טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentEvgeniya Goldman
SubjectTargeting Metastatic Cancer with Nanotechnology
DepartmentDepartment of Biotechnology
Supervisor Professor Schroeder Avi
Full Thesis textFull thesis text - English Version


Abstract

Despite advances in the field of cancer treatment, current therapies are limited once patients have been diagnosed with metastatic cancer. Therefore, targeting metastasis remains an unsolved and important research field. Nanotechnology is a promising candidate for targeting and detecting small clusters of diseased cells in the body. However, fundamental understandings regarding the basic interactions between nanomaterials and metastatic sites are lacking.

Nanotherapeutics offer many potential benefits such as reducing the side-effects of chemotherapeutic agents, protecting the encapsulated drug from degradation, carrying multiple drugs concomitantly and targeting to specific tissues. To date, nanotherapeutics have taken advantage of the enhanced permeability and retention effect (EPR) to target well-vascularized primary tumors. Contrarily, small metastases are usually poorly-vascularized, thereby thought to hinder the use of nanoparticles. Nevertheless, we detected the accumulation of nanoparticles in experimental breast cancer metastasis post intravenous administration.   

In this research program, we aim to study the profile of nanoparticles' biodistribution to metastatic sites and their potential clinical benefits for treating metastatic cancer. To track their biodistribution in vivo, the liposomes were labeled with multi-modal diagnostic agents, including indocyanine green and rhodamine for whole-animal fluorescent imaging, gadolinium for magnetic resonance imaging, and europium for a quantitative biodistribution analysis. Comparing animals bearing only metastasis (simulating a patient after surgery) to animals bearing both metastasis and a primary tumor (simulating a patient before surgery), we noticed that the primary tumor acts as a sink, decreasing the liposomal accumulation in the metastatic tissue. The accumulation of liposomes in the metastases peaked at 24-hours post the intravenous administration, similar to the time they peaked in the primary tumor. The efficiency of liposomal targeting to the metastatic tissue exceeded that of a non-liposomal agent by 4.5-fold.  Liposomes were detected at very early stages in the metastatic progression, including metastatic lesions smaller than 2 millimeters in diameter. Surprisingly, while nanoparticles target breast cancer metastasis, they may also be found in elevated levels in the pre-metastatic niche, several days before metastases are visualized by magnetic resonance imaging (MRI) or histologically in the tissue.

This study highlights the promise of diagnostic and therapeutic nanoparticles for treating metastatic cancer, possibly even for preventing the onset of the metastatic dissemination by targeting the pre-metastatic niche.

We wanted to take the research one step forward, to prepare particles for treating cancer with the emphasis on disease metabolic needs. Specifically to exploit the fact of increased sugar consumption by cancer cells and to prepare nanotherapeutic particles with different carbohydrates on the surface for better targeting. We prepared these particles and tested them in-vitro and in-vivo, and we have learned very important insights regarding this system.

Understanding the interactions between cells, cells receptors and liposomes could help construct optimal liposomal formulations that will improve therapeutic efficiency.