分类： 生物学 >> 生物物理学 >> 影像医学与生物医学工程 提交时间： 2016-05-11
Gao, Duo
Gao, Liquan
Zhang, Chenran
Liu, Hao
Jia, Bing
Wang, Fan
Liu, Zhaofei
Gao, Duo
Gao, Liquan
Zhang, Chenran
Liu, Hao
Jia, Bing
Wang, Fan
Liu, Zhaofei
Zhu, Zhaohui
Wang, Fan
摘要： Integrin alpha v beta 6 is widely upregulated in variant malignant cancers but is undetectable in normal organs, making it a promising target for cancer diagnostic imaging and therapy. Using streptavidin-biotin chemistry, we synthesized an integrin alpha v beta 6-targeted near-infrared phthalocyanine dye-labeled agent, termed Dye-SA-B-HK, and investigated whether it could be used for cancer imaging, optical imaging-guided surgery, and phototherapy in pancreatic cancer mouse models. Dye-SA-B-HK specifically bound to integrin alpha v beta 6 in vitro and in vivo with high receptor binding affinity. Using small-animal optical imaging, we detected subcutaneous and orthotopic BxPC-3 human pancreatic cancer xenografts in vivo. Upon optical image-guidance, the orthotopically growing pancreatic cancer lesions could be successfully removed by surgery. Using light irradiation, Dye-SA-B-HK manifested remarkable antitumor effects both in vitro and in vivo. F-18-FDG positron emission tomography (PET) imaging and ex vivo fluorescence staining validated the observed decrease in proliferation of treated tumors by Dye-DA-B-HK phototherapy. Tissue microarray results revealed overexpression of integrin alpha v beta 6 in over 95% cases of human pancreatic cancer, indicating that theranostic application of Dye-DA-B-HK has clear translational potential. Overall, the results of this study demonstrated that integrin alpha v beta 6-specific Dye-SA-B-HK is a promising theranostic agent for the management of pancreatic cancer. (C) 2015 Elsevier Ltd. All rights reserved.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
Sun, Xianlei
Gao, Duo
Gao, Liquan
Zhang, Chenran
Yu, Xinhe
Jia, Bing
Wang, Fan
Liu, Zhaofei
Sun, Xianlei
Gao, Duo
Gao, Liquan
Zhang, Chenran
Yu, Xinhe
Jia, Bing
Wang, Fan
Liu, Zhaofei
Wang, Fan
摘要： 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.
分类： 生物学 >> 生物物理学 >> 影像医学与生物医学工程 提交时间： 2016-05-05
Zhang, Chenran
Gao, Liquan
Liu, Hao
Gao, Duo
Lai, Jianhao
Jia, Bing
Wang, Fan
Liu, Zhaofei
Zhang, Chenran
Gao, Liquan
Liu, Hao
Gao, Duo
Lai, Jianhao
Jia, Bing
Wang, Fan
Liu, Zhaofei
Cai, Yuehong
Wang, Fan
摘要： Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-alpha CD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-alpha CD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-alpha CD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral micro distribution analysis indicated TAM-specific localization of the IRD-alpha CD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-alpha CD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-alpha CD206 PIT. These results demonstrate the utility of the IRD-alpha CD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics. (C) 2016 Elsevier Ltd. All rights reserved.
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