Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic 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 (TAM). 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) nanoparticles deplete TAMs in both solid tumor and ascites models of ovarian cancer. As a therapeutic agent, these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to antiangiogenic therapy, (ii) prevent antiangiogenic therapy–induced increases in cancer stem–like cells in both murine and human tumor cell models, (iii) prevent antiangiogenic therapy–induced increases in VEGF-C, and (iv) prevent antiangiogenic therapy–induced BRCA1 gene expression. Combined, this work strongly supports the development of TAM-targeted nanoparticle therapy. Mol Cancer Ther; 17(1); 96–106. ©2017 AACR.

中文翻译：

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靶向肿瘤相关巨噬细胞的纳米粒子疗法的治疗效果

尽管最初受到鼓励，抗血管生成疗法已证明对卵巢癌的益处有限。实验室研究表明，抗血管生成治疗引起的缺氧会导致肿瘤“干性”，因为对抗血管生成治疗的耐药性不断发展并限制了治疗效果。抗血管生成治疗的抗性和肿瘤干性的诱导可能是由促血管生成肿瘤相关巨噬细胞 (TAM) 介导的。因此，TAM 已被提议作为治疗靶点。我们在此证明，卵巢 TAM 表达高水平的叶酸受体 2 (FOLR2)，并且可以使用 G5-树枝状聚合物纳米颗粒将甲氨蝶呤作为配体和毒素进行选择性靶向。G5-甲氨蝶呤 (G5-MTX) 纳米颗粒在实体瘤和卵巢癌腹水模型中消耗 TAM。作为治疗剂，这些纳米颗粒比顺铂更有效。重要的是，这些纳米颗粒可以 (i) 克服对抗血管生成治疗的抵抗，(ii) 防止抗血管生成治疗诱导的小鼠和人类肿瘤细胞模型中癌症干细胞样细胞的增加，(iii) 防止抗血管生成治疗诱导的 VEGF- C, 和 (iv) 阻止抗血管生成治疗诱导的 BRCA1 基因表达。结合起来，这项工作有力地支持了 TAM 靶向纳米颗粒疗法的发展。摩尔癌症治疗; 17(1); 96-106。©2017 AACR。(iv) 防止抗血管生成疗法诱导的 BRCA1 基因表达。结合起来，这项工作有力地支持了 TAM 靶向纳米颗粒疗法的发展。摩尔癌症治疗; 17(1); 96-106。©2017 AACR。(iv) 防止抗血管生成疗法诱导的 BRCA1 基因表达。结合起来，这项工作有力地支持了 TAM 靶向纳米颗粒疗法的发展。摩尔癌症治疗; 17(1); 96-106。©2017 AACR。