Targeted imaging of tumor-associated M2 macrophages using a macromolecular contrast agent PG-Gd-NIR813.
Tumor-associated macrophages (TAMs) are diverse population containing multiple subtypes. M2 macrophages promote tumor growth and metastasis, in part by secreting a wide range of proangiogenic factors and growth factors. Selective depletion of M2 macrophages has been evaluated as a novel approach to anti-cancer therapy. In this study, a dual magneto-optical imaging probe, PG-Gd-NIR813 was synthesized and evaluated for non-invasive assessment of TAMs after intravenous injection. PG-Gd-NIR813 injected in nude rats bearing C6 tumors showed high uptake of the polymeric contrast agent in the tumor at 1 and 48 h after injection both in vivo and ex vivo optical imaging. T(1)-weighted MR imaging results showed accumulation of PG-Gd-NIR813 into the tumor necrotic area, which was confirmed by TUNEL staining of resected tumors. The uptake of PG-Gd-NIR813 within tumor necrosis decreased after animals were treated by the macrophage-depleting agent. Immunohistochemical staining demonstrated that PG-Gd-NIR813 colocalized with CD68 (marker for macrophages) and CD169 (marker for activated macrophages), but not with CD163 (residential macrophages). Using combined near-infrared fluorescence imaging and magnetic resonance imaging (MRI), we demonstrated that the accumulation of PG-Gd-NIR813 in tumors was mediated through M2 TAMs. Therefore, poly(L-glutamic acid) based reagents could be potentially used to image response to antitumor therapies targeted at M2 TAMs. Furthermore, poly(L-glutamic acid) is a promising carrier for candidate immunotherapeutics targeting M2 TAMs.
Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Marites P
MP
Melancon
Wei
W
Lu
Qian
Q
Huang
Prakash
P
Thapa
Dapeng
D
Zhou
Chaan
C
Ng
Chun
C
Li
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics; D005682:Gadolinium / Q000737:chemistry / Q000493:pharmacokinetics; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D008264:Macrophages / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis*; D011099:Polyglutamic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats
D001549:Benzamides; D003287:Contrast Media; D007211:Indoles; C524070:NIR 813; D011099:Polyglutamic Acid; D005682:Gadolinium