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首页> 外文期刊>Molecular cancer therapeutics >HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer
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HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer

机译：HPMA-共聚物纳米载体靶向肿瘤相关的巨噬细胞在原发性和转移性乳腺癌中

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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 tumorbearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the PAlexa647-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. (C) 2017 AACR.
机译：聚合物纳米载体如N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物将药物赋予实体瘤，并避免常规化疗的全身毒性。因为HPMA共聚物可以靶向炎症的位点并积聚在先天的免疫细胞内，因此我们假设HPMA共聚物可以靶向肿瘤相关的巨噬细胞（TAM），在主要和转移性肿瘤微环境中。我们验证了这一假设，首先在体外分离的骨髓巨噬细胞培养物中的初步实验，随后在熟悉的细胞源性表征4T1乳腺癌细胞系中产生的自发性转移鼠乳腺癌模型中。使用我们的标准化实验条件，我们在7天后检测到初级原位肿瘤生长和在立即移植到乳腺脂肪垫的原位移植后28天的转移肿瘤。我们研究了与Alexa Fluor 647和叶酸（P-Alexa647-Fa）和与IRDYE 800CW（P-IRDYE）缀合的HPMA共聚物缀合的HPMA共聚物的摄取，并在其舌内注射进入原发性和转移性阴压症小鼠之后。在这些小鼠的所有原发性和转移性肿瘤部位观察到P-IRDYE的显着摄取，并且PALEXA647-FA信号在CD11b（+）TAM中发现了泛巨噬细胞标记CD68的CD11B（+）TAM。这些发现首次证明了P-Alexa647-Fa缀合物的新能力，以将其在原发性和转移性乳腺肿瘤中与CD11b（+）CD68（+）TAM上的CD11b（+）CD68（+）TAM进行结合。这强调了该HPMA纳米载体的潜力，以提供特异性靶向肿瘤促进巨噬细胞活化和/或极化在肿瘤发育过程中的功能性治疗剂。 （c）2017年AACR。

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  • 来源
    《Molecular cancer therapeutics》 |2017年第12期|共10页
  • 作者

    Zimel Melissa N.; Horowitz Chloe B.; Rajasekhar Vinagolu K.; Christ Alexander B.; Wei Xin; Wu Jianbo; Wojnarowicz Paulina M.; Wang Dong; Goldring Steven R.; Purdue P. Edward; Healey John H.;

  • 作者单位

    Mem Sloan Kettering Canc Ctr Dept Surg Orthopaed Serv 1275 York Ave New York NY 10065 USA;

    Mem Sloan Kettering Canc Ctr Dept Surg Orthopaed Serv 1275 York Ave New York NY 10065 USA;

    Mem Sloan Kettering Canc Ctr Dept Surg Orthopaed Serv 1275 York Ave New York NY 10065 USA;

    Hosp Special Surg 535 E 70th St New York NY 10021 USA;

    Univ Nebraska Med Ctr Dept Pharmaceut Sci Omaha NE USA;

    Univ Nebraska Med Ctr Dept Pharmaceut Sci Omaha NE USA;

    Sloan Kettering Inst Dept Canc Biol &

    Genet New York NY USA;

    Univ Nebraska Med Ctr Dept Pharmaceut Sci Omaha NE USA;

    Hosp Special Surg 535 E 70th St New York NY 10021 USA;

    Hosp Special Surg 535 E 70th St New York NY 10021 USA;

    Mem Sloan Kettering Canc Ctr Dept Surg Orthopaed Serv 1275 York Ave New York NY 10065 USA;

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  • 正文语种 eng
  • 中图分类 肿瘤学;
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