Periodic Reporting for period 2 - HypoSens (Nano-confined photonic system for detection of breast cancer spread to the lymph nodes)
Periodo di rendicontazione: 2018-05-01 al 2019-10-31
HypoSens is strategically designed to offer a minimally-invasive alternative to the Sentinel Lymph Node Biopsy, the current surgical procedure for breast cancer staging.
Cancer metastasis occurs when highly aggressive tumour cells escape from the primary tumour mass and travel through the blood and/or lymphatic systems towards a target organ. In particular, breast cancer metastasis develops mostly via the lymphatic system. The lymph node that is closest to the tumour is called the sentinel lymph node (SLN). Diagnosing the presence of cancerous cells within the SLN is therefore critical for patient stratification, accurate prognosis, and for providing optimum treatment plans.
Currently, the SLN is identified by injecting dyed radionuclide tracers near the tumour. These tracers accumulate in the SLN and are detected visually and/or with a device that detects radioactivity. The sentinel node is removed (SLN biopsy (SLNB)) and checked for cancer cells by histopathological analysis, which can take up to 2 weeks. A negative SLNB result suggests that cancer has not spread to other organs. A positive SLNB result indicates potential metastasis to regional lymph nodes and potentially to other organs. This is considered a strong predictor of recurrences and survival, and help oncologists to diagnose the cancer stage, give some prognostic indications, and define the appropriate treatment schedule.
However, current SLNB procedure is invasive, induces allergies or lymphedema, requires skilled clinical personnel, is quite expensive, and takes about 2 weeks of time to render results. All these facts negatively impact the patients, the oncologists and other health professionals, and the public health system.
The HypoSens prognostic system consists of a minimally-invasive near-infrared (NIR) device able to register signals through the skin, that process data collected by tumour-targeted nanoparticles containing specific sensors able to determine local oxygen (O2) concentration and local temperature (T) distribution in the SLN.
The initial target of the project is metastatic breast cancer, with potential later involvement in other cancer indications via the use of different tumour-targeting moieties.
The technical objectives for the HypoSens project were:
• To design organic molecules to serve as T & O2 sensing tools; and to develop enhanced synthesis, encapsulation and decoration processes to produce necessary amounts of nanoconfined sensors.
• To design, develop, construct, and optimize an ultra-sensitive and time-resolved all-optical ratiometric sensing technique for local T and local O2 level measurement.
• To validate the nanosensors and the photonic device on preclinical in vitro and in vivo tumour xenograft models, and on clinical SLNB ex vivo.
After 36 months of execution, HypoSens project has overcome difficult scientific and technical challenges, being able to fulfil most of the initial goals. Importantly, HypoSens nano-confined sensing system is the first of its kind to simultaneously monitor local T and O2 concentration from a single object after injection in mouse models. Furthermore, the fact that HypoSens employs tumour-targeted technologies opens a wide spectrum for future market applications of the biophotonics imaging system.
Cancer metastasis occurs when highly aggressive tumour cells escape from the primary tumour mass and travel through the blood and/or lymphatic systems towards a target organ. In particular, breast cancer metastasis develops mostly via the lymphatic system. The lymph node that is closest to the tumour is called the sentinel lymph node (SLN). Diagnosing the presence of cancerous cells within the SLN is therefore critical for patient stratification, accurate prognosis, and for providing optimum treatment plans.
Currently, the SLN is identified by injecting dyed radionuclide tracers near the tumour. These tracers accumulate in the SLN and are detected visually and/or with a device that detects radioactivity. The sentinel node is removed (SLN biopsy (SLNB)) and checked for cancer cells by histopathological analysis, which can take up to 2 weeks. A negative SLNB result suggests that cancer has not spread to other organs. A positive SLNB result indicates potential metastasis to regional lymph nodes and potentially to other organs. This is considered a strong predictor of recurrences and survival, and help oncologists to diagnose the cancer stage, give some prognostic indications, and define the appropriate treatment schedule.
However, current SLNB procedure is invasive, induces allergies or lymphedema, requires skilled clinical personnel, is quite expensive, and takes about 2 weeks of time to render results. All these facts negatively impact the patients, the oncologists and other health professionals, and the public health system.
The HypoSens prognostic system consists of a minimally-invasive near-infrared (NIR) device able to register signals through the skin, that process data collected by tumour-targeted nanoparticles containing specific sensors able to determine local oxygen (O2) concentration and local temperature (T) distribution in the SLN.
The initial target of the project is metastatic breast cancer, with potential later involvement in other cancer indications via the use of different tumour-targeting moieties.
The technical objectives for the HypoSens project were:
• To design organic molecules to serve as T & O2 sensing tools; and to develop enhanced synthesis, encapsulation and decoration processes to produce necessary amounts of nanoconfined sensors.
• To design, develop, construct, and optimize an ultra-sensitive and time-resolved all-optical ratiometric sensing technique for local T and local O2 level measurement.
• To validate the nanosensors and the photonic device on preclinical in vitro and in vivo tumour xenograft models, and on clinical SLNB ex vivo.
After 36 months of execution, HypoSens project has overcome difficult scientific and technical challenges, being able to fulfil most of the initial goals. Importantly, HypoSens nano-confined sensing system is the first of its kind to simultaneously monitor local T and O2 concentration from a single object after injection in mouse models. Furthermore, the fact that HypoSens employs tumour-targeted technologies opens a wide spectrum for future market applications of the biophotonics imaging system.
During HypoSens project execution significant results were achieved:
• Several families of metallated sensitizers, substituted perylene-, perylene -derivatives- emitter molecules, and organophosphate bearing unsaturated double bonds, were designed (considering the scattering properties of the surrounding tissue) and synthesised. All of them were optimized for T and O2-sensing, through the triplet–triplet annihilation upconversion (TTA-UC).
• An efficient and reliable method for the encapsulation of the sensing molecules within a biocompatible wax-based matrix was developed, and the decoration of these nanoparticles with tumour-targeting antibodies was optimized.
• A prototype optical device and a controlling software were designed and constructed to detect the emission of the sensing molecules and detect the local T and local O2 levels, thanks to the use of specific calibration curves.
• The integration in the device of the wavefront shaping technology to focus through scattering media was successfully achieved, enhancing the emission detected in vivo through the mouse skin.
• In vitro and in vivo models were set up for the validation of the sensing nanoparticles and the HypoSens device.
• Local T and local O2 sensing in vivo was successfully achieved after injection of the TTA-UC nanoparticles in mouse models.
• Decorated nanoparticles were detected ex vivo in SLNB patient samples with a 100% of sensitivity.
Altogether, the mentioned results allowed continuation of the exploitation and dissemination plans. The possibility of submitting a new patent application is being studied. Additionally, new contacts with potential licensees of the technology have been reinforced and the consortium will keep business conversations with some of them. In parallel, preliminary outcomes, side-ground developments, and results have been disseminated throughout the project development in scientific seminars, congresses, forums, and journals.
• Several families of metallated sensitizers, substituted perylene-, perylene -derivatives- emitter molecules, and organophosphate bearing unsaturated double bonds, were designed (considering the scattering properties of the surrounding tissue) and synthesised. All of them were optimized for T and O2-sensing, through the triplet–triplet annihilation upconversion (TTA-UC).
• An efficient and reliable method for the encapsulation of the sensing molecules within a biocompatible wax-based matrix was developed, and the decoration of these nanoparticles with tumour-targeting antibodies was optimized.
• A prototype optical device and a controlling software were designed and constructed to detect the emission of the sensing molecules and detect the local T and local O2 levels, thanks to the use of specific calibration curves.
• The integration in the device of the wavefront shaping technology to focus through scattering media was successfully achieved, enhancing the emission detected in vivo through the mouse skin.
• In vitro and in vivo models were set up for the validation of the sensing nanoparticles and the HypoSens device.
• Local T and local O2 sensing in vivo was successfully achieved after injection of the TTA-UC nanoparticles in mouse models.
• Decorated nanoparticles were detected ex vivo in SLNB patient samples with a 100% of sensitivity.
Altogether, the mentioned results allowed continuation of the exploitation and dissemination plans. The possibility of submitting a new patent application is being studied. Additionally, new contacts with potential licensees of the technology have been reinforced and the consortium will keep business conversations with some of them. In parallel, preliminary outcomes, side-ground developments, and results have been disseminated throughout the project development in scientific seminars, congresses, forums, and journals.
The HypoSens project will provide an integrated optical imaging device and associated nano-sensors delivering a breast cancer metastasis prognosis solution well into TRL5-6. Its value can be appreciated by considering the inexistence of a non-invasive (or even a minimally invasive) technique in clinical use. HypoSens solves the technological hurdles that previously inhibited the accurate measurement of local T and O2 levels as indicators of breast cancer cells in SLN.
This project has strong potential for breakthrough innovation for the European health care sector and beyond. It will give millions of women an opportunity to have a less painful procedure in the diagnosis and treatment of breast cancer. The ability to provide final diagnosis results immediately will also save the patients anxiety as compared to the current state where they would need to wait many days to get the results for SLNB. Even though luminescence imaging devices are already available on the market this device goes beyond the state of the art by using wavefront shaping to overcome the limits of imaging through scattering tissue and also nano-confinement of the sensing molecules to avoid O2 quenching which kills the phosphorescent triplet state.
The patient, family, health, and economic burdens of metastatic breast cancer are large. Accordingly, one of the biggest benefit of early detection is early treatment, which can help reduce severe, painful symptoms, increase life expectancy and improve outlook.
From a wide adoption of HypoSens, we aim to reduce the annual cancer related economic and social burden. Due to its portable and affordable nature, we aim to provide our cancer prognosis system in a decentralised manner that will ensure widespread accessibility in remote areas where conventional imaging systems/SLNB surgery would not be readily available. The HypoSens device will be the first of its kind to accurately monitor and provide an in-depth insight into the cellular behaviour and progression of metastatic cancers. This development in turn is expected to immensely improve the quality of personalised cancer treatment through patient stratification and personalized medicine.
This project has strong potential for breakthrough innovation for the European health care sector and beyond. It will give millions of women an opportunity to have a less painful procedure in the diagnosis and treatment of breast cancer. The ability to provide final diagnosis results immediately will also save the patients anxiety as compared to the current state where they would need to wait many days to get the results for SLNB. Even though luminescence imaging devices are already available on the market this device goes beyond the state of the art by using wavefront shaping to overcome the limits of imaging through scattering tissue and also nano-confinement of the sensing molecules to avoid O2 quenching which kills the phosphorescent triplet state.
The patient, family, health, and economic burdens of metastatic breast cancer are large. Accordingly, one of the biggest benefit of early detection is early treatment, which can help reduce severe, painful symptoms, increase life expectancy and improve outlook.
From a wide adoption of HypoSens, we aim to reduce the annual cancer related economic and social burden. Due to its portable and affordable nature, we aim to provide our cancer prognosis system in a decentralised manner that will ensure widespread accessibility in remote areas where conventional imaging systems/SLNB surgery would not be readily available. The HypoSens device will be the first of its kind to accurately monitor and provide an in-depth insight into the cellular behaviour and progression of metastatic cancers. This development in turn is expected to immensely improve the quality of personalised cancer treatment through patient stratification and personalized medicine.