Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages in vitro and in vivo where it regulates the expression of tumor-promoting genes. In a myeloid lineage MYC KO mouse model, MYC had important roles in macrophage maturation and function leading to reduced tumor growth. We therefore hypothesized that targeted delivery of a MYC inhibitor to established M2 TAMs could reduce polarization toward an M2 phenotype in breast cancer models./nMethods: In this study, we developed a MYC inhibitor prodrug (MI3-PD) for encapsulation within perfluorocarbon nanoparticles, which can deliver drugs directly to the cytosol of the target cell through a phagocytosis independent mechanism. We have previously shown that M2-like TAMs express significant levels of the vitronectin receptor, integrin β3, and in vivo targeting and therapeutic potential was evaluated using αvβ3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvβ3-MI3-PD nanoparticles./nResults: We observed that rhodamine, delivered by αvβ3-rhodamine NP, was incorporated into M2 tumor promoting macrophages through both phagocytosis-independent and dependent mechanisms, while NP uptake in tumor suppressing M1 macrophages was almost exclusively through phagocytosis. In a mouse model of breast cancer (4T1-GFP-FL), M2-like TAMs were significantly reduced with αvβ3-MI3-PD NP treatment. To validate this effect was independent of drug delivery to tumor cells and was specific to the MYC inhibitor, mice with integrin β3 knock out tumors (PyMT-Bo1 β3KO) were treated with αvβ3-NP or αvβ3-MI3-PD NP. M2 macrophages were significantly reduced with αvβ3-MI3-PD nanoparticle therapy but not αvβ3-NP treatment./nConclusion: These data suggest αvβ3-NP-mediated drug delivery of a c-MYC inhibitor can reduce protumor M2-like macrophages while preserving antitumor M1-like macrophages in breast cancer.

中文翻译：

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c-myc抑制剂的纳米治疗可靶向乳腺癌巨噬细胞，并保留抗肿瘤巨噬细胞。

肿瘤相关的巨噬细胞（TAM）增强了小鼠的肿瘤生长，并与乳腺癌患者的不良预后相关。虽然早期疗法试图消耗所有的巨噬细胞，但目前的疗法旨在重编程促肿瘤巨噬细胞（M2），并保留抗肿瘤免疫反应（M1）所需的那些巨噬细胞。最近的研究表明，c-MYC（MYC）在体外和体内均在M2巨噬细胞中被诱导，在那里它调节肿瘤促进基因的表达。在骨髓谱系MYC KO小鼠模型中，MYC在巨噬细胞成熟和功能中起重要作用，导致肿瘤生长减少。因此，我们假设在乳腺癌模型中将MYC抑制剂靶向递送至已建立的M2 TAM可以减少朝着M2表型的极化。方法：在这项研究中，我们开发了一种MYC抑制剂前药（MI3-PD），用于包裹在全氟化碳纳米颗粒中，可以通过不依赖吞噬作用的机制将药物直接递送至靶细胞的胞质溶胶。先前我们已经证明M2类TAMs表达大量的玻连蛋白受体，整联蛋白β3，并且使用αvβ3整联蛋白靶向的若丹明标记的纳米颗粒（NP）或整联蛋白αvβ3-MI3-PD纳米颗粒评估了体内靶向和治疗潜力。 n结果：我们观察到由αvβ3-若丹明NP递送的若丹明通过吞噬作用非依赖性和依赖性机制被掺入M2肿瘤促进巨噬细胞，而在抑制M1巨噬细胞的肿瘤中NP摄取几乎完全是通过吞噬作用。在乳腺癌小鼠模型（4T1-GFP-FL）中，αvβ3-MI3-PDNP治疗可显着降低M2类TAM。为了验证这种作用不依赖于药物向肿瘤细胞的递送，而且对MYC抑制剂具有特异性，将整合素β3基因敲除的小鼠（PyMT-Bo1β3KO）用αvβ3-NP或αvβ3-MI3-PDNP处理。αvβ3-MI3-PD纳米粒子治疗可显着减少M2巨噬细胞，但αvβ3-NP治疗则无。 这些数据表明，αvβ3-NP介导的c-MYC抑制剂给药可以减少乳腺癌中的M2类巨噬细胞，同时保留抗肿瘤的M1类巨噬细胞。