancerous tumors, the nanoparticles were attached to sulfate groups that bind to a protein called P-selectin, which - according to previous research in Prof. Sacchi-Painero's laboratory - is overexpressed on cancer cells, as well as on new blood vessels recruited by the cancerous tumors to provide them with nutrients and oxygen.
In the next step, the researchers incorporated two existing FDA-approved drug pairs into the platform: one drug pair (BRAF and MEK inhibitors), which is used to treat melanoma (skin cancer) that carries a mutation in the BRAF gene (50% of all melanoma cases), and a second drug pair (PARP and PD-L1 inhibitors), which is intended to treat breast cancer characterized by a mutation or deficiency of the BRCA gene. The innovative treatment was tested in two different environments: in XNUMXD models of cancer cells in the laboratory, and in laboratory animals as models of both types of primary tumors (melanoma and breast) and their metastases in the brain.
The findings revealed that thanks to the nanoparticles targeting the P-selectin protein, the drug pairs accumulated mainly in the primary tumors, and did not cause damage to healthy tissues in the body. Moreover, the targeted nanoparticles were able to penetrate the blood-brain barrier, and reached the metastases in the brain in a targeted manner and not the healthy brain tissue. It was also found that the effectiveness of the drugs delivered together, directly to the tumors, was significantly higher compared to the drugs administered separately by regular injection, even at a dose 30 times lower than that used in previous preclinical trials. Treatment with nanoparticles significantly reduced the tumor and delayed their development for a period of 2.5 times longer than the regular treatment, and even extended the life of the laboratory animals: the median survival of mice treated with the nanoparticles was 2 times that of mice that received the drugs freely, and 3 times that of the control group, which was not treated at all.
"In our research, we developed an innovative platform of biodegradable polymeric nanoparticles for delivering drug pairs to tumors and metastases. We found that drug pairs delivered in this way significantly increase the therapeutic effect in skin cancer tumors (BRAF type), breast cancer (BRCA type), and their metastases in the brain. Because our platform is inherently multifunctional, it can be used to deliver many different drug pairs that enhance each other, to optimize the treatment of a wide range of primary and metastatic tumors that express the P-selectin protein, such as brain cancer (glioblastoma), pancreatic cancer (pancreatic ductal adenocarcinoma), and renal cell cancer," concludes Prof. Sacchi-Painero.
The project has received competitive research grants from the Spanish bank Fundacion “La Caixa”, the Melanoma Research Alliance (MRA), the National Science Foundation (ISF), and the Israel Cancer Research Foundation (ICRF). It is also part of a larger research project being conducted in Prof. Sacchi-Painero’s laboratory, supported by an Advanced grant from the European Research Council (ERC), an ERC Proof of Concept (PoC), an EU- Innovative Training Networks (ITN), and the Kahn Foundation.
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