Periodic Reporting for period 1 - NanoFEITH (Nanoparticles for Fluorescence-Enhanced Imaging and Therapy of Breast Cancer)
Période du rapport: 2018-06-01 au 2020-05-31
Despite significant medical advances, breast cancer (BC) remains a leading cause of cancer-related death in women worldwide, with approximately 2.1 million cases reported each year worldwide. Triple negative breast cancers (TNBCs) represent around 15-20% of BC tumors and do not express any predictive / therapeutic biological markers. Therefore, for TNBCs, non-targeted chemotherapy is the only treatment option, and although most patients initially respond well to this treatment, most of them relapse with distant metastases. Consequently, there is an imminent need to develop novel targeted strategies for the diagnosis and treatment of TNBC. Nanotechnology offers new promise in mitigating TNBC mortality, through the possibility of combining precise early-stage TNBC diagnosis with more effective and safe treatments, in the same nanostructured device (termed theranostic). The aim of this project was to apply a multidisciplinary approach in order to develop and evaluate a novel multifunctional theranostic nanostructure, which would be able to combine ultra-sensitive fluorescence imaging of TNBC tumours with multimodal cancer treatment.
This project may offer new possibilities for cancer detection, prevention, and treatment. The approach used here, based on fluorescence imaging in the near-infrared wavelength range, promises to enable real-time specific imaging that minimizes the harmful side effects of diagnostic/therapeutic methods used in current practice. The insights provided through this project may be highly transferable to the clinic, with the potential to benefit the quality of life of patients with BC, which is a leading cause of death among women. Novel treatment methods for aggressive BC also have the potential to reduce the burden of healthcare systems in Europe and worldwide, accompanied by financial benefits. The development and evaluation of the multifunctional nanoparticles explored in this project may also provide new opportunities for on-demand therapy and pave the way toward a new era of personalized nanomedicine.
The overall objective of the project was to synthesize nano-engineered particles based on gold (Au) nanobipyramids (AuNBPs) that dramatically improve imaging sensitivity and pave the way for novel high-performance diagnostic devices. Meanwhile, targeted chemotherapeutic drug delivery is integrated in the proposed nanostructures, aiming to optimize drug delivery to tumours and reduce harmful effects to healthy tissues, as well as making the nanostructures suitable for image-guided therapy.
This project may offer new possibilities for cancer detection, prevention, and treatment. The approach used here, based on fluorescence imaging in the near-infrared wavelength range, promises to enable real-time specific imaging that minimizes the harmful side effects of diagnostic/therapeutic methods used in current practice. The insights provided through this project may be highly transferable to the clinic, with the potential to benefit the quality of life of patients with BC, which is a leading cause of death among women. Novel treatment methods for aggressive BC also have the potential to reduce the burden of healthcare systems in Europe and worldwide, accompanied by financial benefits. The development and evaluation of the multifunctional nanoparticles explored in this project may also provide new opportunities for on-demand therapy and pave the way toward a new era of personalized nanomedicine.
The overall objective of the project was to synthesize nano-engineered particles based on gold (Au) nanobipyramids (AuNBPs) that dramatically improve imaging sensitivity and pave the way for novel high-performance diagnostic devices. Meanwhile, targeted chemotherapeutic drug delivery is integrated in the proposed nanostructures, aiming to optimize drug delivery to tumours and reduce harmful effects to healthy tissues, as well as making the nanostructures suitable for image-guided therapy.
In this project, we developed mesoporous silica (MS)-coated gold nanobipyramids (MS-AuNBPs) towards ultrasensitive fluorescence imaging in the near-infrared (NIR) biological window along with targeted TNBC treatment. Our MS-AuNBPs, acting partly as light amplification components, allowed considerable metal enhanced fluorescence of around 14 times for a NIR dye conjugated to their surface, compared to the free dye. Time-resolved fluorescence analysis confirmed the significant increase in the dye’s modified quantum yield, indicating that MS-AuNBPs can considerably increase the brightness of low-quantum-yield NIR dyes. Meanwhile, we tested the chemotherapeutic efficacy of our MS-AuNBPs following loading of the chemotherapeutic, doxorubicin, within the MS pores, and functionalization towards folate receptor-alpha (FRα)-positive cells, as a model TNBC target. We used in vitro fluorescence imaging and viability measurements and found that functionalized particles target FRα-positive cells with significant specificity and have higher potency than free doxorubicin. Finally, using preclinical TNBC murine models, we demonstrated that FRα-targeted particles induce antitumor effects and prolong overall survival to a higher degree than a clinically applied non-targeted nanomedicine (Doxil). Together with their excellent biocompatibility measured in vitro, this project showed that MS-AuNBPs are promising tools to detect and treat TNBCs. Their flexibility to a wide range of fluorophores, therapeutic modalities and targeting agents, highlights their potential clinical utility for high-performance applications against various cancer types.
We have reported the research findings of the project in a manuscript, which has been submitted for publication in a peer-review scientific journal. We also developed a website for the presentation of the project background and results and we have discussed the findings and promise of the project to the general public in 2 events.
We have reported the research findings of the project in a manuscript, which has been submitted for publication in a peer-review scientific journal. We also developed a website for the presentation of the project background and results and we have discussed the findings and promise of the project to the general public in 2 events.
We engineered a new, targeted multifunctional nanostructure that combines Near-Infrared (NIR) metal enhanced fluorescence imaging of triple negative breast cancer cells with local chemotherapeutic drug delivery. This nanostructure consisted of: (i) a plasmonic gold Au nanobipyramids (AuNBP) core that acts as a light amplification component for NIR dyes, (ii) a mesoporous silica (MS) coating around the AuNBPs, serving as a spacer of controlled distance between the AuNBPs and the NIR fluorescent dyes, which is a prerequisite for large fluorescence enhancement. Meanwhile, this MS layer, containing several channel-like nanopores, allows our nanostructures to serve as anticancer-drug carriers, (iii) a surface labelling of the MS layer with the NIR fluorophore DyLight™ 800 (DL800), to investigate its fluorescence enhancement by the AuNBP core, and potential in triple negative breast cancer cell imaging, and (iv) a surface functionalization of the nanostructures with folic acid (FA) for FRα targeting. We showed that dye conjugation to the AuNBPs allows considerable fluorescence enhancement of around 14 times compared to the free dye. Using time-resolved photoluminescence measurements, we also demonstrated a significant increase in the modified quantum yield for DL800 bound to AuNBPs, which illustrates that these particles can considerably increase the brightness of low-quantum-yield NIR dyes and therefore improve their possible performance in clinical applications. In the absence of drug loading, our nanostructures presented excellent biocompatibility in vitro, indicating their suitability for such applications. Furthermore, in vitro fluorescence imaging and viability measurements, showed that FA-functionalized, doxorubicin-loaded particles target FRα-positive cells with significant specificity and reduced their viability more than free doxorubicin. Finally, using preclinical murine tumor models, we illustrated that our FRα targeted particles induce antitumor effects and prolong overall survival in animals, to a higher degree than a clinically applied non-targeted nanomedicine (Doxil).
The results of the project highlighted the potential clinical utility of our targeted multifunctional nanostructure for concomitant imaging/detection and treatment of breast cancer. Furthermore, the high flexibility of our nanostructure to several therapeutic modalities and targeting agents allows for modifications to improve further its potency and efficacy. For instance, in parallel to localized drug delivery, the AuNBP core of our nanostructures could also be used as a photothermal therapy mediator for multimodal treatment of aggressive subtypes of breast cancers. Therefore, further development and clinical testing of the proposed nanostructures could have the potential to lead to improved cancer detection and therapy.
The results of the project highlighted the potential clinical utility of our targeted multifunctional nanostructure for concomitant imaging/detection and treatment of breast cancer. Furthermore, the high flexibility of our nanostructure to several therapeutic modalities and targeting agents allows for modifications to improve further its potency and efficacy. For instance, in parallel to localized drug delivery, the AuNBP core of our nanostructures could also be used as a photothermal therapy mediator for multimodal treatment of aggressive subtypes of breast cancers. Therefore, further development and clinical testing of the proposed nanostructures could have the potential to lead to improved cancer detection and therapy.