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Molecular imaging of tumor-infiltrating macrophages in a preclinical mouse model of breast cancer.

Sun X, Gao D, Gao L, Zhang C, Yu X, Jia B, Wang F, Liu Z - Theranostics (2015)

Bottom Line: However, ZA alone did not lead to the inhibition of 4T1 tumor growth.The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs.Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.

View Article: PubMed Central - PubMed

Affiliation: 1. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China;

ABSTRACT
Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206)-targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti-macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.

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Longitudinal in vivo NIRF images (A) and quantified tumor uptake (B) of 4T1 tumor-bearing mice at 24 h after Dye-anti-CD206 injection on days 0, 3, 7, and 11 after zoledronic acid (ZA; 150 μg/kg in PBS daily for 7 days) or PBS treatment (control). Tumors are indicated by the dashed circles. (C-D) Immunofluorescence staining (C) and quantified integrated optical density (IOD) expressed in relative percentages (D) of murine CD206 in 4T1 tumor tissues on days 0, 3, 7, and 11 after ZA or PBS treatment. *, P <0.05; **, P <0.01; ***, P <0.001.
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Figure 4: Longitudinal in vivo NIRF images (A) and quantified tumor uptake (B) of 4T1 tumor-bearing mice at 24 h after Dye-anti-CD206 injection on days 0, 3, 7, and 11 after zoledronic acid (ZA; 150 μg/kg in PBS daily for 7 days) or PBS treatment (control). Tumors are indicated by the dashed circles. (C-D) Immunofluorescence staining (C) and quantified integrated optical density (IOD) expressed in relative percentages (D) of murine CD206 in 4T1 tumor tissues on days 0, 3, 7, and 11 after ZA or PBS treatment. *, P <0.05; **, P <0.01; ***, P <0.001.

Mentions: We performed serial NIRF imaging using Dye-anti-CD206 in the 4T1 tumor-bearing mouse model to determine whether it can be used to dynamically monitor CD206 expression during anti-macrophage therapy using ZA. NIRF scans of both control and ZA-treated 4T1 tumor mice were acquired on days 0, 3, 7, and 11. As shown in Figure 4A, Dye-anti-CD206 showed high-contrast uptake in the control and ZA-treated 4T1 tumors on day 0. With the ZA treatment, the fluorescence intensity of Dye-anti-CD206 in the ZA-treated tumors gradually decreased relative to that of the control tumors. The quantified tumor uptake of Dye-anti-CD206 in the ZA-treated tumors was significantly lower than that in the control tumors on days 3 (5.27 ± 0.86 % vs. 7.22 ± 1.36 %, P <0.05), 7 (5.40 ± 0.69 % vs. 7.63 ± 0.85 %, P <0.01), and 11 (6.27 ± 0.11 % vs. 7.76 ± 0.84 %, P <0.05) (Figure 4B). The lower tumor uptake of Dye-anti-CD206 in the ZA-treated tumors compared to that in the control tumors suggested a decrease in the expression of CD206.


Molecular imaging of tumor-infiltrating macrophages in a preclinical mouse model of breast cancer.

Sun X, Gao D, Gao L, Zhang C, Yu X, Jia B, Wang F, Liu Z - Theranostics (2015)

Longitudinal in vivo NIRF images (A) and quantified tumor uptake (B) of 4T1 tumor-bearing mice at 24 h after Dye-anti-CD206 injection on days 0, 3, 7, and 11 after zoledronic acid (ZA; 150 μg/kg in PBS daily for 7 days) or PBS treatment (control). Tumors are indicated by the dashed circles. (C-D) Immunofluorescence staining (C) and quantified integrated optical density (IOD) expressed in relative percentages (D) of murine CD206 in 4T1 tumor tissues on days 0, 3, 7, and 11 after ZA or PBS treatment. *, P <0.05; **, P <0.01; ***, P <0.001.
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Figure 4: Longitudinal in vivo NIRF images (A) and quantified tumor uptake (B) of 4T1 tumor-bearing mice at 24 h after Dye-anti-CD206 injection on days 0, 3, 7, and 11 after zoledronic acid (ZA; 150 μg/kg in PBS daily for 7 days) or PBS treatment (control). Tumors are indicated by the dashed circles. (C-D) Immunofluorescence staining (C) and quantified integrated optical density (IOD) expressed in relative percentages (D) of murine CD206 in 4T1 tumor tissues on days 0, 3, 7, and 11 after ZA or PBS treatment. *, P <0.05; **, P <0.01; ***, P <0.001.
Mentions: We performed serial NIRF imaging using Dye-anti-CD206 in the 4T1 tumor-bearing mouse model to determine whether it can be used to dynamically monitor CD206 expression during anti-macrophage therapy using ZA. NIRF scans of both control and ZA-treated 4T1 tumor mice were acquired on days 0, 3, 7, and 11. As shown in Figure 4A, Dye-anti-CD206 showed high-contrast uptake in the control and ZA-treated 4T1 tumors on day 0. With the ZA treatment, the fluorescence intensity of Dye-anti-CD206 in the ZA-treated tumors gradually decreased relative to that of the control tumors. The quantified tumor uptake of Dye-anti-CD206 in the ZA-treated tumors was significantly lower than that in the control tumors on days 3 (5.27 ± 0.86 % vs. 7.22 ± 1.36 %, P <0.05), 7 (5.40 ± 0.69 % vs. 7.63 ± 0.85 %, P <0.01), and 11 (6.27 ± 0.11 % vs. 7.76 ± 0.84 %, P <0.05) (Figure 4B). The lower tumor uptake of Dye-anti-CD206 in the ZA-treated tumors compared to that in the control tumors suggested a decrease in the expression of CD206.

Bottom Line: However, ZA alone did not lead to the inhibition of 4T1 tumor growth.The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs.Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.

View Article: PubMed Central - PubMed

Affiliation: 1. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China;

ABSTRACT
Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206)-targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti-macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.

Show MeSH
Related in: MedlinePlus