Abstract
Necrosis only occurs in pathological situations and is directly related to disease severity and, therefore, is an important biomarker. Tumor necrosis occurs in most solid tumors due to improperly functioning blood vessels that cannot keep up with the rapid growth, especially in aggressively growing tumors. The amount of necrosis per tumor volume is often correlated to rapid tumor proliferation and can be used as a diagnostic tool. Furthermore, efficient therapy against solid tumors will directly or indirectly lead to necrotic tumor cells, and detection of increased tumor necrosis can be an early marker for therapy efficacy. We propose the application of necrosis avid contrast agents to detect therapy-induced tumor necrosis. Herein, we advance gallium-68-labeled IRDye800CW, a near-infrared fluorescent dye that exhibits excellent necrosis avidity, as a potential PET tracer for in vivo imaging of tumor necrosis. We developed a reliable labeling procedure to prepare [68Ga]Ga-DOTA-PEG4-IRDye800CW ([68Ga]Ga-1) with a radiochemical purity of >96% (radio-HPLC). The prominent dead cell binding of fluorescence and radioactivity from [68Ga]Ga-1 was confirmed with dead and alive cultured 4T1-Luc2 cells. [68Ga]Ga-1 was injected in 4T1-Luc2 tumor-bearing mice, and specific fluorescence and PET signal were observed in the spontaneously developing tumor necrosis. The ip injection of D-luciferin enabled simultaneous bioluminescence imaging of the viable tumor regions. Tumor necrosis binding was confirmed ex vivo by colocalization of fluorescence uptake with TUNEL dead cell staining and radioactivity uptake in dichotomized tumors and frozen tumor sections. Our presented study shows that [68Ga]Ga-1 is a promising PET tracer for the detection of tumor necrosis.
Highlights
Excessive occurrence of cell death is a hallmark for severe disease in many pathologies, such as sepsis [1], pancreatitis [2], or acute myocardial infarction [3]
We performed single photon emission computed tomography (SPECT)-imaging of necrosis using indium-111 labeled IRDye800CW, as a necrosisavid contrast agent (NACA). is necrosis avid contrast agents (NACAs) was retained in the necrotic cores of 4T1-Luc2 tumors for several days, enabling SPECT imaging of tumor necrosis with high contrast [22]
We proposed to label the NACA with a short-lived isotope
Summary
Excessive occurrence of cell death is a hallmark for severe disease in many pathologies, such as sepsis [1], pancreatitis [2], or acute myocardial infarction [3]. Most solid tumors develop necrotic tissue due to the growth rate of the tumor mass surpassing the rate of vascularization. Tumor necrosis is often associated with aggressive tumor types and poor disease prognosis [4, 5]. Noninvasive techniques for necrosis detection are lacking in the clinic. Ere have been several agents reaching clinical trials targeting apoptosis markers, for instance, radiolabeled Annexin V, which targets exposed phosphoserines [6], or [18F]ICMT-11 targeting caspase-3/7 activation [7, 8]. Due to the lack of specificity, these tracers have so far failed to reach the clinic [9,10,11].
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