Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701–10. ©2017 AACR.

中文翻译：

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HPMA-共聚物纳米载体靶向原发性和转移性乳腺癌中的肿瘤相关巨噬细胞

N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物等聚合物纳米载体将药物递送至实体瘤并避免常规化疗的全身毒性。因为 HPMA 共聚物可以靶向炎症部位并在先天免疫细胞内积累，我们假设 HPMA 共聚物可以靶向原发性和转移性肿瘤微环境中的肿瘤相关巨噬细胞 (TAM)。我们首先在体外分离骨髓巨噬细胞培养物的初步实验中验证了这一假设，随后在由成熟的、细胞遗传学特征的 4T1 乳腺癌细胞系生成的自发转移性鼠乳腺癌模型中验证了这一假设。使用我们标准化的实验条件，我们在 4T1 细胞原位移植到乳腺脂肪垫后第 7 天检测到原发性原位肿瘤生长，并在第 28 天检测到转移性肿瘤。我们研究了与 Alexa Fluor 647 和叶酸 (P-Alexa647-FA) 结合的 HPMA 共聚物以及与 IRDye 800CW (P-IRDye) 结合的 HPMA 共聚物在眶后注射到原发和转移性荷瘤小鼠后的吸收。在这些小鼠的所有原发性和转移性肿瘤部位都观察到 P-IRDye 的显着吸收，并且在与泛巨噬细胞标记物 CD68 共染色的 CD11b+ TAM 中发现了 P-Alexa647-FA 信号。这些发现首次证明了 P-Alexa647-FA 偶联物在原发性和转移性乳腺肿瘤中与 CD11b+CD68+ TAM 共定位的新能力。这强调了这种 HPMA 纳米载体在提供功能疗法方面的潜力，这些疗法专门针对肿瘤发展过程中促进肿瘤的巨噬细胞活化和/或极化。摩尔癌症治疗; 16(12); 2701-10。©2017 AACR。