The development of researchers at Tel Aviv University, which was tested on animals, doubled the therapeutic effectiveness of the drugs and made it possible to reduce by a third the dose of drugs injected into the body * The study was published in a cover article in the prestigious journal Advanced Therapeutics
Researchers at Tel Aviv University, led by Prof. Ronit Sachi-Painero from the Department of Physiology and Pharmacology at the Sackler School of Medicine, have developed an innovative nanotechnology system for drug delivery that significantly increases the effectiveness of melanoma skin cancer treatment and its metastases. The tiny carrier is a biodegradable and safe-to-use polymer called PGA, which consists of repeating units of glutamic acid, and inside it were packed two biological drugs, belonging to families with proven effectiveness in the treatment of melanoma: BRAF inhibitors (daberfenib) and MEK inhibitors (selotinib, approved for use in children with neurofibromatosis type I (NF1 )).
Prof. Sachi-Painero: "One of the well-known problems with biological treatments is the fact that over time the cancer cells develop resistance to the drugs. We assume that by giving two or more treatments, which will attack the cancer cell from different directions, at the same time, in a targeted manner and with great intensity, it is possible to delay and even prevent the development of such resistance."
Doctoral students Yevgeny Pisarvsky, Dr. Rachel Blau and Yana Epstein from the research laboratory of Prof. Sachi-Finero at the Sackler School of Medicine at Tel Aviv University participated in the study. The article was published as a lead article and received a cover in the August 2020 issue of the prestigious journal Advanced Therapeutics.
Prof. Sacchi-Painero: "As part of the research, we sought to solve a common problem related to cocktails: as of today, most oncology treatments are actually cocktails of several drugs; These drugs are given to the patient at the same time, but despite this they do not reach the tumor together - as they differ from each other in their life time in the bloodstream and the time it takes for them to reach the tumor. Therefore, in most cases, the drugs do not work simultaneously, which allows for significant synergy."
To address these challenges, the researchers developed an innovative, biodegradable and efficient drug transport system. They chose two well-known biological drugs for melanoma skin cancer, dabrafenib and selumatinib (which inhibit two different components - BRAF and MEK respectively - in the biological pathway that is damaged and over-activated in melanoma cells) - and asked to launch them together into the tumor using a nanometer carrier. The drug carrier chosen for the task is the polymer PGA, a polymer of glutamic acid, one of the most common amino acids in nature. The carrier was developed in Prof. Sachi-Painero's laboratory, and has previously been successfully tested in animal models in a variety of treatments for pancreatic, breast and ovarian cancer.
In the first stage, the researchers examined the optimal ratio between the two drugs for melanoma, which would allow them to act together in maximum synergy, according to several criteria: level of toxicity, type of toxicity and the mechanism of resistance that the tumor cells develop towards each of the drugs. This is how an optimal ratio is determined, which will ensure maximum efficiency and minimum toxicity. Another significant advantage of the combination of the drugs because of the carrier is a reduced dose, much lower than the dose of each of the drugs when it is given on its own.
In the next step, the researchers adjusted the carrier polymer and the selected drugs through chemical modifications, to enable the connection between them. This integrated system passes through the body in a completely safe manner and does not harm healthy tissues. When it reaches the cancer cells, it meets a protein from the cathepsin family of enzymes, which characterizes cancerous tumors. The protein breaks down the polymer and releases the drugs - which become active and attack the tumor with joint forces. Prof. Sachi-Painero: "It's like putting several passengers in one taxi, and dropping them off at the same address. Everyone arrives at the same destination, at exactly the same time."
Now the researchers tested the innovative treatment on mice in a melanoma model, and produced promising results: the nanometer polymer brought the two drugs to the melanoma tumor and released them there - in an amount 20 times greater than that which reaches the tumor when the drugs are injected as free drugs in a similar dose.
In addition, the therapeutic effect of the drugs that arrived via the carrier was much longer - 2.5-2 times compared to the control groups and the group treated with free drugs, which were injected using the conventional method. According to the researchers, this means that the new platform allows treatment with a much lower dose - about a third of the dose required when the drugs are given in regular cocktails, and the entire treatment is safer and more effective. Also, through the innovative approach, the drugs can be given in a much higher amount than the maximum dose in the existing method, thus further increasing the effectiveness of the treatment.
Prof. Sacchi-Painero: "In our research, we created an innovative system for transporting drugs for the treatment of melanoma, which transports two effective drugs and releases them simultaneously at the tumor site. The treatment has been proven to be more effective and safer than using both drugs when they are free and given as a cocktail. The platform we developed is modular in nature, and it can adapt to a wide range of drugs. We believe that it has tremendous potential, and its possible applications, for the treatment of a huge variety of diseases, are almost endless."
The research was funded by the Israel Cancer Research Fund (ICRF), the (ERC) European Research Council, the Ministry of Health under the EuroNanoMed-II program, the Melanoma Research Alliance, the Kahn Foundation and the Israel Science Foundation.
Link to the research article:
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One response
Wow!
Usually you should remain skeptical about drugs or technologies that have only been tested on mice, but this time it looks very promising.
Prof. Sachi-Painero is steadily establishing her position as one of Israel's prominent young researchers. strength