Photo by National Cancer Institute/ Unsplash
Tel Aviv University researchers have created a new platform that uses polymeric nanoparticles to deliver paired drugs to specific cancers, including skin and breast cancer. This combined delivery significantly improves both the drugs’ therapeutic effects and their safety.
The study was led by Prof. Ronit Satchi-Fainaro and doctoral student Shani Koshrovski-Michael from the Department of Physiology and Pharmacology at Tel Aviv University’s School of Medicine, in collaboration with other members of Prof. Satchi-Fainaro’s lab: 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 Blau. The study was published in the prestigious journal Science Advances.
“Currently, cancer treatment often involves a combination of multiple drugs that work 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, and their ability to penetrate and accumulate in the tumor,” explained Prof. Satchi-Fainaro. “Therefore, even if multiple drugs are administered simultaneously, they don’t arrive together at the tumor, and their combined effects are not fully realized. To ensure maximal efficacy and minimal toxicity, we sought a way to deliver two drugs simultaneously and selectively to the tumor site without harming healthy organs.”
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The researchers developed biodegradable polymeric nanoparticles (which break down into water and carbon dioxide within one month) capable of encapsulating two different drugs that enhance each other’s activity. These nanoparticles are selectively guided to the cancer site by attaching them 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 melanoma with a BRAF mutation (present in 50% of cases), and PARP and PD-L1 inhibitors for breast cancer with a BRCA mutation or deficiency. Testing in 3D cancer cell models and animal models (representing both primary tumors and brain metastases) showed that the P-selectin-targeted nanoparticles selectively accumulated in primary tumors, sparing healthy tissues. They also successfully crossed the blood-brain barrier to reach brain metastases without harming healthy brain tissue.
Additionally, the combination of two drugs delivered simultaneously was far more effective than administering the drugs separately, even at 30 times lower doses than prior preclinical studies. The nanoparticle treatment significantly reduced tumor size, prolonging time to progression by 2.5 times than standard treatments, and extended the lifespan of mice treated with the nanoparticle platform. Mice had a 2-fold higher median survival compared to those receiving the free drugs and a 3-fold longer survival compared to the untreated control group.
