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Despite advances in cancer therapy, treating cancer after it has metastasized remains an unmet clinical challenge. Parallelly, medical nanotechnologies promise targeting precision that are unattainable using systems of larger scale. In this CIG grant we merged both fields of cancer medicine and nanotechnology, to provide new therapeutic capabilities and expand the scientific state-of-the-art. Specifically, we studied the nano-structural parameters that will enable nanoparticles to target and treat metastatic lesions.
This study involved developing new research tools for detecting nanoparticles in extremely small tissue samples, and even in single cells.
To facilitate the study, I established, with the support of the CIG, a new research group for Targeted Drug Delivery and Personalized Medicine at the Department of Chemical Engineering, Technion – Israel Institute of Technology. The research team is composed undergraduate and graduate students, together with postdoctoral fellows. The students come from various scientific disciplines, including chemistry, biology, engineering and medicine. They are balanced by gender, religion, and socioeconomic backgrounds. Together, our vibrant group attracts international students from Europe, United States and the Far East.
Especially, due to the unique nanoparticle fabrication and detection technologies developed in the team, we host many visiting students, teaching them our techniques.

In this CIG grant we demonstrated (Aim 1) that 100-nm liposomes target triple-negative murine breast-cancer metastases post intravenous administration. Metastatic breast cancer was induced in BALB/c-mice either experimentally, by a tail vein injection of 4T1 cells, or spontaneously, after implanting a primary tumor xenograft. To track their biodistribution in vivo the liposomes were labeled with multiple diagnostic agents, including indocyanine green for whole-animal IVIS imaging, Gadolinium for magnetic resonance imaging, and Europium for quantitative biodistribution analysis. The accumulation of liposomes in the metastases peaked at 24-hours post the intravenous administration, similarly to the time they peaked in the primary tumor.
Liposomes were detected at very early stages in the metastatic progression, including metastatic lesions smaller than 2 millimeters in diameter (Aim 2). Surprisingly (unexpected results), nanoparticles were found in elevated levels even in the pre-metastatic niche, several days before metastases were visualized by MRI or histologically in the lungs.
We then studied the potency of different drugs (Aim 3) in the primary tumor versus the metastasis. Metastatic cells are known to differ from cells of the primary tumor in their ability to colonize in new tissue sites. However, their sensitivity to medicine, in comparison to the primary tumor remains unknown. We found that the metastatic cells are more resistant to medication in comparison to the cancer cells of the primary tumor. Furthermore, metastases located in different tissues are responsive to different medications.
This CIG study elucidated that nanoparticles target breast cancer metastasis, making them promising modalities for diagnosing and treating the metastatic disease. We are continuing the research trajectory the CIG helped establish with a goal of becoming a significant contributor to this emerging research field.
The results of this research program were disseminated in multiple ways: research papers, lectures in conferences, lectures to the general public, and press releases in the written and televised media. Altogether, this research program has been extremely visible to the professional and general public.

Project planning and status – this program has successfully achieved its goals as set originally. The timing and budget were tailored for the needs of the project.
• One main goal of the CIG is reintegration – from this perspective the grant enabled me to hire talented personnel and also support some of my salary. This very much helped me and my family to return to the EU-affiliated country and establish this new line of research.
• Gender – the lab I established with the help of the CIG is balanced by gender, creating a professional environment in which diversity promotes scientific excellence.
The CIG program is a wonderful platform for supporting early stage researchers. The resources can be used for personnel and experimental expenses, and enabled me to attain the next grants I needed for supporting our research.
The officers of the CIG program are accessible and helpful.
I would like to take this opportunity to thank all those involved in facilitating this generous grant.
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