3D Metastatic Tumor Model Coupled with Targeted mRNA Immunotherapy for the Effective Management of Breast Cancer Brain Metastases

Breast Cancer Brain Metastases (BC-BM) signifies second most common (30%) among all cancers, majorly effecting women population in the age group 45-69, and almost 40% of BC patients have been diagnosed with BC-BM during BC disease conditions. Conventional BC-BM management (chemo + radiotherapy), despite of progression into loco-regional therapies, have showed major limitations for effective management of BC-BM includes blood–brain barrier (BBB) in brain and substantial diagnosis at preliminary stage of disease. In last two decades several pre-clinical and clinical investigations of BC vaccines based on tumour-associated antigens and tumour-specific antigens approaches but none of the has been approved for either treatment or prevention. However, messenger RNA (mRNA)-based vaccination has the potential to expand the responders using targeted lipid nanoparticles (LNP) to counter challenging tumor microenvironment (TME) and BBB obstacles for metastatic tumour. Thus, 3D-METACARE will be focused on the fabrication of targeted LNP-HER2+mRNA immunotherapy decorated with mannose to effectively target Macrophage mannose receptor 1 with improved permeation through BBB and will target BC-BM. Followed by, robust 3D spheroid (cancer cell lines) and organoid (cancer tissues) model of BC and BC-BM, respectively will be established as effective preclinical models for understanding metastatic behaviour of HER2+ cancer and screening of anticancer therapies. Further, in-vitro 3D models will be conjugated with modified Raman spectroscopy techniques (SERS, CARS and SERM) for quantitative determination of the immunotherapeutic impact (T cell analysis) of LNP-mRNA in the ex-vivo BC and BC-BM models and metabolic activities in the native TME. Overall, 3DMETACARE will be novel interdisciplinary (nanotechnology+bioengineering+photonics) platform converging on current EU’s leading cancer research priorities such as early diagnosis and targeted therapeutics.