Periodic Reporting for period 3 - 3DBrainStrom (Brain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines)
Período documentado: 2022-04-01 hasta 2023-09-30
This research project will result in a paradigm shift by generating new preclinical cancer models that bridge the translational gap in cancer therapeutics. I believe that our unique multidisciplinary background2 position us in a perfect state to provide the much needed breakthrough in clinically-relevant anticancer therapies at the nano-scale. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently, the way we prevent and treat cancer.
(a) Tumor spheroids- We created 3D spheroids from 131/4-5B1 melanoma cells with human cerebral microvascular endothelial cells (hCMEC/D3) and human astrocytes. The spheroids were used for invasion assays in matrigel and for internalization kinetics studies of our nanomedicines (Fig 1A).
(b) 3D-printed tumor models- One of our proposed bio-ink formulations is comprised of fibrinogen and thrombin, which form fibrin hydrogel. The stiffness of the hydrogel can be manipulated by changing the initial concentration of gelatin (7.5 15 or 30% w/v) to resemble the physiological stiffness of different tissues such as lung, brain or breast (Fig 1B). Bio-ink formulated with 15% gelatin, which shares the physiological stiffness of the brain, was used to print a 3D brain model (Fig 1C). Exploiting our fibrin hydrogel as bio-ink and the sacrificable pluronic hydrogel, we printed a tumor model composed of tumor cells, brain stroma, and a functional vascular network connected to a microfluidic pump (Fig 1D). The inner surface of the resulting vascular network was coated with endothelial cells, which successfully formed a vascular lumen (Fig 1E-F).