Journal
JOURNAL OF NUCLEAR MEDICINE
Volume 56, Issue 8, Pages 1272-1277Publisher
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.115.158956
Keywords
tumor-associated macrophages; Zr-89; PET; high-density lipoprotein; breast cancer
Funding
- NCI NIH HHS [R01 CA173861, R01 CA155432, P30 CA008748, R01 CA190400] Funding Source: Medline
- NHLBI NIH HHS [R01 HL125703, R01 HL118440] Funding Source: Medline
- NIBIB NIH HHS [R01 EB009638, K25 EB016673] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA155432, P30CA008748, R01CA190400, R01CA173861] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL125703, R01HL118440] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [K25EB016673, R01EB009638] Funding Source: NIH RePORTER
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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.
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