Magnetic resonance imaging of tumor-associated-macrophages (TAMs) with a nanoparticle contrast agent

Junhan Zhou; Vijaykumar S Meli; Esther Yu-Tin Chen; Rohan Kapre; Raji Nagalla; Wenwu Xiao; Alexander D Borowsky; Kit S Lam; Wendy F Liu; Angelique Y Louie

doi:10.1039/d1ra08061j

Magnetic resonance imaging of tumor-associated-macrophages (TAMs) with a nanoparticle contrast agent

RSC Adv. 2022 Mar 8;12(13):7742-7756. doi: 10.1039/d1ra08061j.

Authors

Junhan Zhou¹, Vijaykumar S Meli², Esther Yu-Tin Chen², Rohan Kapre^{3

4}, Raji Nagalla², Wenwu Xiao^{5

6}, Alexander D Borowsky^{6

7

8}, Kit S Lam^{1

5

6

9}, Wendy F Liu², Angelique Y Louie^{1

3}

Affiliations

¹ Chemistry Graduate Group, University of California Davis CA 95616 USA aylouie@ucdavis.edu.
² Department of Biomedical Engineering, University of California Irvine CA 92697 USA.
³ Department of Biomedical Engineering, University of California Davis CA 95616 USA.
⁴ Biostatistics Graduate Group, University of California Davis CA 95616 USA.
⁵ Department of Biochemistry and Molecular Medicine, University of California Davis CA 95616 USA.
⁶ Comprehensive Cancer Center, University of California Davis CA 95616 USA.
⁷ Department of Pathology and Laboratory Medicine, University of California Davis CA 95616 USA.
⁸ Center for Immunology and Infectious Diseases, University of California Davis CA 95616 USA.
⁹ Division of Hematology &Oncology, Department of Internal Medicine, University of California Davis CA 95616 USA.

Abstract

In the tumor micro-environment, tumor associated macrophages (TAMs) represent a predominant component of the total tumor mass, and TAMs play a complex and diverse role in cancer pathogenesis with potential for either tumor suppressive, or tumor promoting biology. Thus, understanding macrophage localization and function are essential for cancer diagnosis and treatment. Typically, tissue biopsy is used to evaluate the density and polarization of TAMs, but provides a limited "snapshot" in time of a dynamic and potentially heterogeneous tumor immune microenvironment. Imaging has the potential for three-dimensional mapping; however, there is a paucity of macrophage-targeted contrast agents to specifically detect TAM subtypes. We have previously found that sulfated-dextran coated iron oxide nanoparticles (SDIO) can target macrophage scavenger receptor A (SR-A, also known as CD204). Since CD204 (SR-A) is considered a biomarker for the M2 macrophage polarization, these SDIO might provide M2-specific imaging probes for MRI. In this work, we investigate whether SDIO can label M2-polarized cells in vitro. We evaluate the effect of degree of sulfation on uptake by primary cultured bone marrow derived macrophages (BMDM) and found that a higher degree of sulfation led to higher uptake, but there were no differences across the subtypes. Further analysis of the BMDM showed similar SR-A expression across stimulation conditions, suggesting that this classic model for macrophage subtypes may not be ideal for definitive M2 subtype marker expression, especially SR-A. We further examine the localization of SDIO in TAMs in vivo, in the mammary fat pad mouse model of breast cancer. We demonstrate that uptake by TAMs expressing SR-A scales with degree of sulfation, consistent with the in vitro studies. The TAMs demonstrate M2-like function and secrete Arg-1 but not iNOS. Uptake by these M2-like TAMs is validated by immunohistochemistry. SDIO show promise as a valuable addition to the toolkit of imaging probes targeted to different biomarkers for TAMs.

Abstract

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