Periodic Reporting for period 1 - PERSEUS (2D Material-Based Multiple Oncotherapy Against Metastatic Disease Using a Radically New ComputedTomography Approach)
Berichtszeitraum: 2023-03-01 bis 2024-02-29
Cancer is a highly prevalent disease around the world. Europe accounts for a quarter of the world’s cancer cases despite that only a tenth of the world’s population lives there. According to Europe’s Beating Cancer Plan, deaths due to cancer are expected to increase by more than 24% by 2035. New actions and approaches to strengthen cancer prevention, treatment and care are therefore urgently needed.
In conventional cancer treatment, radiation therapy and phototherapy are often preferred over surgery due to their minimally invasive nature. However, radiation therapy, while effective, can harm healthy cells and can lead to severe side effects, including the risk of secondary tumours and organ damage. Additionally, deep-seated tumours pose a challenge for conventional light-based treatments due to limited tissue penetration.
PERSEUS pioneers a ground-breaking approach to treating some of the most challenging and deep-seated cancers, including pancreatic ductal adeno carcinoma, triple-negative breast cancer and colorectal cancers and their metastases. To achieve this goal, PERSEUS develops an innovative nanotechnology-based therapy using a nano-system (NS) that is activated by the low dose and low energy of Computed Tomography (CT) beams. These NSs can enhance soft X-ray radiation absorption (e.g. from the CT) and can locally transform soft X-rays into three simultaneous oncotherapies, highly effective in killing cancer cells: generation of highly reactive chemicals containing oxygen (ROS) that kill cancer cells, increase the sensitivity of tumour cells to radiation interaction with the cell’s DNA (radiosensitization) and increase of local temperature. These processes can break up the integrity of the cell structure by damaging proteins, nucleic acids, lipids, membranes etc., which can lead to activation of cell death processes such as necrosis (death due to factors external to the cell or tissue), and apoptosis (programmed cell death) and slowing down or blocking the DNA replication of the cancer cells.
The NSs are encapsulated into liposomes, tiny synthetic vesicles that serve as delivery vehicles, navigating through the vascular system to specifically target tumour masses.
Unlike conventional methods, low energy/low dose X-rays (e.g. from a CT beam) are used to activate directly the NSs after targeting the tumour. The NSs can reach the tumour site by flowing through the blood system. Hence, it is the NS that contributes to the elimination of cancer cells due to their physico-chemical properties strictly tied to the NS design (contrary to conventional radiotherapy where the elimination of cancer cells is resulting directly from high energy X-ray radiation). Since ROS, radiosensitization and temperature increase are cancerogenic agents whose efficacy does not depend on the cell nature, the therapy is agnostic to the type of cancer and to gender incidence.
The cell death occurs directly into the tumour mass, minimizing damage to healthy tissue and reducing side effects. The treatment can even help the body's immune system to recognize and fight cancer at distal sites from the primary tumour (abscopal effect). The NSs are designed to be biocompatible and inactive in absence of X-ray radiation, thus allowing a safe body clearance (the ability of an organ to purify from a substance in the time unit).
Overall objectives:
- Development of the NSs having the optimal size and the desired X-ray induced physical properties
- Assessment and validation of the NSs design, efficacy and safety through in vitro experiments
- Pre-clinical proof-of-concept of NSs for cancer therapy in in vivo models
- Pre-clinical treatment of metastases
In conventional cancer treatment, radiation therapy and phototherapy are often preferred over surgery due to their minimally invasive nature. However, radiation therapy, while effective, can harm healthy cells and can lead to severe side effects, including the risk of secondary tumours and organ damage. Additionally, deep-seated tumours pose a challenge for conventional light-based treatments due to limited tissue penetration.
PERSEUS pioneers a ground-breaking approach to treating some of the most challenging and deep-seated cancers, including pancreatic ductal adeno carcinoma, triple-negative breast cancer and colorectal cancers and their metastases. To achieve this goal, PERSEUS develops an innovative nanotechnology-based therapy using a nano-system (NS) that is activated by the low dose and low energy of Computed Tomography (CT) beams. These NSs can enhance soft X-ray radiation absorption (e.g. from the CT) and can locally transform soft X-rays into three simultaneous oncotherapies, highly effective in killing cancer cells: generation of highly reactive chemicals containing oxygen (ROS) that kill cancer cells, increase the sensitivity of tumour cells to radiation interaction with the cell’s DNA (radiosensitization) and increase of local temperature. These processes can break up the integrity of the cell structure by damaging proteins, nucleic acids, lipids, membranes etc., which can lead to activation of cell death processes such as necrosis (death due to factors external to the cell or tissue), and apoptosis (programmed cell death) and slowing down or blocking the DNA replication of the cancer cells.
The NSs are encapsulated into liposomes, tiny synthetic vesicles that serve as delivery vehicles, navigating through the vascular system to specifically target tumour masses.
Unlike conventional methods, low energy/low dose X-rays (e.g. from a CT beam) are used to activate directly the NSs after targeting the tumour. The NSs can reach the tumour site by flowing through the blood system. Hence, it is the NS that contributes to the elimination of cancer cells due to their physico-chemical properties strictly tied to the NS design (contrary to conventional radiotherapy where the elimination of cancer cells is resulting directly from high energy X-ray radiation). Since ROS, radiosensitization and temperature increase are cancerogenic agents whose efficacy does not depend on the cell nature, the therapy is agnostic to the type of cancer and to gender incidence.
The cell death occurs directly into the tumour mass, minimizing damage to healthy tissue and reducing side effects. The treatment can even help the body's immune system to recognize and fight cancer at distal sites from the primary tumour (abscopal effect). The NSs are designed to be biocompatible and inactive in absence of X-ray radiation, thus allowing a safe body clearance (the ability of an organ to purify from a substance in the time unit).
Overall objectives:
- Development of the NSs having the optimal size and the desired X-ray induced physical properties
- Assessment and validation of the NSs design, efficacy and safety through in vitro experiments
- Pre-clinical proof-of-concept of NSs for cancer therapy in in vivo models
- Pre-clinical treatment of metastases
During the first year of the project, the PERSEUS team identified the best 2D material candidates for the NS fabrication, and 2D nanoflakes were fabricated with the required size to be incorporated into liposomes. Additionally, the team successfully functionalized them to enhance the NS effectiveness in cancer treatment.
To determine the optimal materials for the NS, theoretical simulations were performed to assess the X-ray absorption rates of the various candidates and therefore to select the material with the highest absorption capacity which is correlated to more effective cancer treatment.
Furthermore, the consortium conducted a preliminary test on ROS generation—one of the three cancer-killing therapies designed for the NS - in cancer cell lines. Remarkably, following NS uptake, human colon adenocarcinoma cells treated with X-ray irradiation exhibited 25-30% more ROS production compared to untreated samples.
The NSs were found to be biocompatible, and no endotoxin contamination was detected. Moreover, NS components were successfully incorporated into lipid nanoparticles using a novel strategy.
Additionally, in the first year an Expert Advisory board was organised to obtain strategic and independent advice and to ensure PERSEUS can have maximum impact for the public benefit.
To determine the optimal materials for the NS, theoretical simulations were performed to assess the X-ray absorption rates of the various candidates and therefore to select the material with the highest absorption capacity which is correlated to more effective cancer treatment.
Furthermore, the consortium conducted a preliminary test on ROS generation—one of the three cancer-killing therapies designed for the NS - in cancer cell lines. Remarkably, following NS uptake, human colon adenocarcinoma cells treated with X-ray irradiation exhibited 25-30% more ROS production compared to untreated samples.
The NSs were found to be biocompatible, and no endotoxin contamination was detected. Moreover, NS components were successfully incorporated into lipid nanoparticles using a novel strategy.
Additionally, in the first year an Expert Advisory board was organised to obtain strategic and independent advice and to ensure PERSEUS can have maximum impact for the public benefit.
In vitro proliferation inhibition of human colon adenocarcinoma cells (HT29) was for the first time proved through effective ROS generation from our NS, under low energy continuous X-ray irradiation, as compared to untreated-unirradiated samples.