New nanoparticle platform delivers drug pairs for specific cancers

New nanoparticle platform delivers drug pairs for specific cancers

Tel Aviv University researchers have developed a new platform that uses polymeric nanoparticles to deliver drug pairs to specific cancers, including skin cancer and breast cancer. The researchers explain that the therapeutic effect and safety profile of both drugs are significantly enhanced when they arrive at the tumor site together.

The study was led by Prof. Ronit Satchi-Fainaro and graduate student Shani Koshrovski-Michael from the Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, in collaboration with other members of Prof. Satchi-Fainaro's laboratory: Daniel Rodriguez Ajamil, Dr. Pradip Dey, Ron Kleiner, Dr. Yana Epshtein, Dr. Marina Green Buzhor, Rami Khoury, Dr. Sabina Pozzi, Gal Shenbach-Koltin, Dr. Eilam Yeini and Dr. Rachel Blue. They were joined by Prof. Iris Barshack from the Department of Pathology, Faculty of Medicine, Tel Aviv University, Prof. Roey Amir and Shahar Tevet from the Faculty of Chemistry, Tel Aviv University, and researchers from the Israel Institute of Biological Research, Italy. Portugal and the Netherlands. The study was published in the renowned specialist journalScientific advances.

Prof. Satchi-Fainaro explains: "Currently, cancer treatment often involves a combination of several drugs that act synergistically to enhance their anti-cancer effect. However, these drugs differ in their chemical and physical properties - such as their rate of degradation, their circulation time in the bloodstream, etc. Their ability to penetrate and accumulate in the tumor, therefore, do not reach the tumor together and their combined effect is not fully achieved. To ensure maximum effectiveness and minimal toxicity, we have tried the possibility of administering two drugs simultaneously and selectively tumor site without damaging healthy organs.”

The researchers 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's activity. These nanoparticles are selectively directed to the cancer site by binding to sulfate groups that bind to P-selectin, a protein expressed at high levels on cancer cells as well as on new blood vessels formed by cancer cells to supply them with nutrients and oxygen.

The researchers loaded the platform with two FDA-approved drug pairs: BRAF and MEK inhibitors for the treatment of melanoma (skin cancer) with a BRAF gene mutation (present in 50% of melanoma cases) and intended PARP and PD-L1 inhibitors for breast cancer with a BRCA gene mutation or BRCA deficiency. The novel drug delivery system was tested in two environments: in laboratory 3D cancer cell models and in animal models representing both primary tumor types (melanoma and breast cancer) and their brain metastases.

The results showed that the P-selectin-targeting nanoparticles accumulated selectively in primary tumors and did not damage healthy tissue. Furthermore, the nanoparticles successfully penetrated the blood-brain barrier and reached precise metastases in the brain without damaging healthy brain tissue.

Furthermore, combining two drugs administered simultaneously was far more effective than administering the drugs separately, even at doses 30 times lower than in previous preclinical studies. The nanoparticle treatment significantly reduced tumor size, increased the time to progression by 2.5-fold compared to standard treatments, and extended the lifespan of mice treated with the nanoparticle platform. Mice had a twofold higher median survival rate compared to those that received the free drugs and a threefold longer survival rate compared to the untreated control group.

In our study, we developed an innovative platform that uses biodegradable polymer nanoparticles to deliver drug pairs to primary tumors and metastases. We found that drug pairs administered in this manner significantly enhanced their therapeutic effect on BRAF-mutant skin cancers and BRCA-mutant breast cancers and their brain metastases. Because our platform is inherently versatile, it can deliver many different drug pairs that enhance each other's effects, thereby improving the treatment of a variety of primary tumors and metastases that express the P-selectin protein, such as: B. Glioblastoma (brain cancer) and pancreatic ductal adenocarcinoma and renal cell carcinoma.”

Prof. Ronit Satchi-Fainaro, Department of Physiology and Pharmacology, Tel Aviv University Faculty of Medicine

The project received competitive research grants from Fundación “La Caixa”, Melanoma Research Alliance (MRA), Israel Science Foundation (ISF) and Israel Cancer Research Fund (ICRF). It is also part of a broader research effort in Prof. Satchi-Fainaro's laboratory, supported by an Advanced Grant from the European Research Council (ERC), the ERC Proof of Concept (PoC), the EU Innovative Training Network (ITN) and the Kahn Foundation.

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