^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

Abstract

Given the importance of angiogenesis for a tumor's survival and growth, several therapeutic strategies rely on the selective inhibition of angiogenesis and the destruction of existing tumor vasculature. These strategies raise the need for a noninvasive tool to evaluate tumor vasculature. We describe the radiosynthesis and evaluation of an imaging tracer that specifically binds tumor subendothelial collagen and thereby images tumor vasculature. Methods: 99m Tc-tricarbonyl was prepared and labeled with His-collagen-binding adhesion protein 35 (CNA35). After in vitro specificity testing, in vivo biodistribution and dosimetric studies were performed in healthy nude mice via planar imaging. 99m Tc-(CO) 3 His-CNA35 was evaluated for in vivo imaging of tumor vasculature in a HT29 colorectal carcinoma xenograft. Results: The labeling procedure yielded a compound with 95%-99% radiochemical purity and good in vitro stability. An in vitro binding test confirmed specificity and functionality. 99m Tc-(CO) 3 His-CNA35 rapidly cleared from the blood and predominantly accumulated in the kidneys and liver. The effective dose for a proposed single injection of 500 MBq of 99m Tc-(CO) 3 His-CNA35 is 3.70 mSv per organ or 2.01 mSv/g of tissue.Tumors were successfully visualized, and uptake correlated with ex vivo immunohistochemical staining of tumor vasculature. Conclusion: 99m Tc-(CO) 3 His-CNA35 may be a useful radioligand for the in vivo detection of tumor vasculature through subendothelial collagen binding. A noninvasive method of imaging tumor vasculature that could provide a reliable assessment of tumor vasculature would allow evaluation of the effectiveness of commonly used antiangiogenic therapies and determination of their optimal dosing and scheduling. As a tumor mass grows beyond the support capacity of the vasculature it relies on, the need for new blood vessels arises. The formation of new blood vessels is achieved through angiogenesis, a multistep process that relies on the tumor-driven production of proangiogenic factors. These resulting new blood vessels, however, are structurally and functionally deficient when compared with normal ones. They are disorganized, tortuous, and leaky, leading to heterogeneous blood flow, hypoxia, acidosis, and elevated interstitial fluid pressure, with a disturbed tumor microenvironment as a result (1). Nevertheless, this neovascularization allows the tumor to grow and plays an important role in tumor invasiveness and metastasis. Given the importance of angiogenesis, several therapeutic strategies rely on the selective inhibition of angiogenesis and destruction of tumor vasculature. In several types of cancer, antiangiogenic therapy alone or in combination with standard chemotherapeutic strategies has led to an improvement of survival (2,3). As the importance of these therapies increases, noninvasive methods are needed to provide a reliable assessment of tumor vasculature and thus a means for the management and planning of antiangiogenic therapy.A possible mechanism to target tumor vas...

A novel multivalent 99m Tc-labeled EG2-C4bpα antibody for targeting the epidermal growth factor receptor in tumor xenografts

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Bioenergetic Profiles Diverge During Macrophage Polarization: Implications for the Interpretation of 18F-FDG PET Imaging of Atherosclerosis

“…Some studies demonstrated unchanged glucose uptake by inflammatory activation of macrophages (IFN-γ alone or in combination with TNF-α, IL-1β) (13). Others showed enhanced glucose uptake by classic (combination of TNF-α, IL-1β, IFN-γ, and granulocyte macrophage colony-stimulating factor), but not alternative (IL-4 and IL-13), macrophage polarization (36) and increased glucose uptake by both M1 (cotreatment with IFN-γ and LPS) and M2 (IL-4) polarized macrophages (37). Different sources of macrophages (i.e., human monocyte–derived macrophages in the first (13) and murine bone marrow–derived macrophages in the latter 2 studies (36–38)) and the use of different polarization agents may have contributed to these conflicting data.…”

Optimising the radiolabelling properties of technetium tricarbonyl and His-tagged proteins

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