Dataset Information

Targeted Imaging of Tumor-Associated Macrophages by Cyanine 7-Labeled Mannose in Xenograft Tumors.

ABSTRACT: Mannose receptor is considered as a hallmark of M2-oriented tumor-associated macrophages (TAMs), but its utility in TAMs was rarely reported. Therefore, deoxymannose (DM), a high-affinity ligand of mannose receptor, was labeled with near-infrared dye cyanine 7 (Cy7), and its feasibility of targeted imaging on TAMs was evaluated in vitro and in vivo. The Cy7-DM was synthesized, and its binding affinity with induced TAMs in vitro, whole-body imaging in xenograft tumor mouse model in vivo, and the cellular localization in dissected tissues were evaluated. We demonstrated a high uptake of Cy7-DM by induced M2 macrophages and TAMs in tumor tissues. In vivo near-infrared live imaging visualized abundant TAMs in tumor lesions instead of inflammatory sites by Cy7-DM imaging, and the quantity of Cy7-DM signals in tumors was significantly higher than that shown in inflammatory sites from 1 to 8 hours of imaging. Our results suggest that mannose could rapidly and specifically target TAMs and is a promising candidate for targeted diagnosis of tumor with rich TAMs.

SUBMITTER: Jiang C

PROVIDER: S-EPMC5470129 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Targeted Imaging of Tumor-Associated Macrophages by Cyanine 7-Labeled Mannose in Xenograft Tumors.

Jiang Chong C Cai Huawei H Peng Xiaodong X Zhang Ping P Wu Xiaoai X Tian Rong R

Molecular imaging 20170101

Mannose receptor is considered as a hallmark of M2-oriented tumor-associated macrophages (TAMs), but its utility in TAMs was rarely reported. Therefore, deoxymannose (DM), a high-affinity ligand of mannose receptor, was labeled with near-infrared dye cyanine 7 (Cy7), and its feasibility of targeted imaging on TAMs was evaluated in vitro and in vivo. The Cy7-DM was synthesized, and its binding affinity with induced TAMs in vitro, whole-body imaging in xenograft tumor mouse model in vivo, and the ...[more]

PMID: 28654380

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Project description:UNLABELLED:Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)-facilitated TAM PET imaging in a breast cancer model. METHODS:Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide (89)Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. (89)Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate (89)Zr-PL-HDL and (89)Zr-AI-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of (89)Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry. RESULTS:The phospholipid- and apoA-I-labeled rHDL were produced at 79% ± 13% (n = 6) and 94% ± 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 percentage injected dose per gram for apoA-I- and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and 39.5% of the total cellular DiO@Zr-PL-HDL and DiO@Zr-AI-HDL in tumors, respectively. CONCLUSION:We have developed (89)Zr-labeled TAM imaging agents based on the natural nanoparticle rHDL. In an orthotopic mouse model of breast cancer, we have demonstrated their specificity for macrophages, a result that was corroborated by flow cytometry. Quantitative macrophage PET imaging with our (89)Zr-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment.

Project description:Tumor-associated macrophages (TAMs) are widely implicated in cancer progression, and TAM levels can influence drug responses, particularly to immunotherapy and nanomedicines. However, it has been difficult to quantify total TAM numbers and their dynamic spatiotemporal distribution in a non-invasive and translationally relevant manner. Here, we address this need by developing a pharmacokinetically optimized, 64Cu-labeled polyglucose nanoparticle (Macrin) for quantitative positron emission tomography (PET) imaging of macrophages in tumors. By combining PET with high-resolution in vivo confocal microscopy and ex vivo imaging of optically cleared tissue, we found that Macrin was taken up by macrophages with >90% selectivity. Uptake correlated with the content of macrophages in both healthy tissue and tumors ( R2 > 0.9) and showed striking heterogeneity in the TAM content of an orthotopic and immunocompetent mouse model of lung carcinoma. In a proof-of-principle application, we imaged Macrin to monitor the macrophage response to neo-adjuvant therapy, using a panel of chemotherapeutic and γ-irradiation regimens. Multiple treatments elicited 180-650% increase in TAMs. Imaging identified especially TAM-rich tumors thought to exhibit enhanced permeability and retention of nanotherapeutics. Indeed, these TAM-rich tumors accumulated >700% higher amounts of a model poly(d,l-lactic- co-glycolic acid)- b-polyethylene glycol (PLGA-PEG) therapeutic nanoparticle compared to TAM-deficient tumors, suggesting that imaging may guide patient selection into nanomedicine trials. In an orthotopic breast cancer model, chemoradiation enhanced TAM and Macrin accumulation in tumors, which corresponded to the improved delivery and efficacy of two model nanotherapies, PEGylated liposomal doxorubicin and a TAM-targeted nanoformulation of the toll-like receptor 7/8 agonist resiquimod (R848). Thus, Macrin imaging offers a selective and translational means to quantify TAMs and inform therapeutic decisions.

Dataset Information

Targeted Imaging of Tumor-Associated Macrophages by Cyanine 7-Labeled Mannose in Xenograft Tumors.

Publications

Targeted Imaging of Tumor-Associated Macrophages by Cyanine 7-Labeled Mannose in Xenograft Tumors.

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