PET imaging of tumor-associated macrophages with (89)Zr-labeled high-density lipoprotein nanoparticles Journal Article
| Authors: | Pérez-Medina, C.; Tang, J.; Abdel-Atti, D.; Hogstad, B.; Merad, M.; Fisher, E. A.; Fayad, Z. A.; Lewis, J. S.; Mulder, W. J. M.; Reiner, T. |
| Article Title: | PET imaging of tumor-associated macrophages with (89)Zr-labeled high-density lipoprotein nanoparticles |
| Abstract: | 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 89Zr 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. 89Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate 89Zr-PL-HDL and 89Zr-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 89Zr 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 5 6) and 94% ± 6% (n 5 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-AIHDL in tumors, respectively. Conclusion: We have developed 89Zr-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 89Zr-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc. |
| Keywords: | controlled study; unclassified drug; histopathology; cancer growth; nonhuman; flow cytometry; nuclear magnetic resonance imaging; positron emission tomography; tumor associated leukocyte; mouse; breast cancer; animal experiment; in vivo study; in vitro study; diagnostic imaging; immunology; radioactivity; nanoparticle; ex vivo study; pet; zirconium; zirconium 89; deferoxamine; phospholipid; 89zr; high density lipoprotein; tumor-associated macrophages; apolipoprotein a1; cancer prognosis; priority journal; article; highdensity lipoprotein |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 56 |
| Issue: | 8 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2015-08-01 |
| Start Page: | 1272 |
| End Page: | 1277 |
| Language: | English |
| DOI: | 10.2967/jnumed.115.158956 |
| PROVIDER: | scopus |
| PUBMED: | 26112022 |
| PMCID: | PMC4737475 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
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19Tang
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