Chloe Bazile, Julie Bordenave, Saber Amri, Flavien Raynal, Laetitia Ligat, Manon Farcé, Henri Coste, Pascal Clerc, Olivier Sandre, Corinne Bousquet, Vera Pancaldi, Stéphane Mornet, Veronique Gigoux, Mary Poupot
This study highlights the potential of MNP-mAb6-25 as a nanoplatform for selective targeting TAM-containing NSCLC tumors. This nanotechnology tool may lead to the development of new applications: one involving the imaging-based detection of pro-tumoral M2 TAMs by MRI, and the other involving their potential depletion through the application of localized magnetic fields, paving the way for imaging-guided diagnosis and further therapeutic evaluation.
INTRODUCTION: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, particularly due to resistance induced by tumor-associated macrophages (TAMs)-exhibiting a M2-like phenotype-within the tumor microenvironment. The specific targeting of pro-tumoral M2 TAMs constitutes thus a major challenge in anticancer therapies but current strategies lack specificity. We produced and patented a monoclonal antibody, called mAb6-25, that specifically targets M2-like macrophages (M2M) but not M1-like macrophages (M1M) or monocytes. Here, we investigated the conjugation of this antibody on magnetic nanoparticles (MNPs) as a potential nanoplatform for specific M2 TAM targeting.
METHODS: Magnetic iron oxide multicore nanoflowers (NF) were functionalized with a fluorophore allowing their detection and the mAb6-25 for M2 TAM targeting. The M2M targeting by MNP-mAb6-25 was determined, comparatively to M1M, in 2D and 3D in vitro co-culture models with cancer cells by flow cytometry and confocal microscopy analysis, while MNP-mAb6-25 uptake was evaluated by NMR relaxometry. The in vivo M2 TAM targeting was analyzed in a xenograft mouse model of NSCLC by IVIS optical imaging.
RESULTS: We demonstrated that the MNP-mAb6-25 nanoplatform preferentially binds M2M compared to M1M (13-fold higher uptake in M2M) or cancer cells in monoculture as well as in 2D and 3D co-culture models mixing M2M or M1M with A549 NSCLC cells. Moreover, MNP-mAb6-25 internalized and accumulated in the lysosomes of M2M. The efficacy of intravenously injected MNP-mAb6-25 to target NSCLC sub-cutaneous xenografted models containing M2M was subsequently demonstrated.
CONCLUSION: This study highlights the potential of MNP-mAb6-25 as a nanoplatform for selective targeting TAM-containing NSCLC tumors. This nanotechnology tool may lead to the development of new applications: one involving the imaging-based detection of pro-tumoral M2 TAMs by MRI, and the other involving their potential depletion through the application of localized magnetic fields, paving the way for imaging-guided diagnosis and further therapeutic evaluation.