Therapeutic Impact of Nanoparticle Therapy Targeting Tumor Associate Macrophages

Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) Nps deplete tumor associated macrophages in both solid tumor and ascites models of ovarian cancer. As a therapeutic these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to anti-angiogenic therapy, (ii) prevent antiangiogenic therapy induced increases in cancer stem-like cells in both murine and human tumor cell models, and (iii) prevent anti-angiogenic therapy induced increases in VEGF-C (iv) prevent anti-angiogenic therapy induce BRCA1 gene expression. Combine this work strongly supports the development of TAM targeted nanoparticle therapy.

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