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NANO2021-Nanoteknologi og nye materiale

NANOPARTICLES TO OPTIMIZE THE EFFECTS OF RADIOTHERAPY OF BRAIN TUMORS: MULTI-SCALE MODELING AND EXPERIMENTAL VALIDATION (RXnanoBRAIN)

Alternative title: NANOPARTIKLER FOR Å OPTIMALISERE EFFEKT AV STRÅLETERAPI PÅ HJERNEKREFT: MULTI-SKALA MODELLERING OG EKSPERIMENTELL VALIDERING

Awarded: NOK 3.0 mill.

Glioblastoma multiforme (GBM) is the most difficult type of brain cancer to treat. The challenges are the limitation of irreversible brain damage and the infiltration of cancer cells into the normal tissue, which is the ultimate cause of regrowth. The therapeutic effect can be greatly improved with the help of an image-guided radiation therapy (IGRT). Increased radiation sensitivity based on metal-based nanoparticles attracts significant interest. We will design a new theranostatic (therapeutic and diagnostic) nanoparticle that enables dual-modality (magnetic resonance imaging (MRI) and computed tomography (CT)) tumor imaging and at the same time enhance the effect of the radiation treatment. This allows for more precise tumor localization and reduces the toxicity of surrounding normal tissue. We will demonstrate that the nanoparticles are highly compatible with current CT-guided radiation therapy and new MRI-guided approaches. Using nanomedicine and physics-based modeling and multiscale Monte Carlo simulations, we expect improved treatment effects. Since glioma-associated macrophages (GAMs) may be affected by tumor-derived cytokines and suppress therapeutic immune responses, GAMs involvement in therapeutic response will be characterized. Neuropilin-1 (NRP-1), which is overexpressed by angiogenic endothelial cells, is also implicated in GAM immunopolarization. Using the nanoparticles conjugated to KDKPPR peptide specific for NRP-1, we will characterize vascular, inflammatory and immunological effects.

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Glioblastoma multiforme (GBM) is the most difficult brain cancer to treat. Major challenges are the limitation of irreversible brain damage and the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic ratio can be widely improved using an image-guided radiation therapy (IGRT). Radiosensitization by metal-based nanoparticles attracts significant interests and beyond this, radiotherapy is entering a new era with the emergence of promising clinical concepts for IGRT. We will design a novel theranostic AGuIX® design nanoparticle made of polysiloxane network, gadolinium (Gd) and bismuth (Bi) chelates that enable dual-modality (magnetic resonance (MR) and computed tomography (CT)) tumor imaging and radiation-dose enhancement providing clinicians with more options for precise tumor localization while mitigating toxicity in surrounding healthy tissue. We will demonstrate that the Gd-Bi AGuIX®-based nanoparticles are highly compatible with current CT-guided radiation therapy and emerging MR guided approaches. Using physics modeling and multiscale Monte Carlo simulations, we will provide a progress beyond the state-of-the-art by introducing a novel combination of imaging modalities for IGRT and treatment planning in nanomedicine. As glioma-associated macrophages (GAM) can be influenced by tumor derived cytokines, suppressing adaptive immune responses, their involvement will be characterized. Neuropilin-1 (NRP-1) overexpressed by angiogenic endothelial cells, is also implicated in GAM immune polarization. Using these AGuIX® nanoparticles conjugated to KDKPPR peptide specific to NRP-1, we will characterize vascular, inflammatory, and immunological impacts. As the extracellular matrix (ECM) plays pivotal roles in the infiltrative characteristics of GBM, to characterize the radiosensitization effect, we will evaluate the cell-ECM interactions.

Funding scheme:

NANO2021-Nanoteknologi og nye materiale