PET Imaging of Tumor-Associated Macrophages with 89Zr-Labeled High-Density Lipoprotein Nanoparticles

被引:132
作者
Perez-Medina, Carlos [1 ,2 ,3 ]
Tang, Jun [3 ,4 ]
Abdel-Atti, Dalya [4 ]
Hogstad, Brandon [5 ,6 ,7 ]
Merad, Miriam [5 ,6 ,7 ]
Fisher, Edward A. [8 ,9 ]
Fayad, Zahi A. [3 ]
Lewis, Jason S. [10 ]
Mulder, Willem J. M. [3 ,11 ]
Reiner, Thomas [4 ,10 ]
机构
[1] CIBERES, Ctr Invest Red Enfennedades Resp, Madrid, Spain
[2] CNIC, Ctr Nacl Invest Cardiovasc, Madrid, Spain
[3] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA
[5] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA
[6] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA
[7] Icahn Sch Med Mt Sinai, Immunol Inst, New York, NY 10029 USA
[8] NYU, Sch Med, Leon H Charney Div Cardiol, New York, NY USA
[9] NYU, Sch Med, Marc & Ruti Bell Program Vasc Biol, New York, NY USA
[10] Weill Cornell Med Coll, New York, NY USA
[11] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands
关键词
tumor-associated macrophages; Zr-89; PET; high-density lipoprotein; breast cancer; APOLIPOPROTEIN-A-I; BREAST-CANCER; TISSUE SITES; STRATEGY; DEGRADATION; ANTIBODIES; RECEPTOR; THERAPY; BINDING; KIDNEY;
D O I
10.2967/jnumed.115.158956
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
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 Zr-89 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. Zr-89 was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate Zr-89-PL-HDL and Zr-89-Al-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistributon studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of Zr-89 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-Al-HDL) and accounted for 40.7% and 39.5% of the total cellular DiO@Zr-PL-HDL and DiO@Zr-Al-HDL in tumors, respectively. Conclusion: We have developed Zr-89-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 Zr-89-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment.
引用
收藏
页码:1272 / 1277
页数:6
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