64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts

Abstract

Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, is an antiangiogenic agent clinically used for various cancers. However, repeated use of this agent leads to tumor-decreased vascularity and hypoxia with activation of an HIF-1 signaling pathway, which results in drug delivery deficiency and induction of malignant behaviors in tumors. Here, we developed a novel strategy to treat tumors with bevacizumab-induced vascular decrease and hypoxia using 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), a potential theranostic agent, which possesses high tissue permeability and can target over-reduced conditions under hypoxia in tumors, with a human colon carcinoma HT-29 tumor-bearing mouse model. The long-term treatment with bevacizumab caused decreased blood vessel density and activation of an HIF-1 signaling pathway; increased uptake of 64Cu-ATSM was also observed despite limited blood vessel density in HT-29 tumors. In vivo high-resolution SPECT/PET/CT imaging confirmed reduced vascularity and increased proportion of 64Cu-ATSM uptake areas within the bevacizumab-treated tumors. 64Cu-ATSM therapy was effective to inhibit tumor growth and prolong survival of the bevacizumab-treated tumor-bearing mice without major adverse effects. In conclusion, 64Cu-ATSM therapy effectively enhanced anti-tumor effects in tumors with bevacizumab-induced vascular decrease and hypoxia. 64Cu-ATSM therapy could represent a novel approach as an add-on to antiangiogenic therapy.

A study of evaluating specific tissue oxygen saturation values of gastrointestinal tumors by removing adherent substances in oxygen saturation imaging

“…Positron emission tomography (PET)-based hypoxia imaging using various probes has been reported for assessing StO2 noninvasively. PET-based hypoxia imaging with probes such as FMISO [ 17 , 18 ], 64Cu-ATSM [ 19 ], and 18F-FAZA [ 20 ] has been reported as a method for non-invasive estimation of StO2 levels. In the basic mechanism of action, a probe labeled with a radioisotope (RI) is accumulated within cells under the hypoxic condition, which allows visualization of the hypoxic tumor region and its quantitative analysis.…”

Radiochemical and radiopharmacological characterization of a 64Cu‐labeled α‐MSH analog conjugated with different chelators

“…Besides, modification via peptide cyclization could also improve the resistance to proteolysis and the receptor binding affinity . Recently, 64 Cu‐labeled α‐MSH derivatives have been of great interest since 64 Cu emits both positrons and electrons, which make it useful for imaging via positron emission tomography (PET) and for targeted radiotherapy of cancer . 64 Cu(II) has to be incorporated into biomolecules (peptides, antibodies, etc) via bifunctional chelators since there are usually no functional groups in biomolecules that could coordinate with 64 Cu directly and steadily.…”

Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status

“…Due to suboptimal pharmacokinetics, 18 F-FMISO is not ideal for imaging hypoxia however, and alternative tracers are being investigated. For example, [ 64 Cu]-diacetyl-bis-( N 4 -methylthiosemicarbazone) ([ 64 Cu]-ATSM) has been shown to be superior in terms of imaging performance, and may even play a role as an add-on for anti-angiogenic tumour treatment [ 40 , 74 , 75 , 76 ]. Similar to FMISO, ATSM also demonstrates a strong correlation between the presence of angiogenic markers and the appearance of hypoxic regions.…”

“…Although PSMA is not expressed in non-prostate tumours, nor in healthy vasculature, expression does occur in endothelial cells of tumour-associated neovasculature [ 86 ]. Two excellent reviews of PSMA-based imaging in non-prostate imaging have been recently published [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], but we would like to briefly present the findings regarding angiogenesis here. The functional role of PSMA in angiogenesis is not clear at this moment, nor is PSMA a requirement for tumour-associated neovascularisation—but PSMA expression is associated to tumours that critically depend on angiogenesis.…”