Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using 211At-CXCR4 monoclonal antibody

Abstract

to explore stem-cell-targeted radioimmunotherapy with α-particles in acute myelogenous leukemia (AML), pharmacokinetics and dosimetry of the 211 At-labeled anti-C-X-C chemokine receptor type 4 monoclonal antibody ( 211 At-CXCR4 mAb) were conducted using tumor xenografted mice. The biological half-life of 211 At-CXCR4 mAb in blood was 15.0 h. The highest tumor uptake of 5.05%ID/g with the highest tumor-to-muscle ratio of 8.51 ± 6.14 was obtained at 6 h. Radiation dosimetry estimated with a human phantom showed absorbed doses of 0.512 mGy/MBq in the bone marrow, 0.287 mGy/MBq in the kidney, and <1 mGy/MBq in other major organs except bone. Sphere model analysis revealed 22.8 mGy/MBq in a tumor of 10 g; in this case, the tumor-to-bone marrow and tumor-to-kidney ratios were 44.5 and 79.4, respectively. The stem-cell-targeted α-particle therapy using 211 At-CXCR4 mAb for AML appears possible and requires further therapeutic studies.Targeted α-particle therapy (TAT) has great potential for the treatment of cancer based on the specific delivery of a high radiation dose from α-particles emitting radionuclides to tumors while minimizing systemic toxic effects, and it may lead to additional treatment options for many types of advanced or refractory cancer 1 . The high level of radiobiological effectiveness of α-particles, in comparison with β-particles emissions, requires fewer radiation tracks to induce cell death. The short path length of α-particles radiation confines its cytotoxic effect to the target tissue and the surrounding tumor microenvironment while limiting toxic effects to non-neoplastic tissues.Following the successful clinical TAT with 223 Ra dichloride for the treatment of metastatic castration-resistant prostate cancer with bone metastases and the clinical experience with 213 Bi-and 225 Ac-labeled compounds 2-4 , there has been an increased interest in new applications of TAT for many tumor types. Among the α-particles-emitting radionuclides for TAT, 211 At can be produced using a cyclotron with an α-particle beam, and its separation and purification from the target has been established after decades of continuous research. After a branch decay with a half-life of 7.21 h, 211 At completely emits α-particles with 100% probability. A few clinical applications of 211 At for the treatment of malignant neoplasms have been reported 5,6 .The failure of medical and radiological anti-cancer therapies is partially attributable to the heterogeneity of cancer. One of the mechanisms explaining cancer heterogeneity is the existence of cancer stem cells (CSCs) 7 . CSCs exhibit self-renewal activity and long-term proliferating capability 8 . The concept of neoplastic stem cells may explain the failure of various therapies to achieve long-lasting responses in patients 9 , because CSCs are suggested as a potential source of resistance to different types of anti-neoplastic drug. Anti-neoplastic drugs are considered to act on mature neoplastic cells rather than on CSCs in many neoplastic tissues. This is partially owing to th...

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature

“…They also have the potential to increase the effectiveness of immunotherapy [ 324 , 325 ]. An anti-CXCR4 antibody, or peptides recognizing CXCR4, have also been tested to target cytotoxic substances against cancer stem cells in acute myelogenous leukemia [ 326 ], breast cancer cells [ 327 ], colorectal cancer cells [ 328 ] and multiple myeloma [ 329 ]. This method can also be used to retarget an adenovirus vector against a tumor cell in gene therapy [ 330 ].…”

Evaluation of Effect of Ninjin'yoeito on Regional Brain Glucose Metabolism by 18F-FDG Autoradiography With Insulin Loading in Aged Mice

“…All mice were housed in a 12 h light/dark cycle at room temperature maintained at 23–25°C and relative humidity at 45–60%. Food and water were provided ad libitum , and the treatment and care of animals met all the criteria of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International ( http://www.aaalac.org/ ) ( 16 ). The experimental protocol is shown in Figure 1 .…”

Evaluation of organ glucose metabolism by 18F-FDG accumulation with insulin loading in aged mice compared with young normal mice

“…The room temperature was maintained between 23 and 25 °C, and the relative humidity was maintained between 45 and 55%. The institutional laboratory housing provided a 12-h light/dark cycle and met all the criteria of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International ( http://www.aaalac.org/ ) 55 . All animals were fasted overnight and then divided into four subgroups: young control group, aged control group, young insulin-loaded group, and aged insulin-loaded group.…”