Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Theranostics. 2020 Jun 12;10(17):7510-7526. doi: 10.7150/thno.44523. eCollection 2020.
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 and 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. 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 targeting and therapeutic potential was evaluated using αvβ3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvβ3-MI3-PD nanoparticles. 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. 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.
肿瘤相关巨噬细胞（TAMs）促进小鼠肿瘤生长，并与乳腺癌患者预后不良相关。虽然早期的治疗方法试图耗尽所有巨噬细胞，但目前的治疗方法旨在重新编程促肿瘤巨噬细胞（M2）并保留那些对抗肿瘤免疫反应（M1）所必需的巨噬细胞。最近的研究表明，c-MYC（MYC）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。在髓系 MYC KO 小鼠模型中，MYC 在巨噬细胞成熟和功能中发挥重要作用，导致肿瘤生长减少。因此，我们假设将 MYC 抑制剂靶向递送至已建立的 M2 TAMs 中，可以减少乳腺癌模型中向 M2 表型的极化。在这项研究中，我们开发了一种 MYC 抑制剂前药（MI3-PD），用于封装在全氟碳纳米粒子中，该纳米粒子可以通过一种非吞噬作用的机制将药物直接递送到靶细胞的细胞质中。我们之前已经表明，M2 样 TAMs 表达高水平的 vitronectin 受体、整合素β3，并且使用αvβ3 整合素靶向罗丹明标记的纳米粒子（NP）或整合素αvβ3-MI3-PD 纳米粒子评估了靶向和治疗潜力。我们观察到，通过 αvβ3-rhodamine NP 递送的罗丹明通过非吞噬作用和依赖吞噬作用的机制被掺入到 M2 肿瘤促进巨噬细胞中，而 NP 在抑制肿瘤的 M1 巨噬细胞中的摄取几乎完全通过吞噬作用。在乳腺癌小鼠模型（4T1-GFP-FL）中，用αvβ3-MI3-PD NP 治疗显著减少了 M2 样 TAMs。为了验证这种效果不依赖于药物递送至肿瘤细胞，并且是 MYC 抑制剂特异性的，用整合素β3 敲除肿瘤（PyMT-Bo1 β3KO）的小鼠用αvβ3-NP 或αvβ3-MI3-PD NP 治疗。用αvβ3-MI3-PD 纳米颗粒治疗可显著减少 M2 样巨噬细胞，但用αvβ3-NP 治疗则不能。这些数据表明，通过αvβ3-NP 介导的 c-MYC 抑制剂药物递送可以减少促肿瘤 M2 样巨噬细胞，同时保留乳腺癌中的抗肿瘤 M1 样巨噬细胞。
