Introduction
Topics investigated | Method/biomarker | Target | Radionuclide | Model | Activity/dose range | Remark | References |
---|---|---|---|---|---|---|---|
DNA damage | ɣ-H2AX, 53BP1 foci in PMBCs | Blood | 177Lu, 131I, 223Ra | Patients | < 100 mGy | Ex vivo and in vivo data | |
DNA damage | ɣ-H2AX, 53BP1 foci in tumor cells | Neuroendocrine tumor, (SST2), prostate tumor (PSMA) | 177Lu, 213Bi | Cell culture, mouse | < 2.5 MBq 177Lu in vitro, 30 MBq 177Lu in vivo, 0.3 MBq 213Bi in vitro, < 6.6 MBq 213Bi in vivo | SST2 agonist vs. antagonist | |
DNA damage Imaging | [111In]In-anti-γH2AX-TAT, [89Zr]Zr-DFO-anti-γH2AX-TAT | Neuroendocrine tumor, pancreatic carcinoma | 177Lu, 225Ac | Mouse | < 20 MBq 177Lu, 37 kBq 225Ac | DNA damage monitoring after [177Lu]Lu-DOTA-TATE therapy | |
Preclinical therapeutic value, cell survival, cell cycle progression | Tumor volume, cell survival, cell cycle analysis | Non-Hodgkin lymphoma (CD37) | 177Lu | Cell culture, mouse, patient samples | < 6 MBq/mL 177Lu in vitro, < 500 MBq/kg 177Lu in vivo | Radioimmunotherapy | [21] |
In vitro cytotoxicity | Cell-free plasmid DNA damage, DNA damage, cell survival, cell viability, microautoradiography cell distribution assay | Breast cancer (HER2), prostate tumor | 67Ga, 111In | Cell culture | < 0.3 MBq/mL 67Ga in vitro; 1.1 Bq/cell (15 MBq/mL) 67Ga or 111In in vitro, 0.1 MBq/mL 67Ga or 111In cell free | Auger electrons | |
Combination with other agents: radiosensitizing agents | 53BP1, micronuclei in cell cultures, cell survival, cell viability, cell cycle progression, DNA damage response, gene expression, tumor perfusion, tumor, tumor radioactivity uptake, tumor volume | Neuroendocrine tumor (SST2), small cell lung cancer (SST2), prostate tumor (PSMA), neuroblastoma PARP, protein folding, DNA and DNA synthesis, Hedgehog signaling, nicotinamide phosphoribosyltransferase, topoisomerase I, proteasome, P53-MDM2 interaction nutlin-3, and the copper-chelated form of the oxidizing agent disulfiram, G2/M cell cycle arrest | 177Lu, 131I | Cell culture, spheroids, mouse, patients | < 6 MBq/mL 177Lu in vitro, < 30 MBq 177Lu in vivo, < 6 MBq 177Lu ex vivo patients, 4 × 7.8 GBq patients, 0.37 MBq/mL 131I in vitro, 20 MBq 131I in vivo | Olaparib, 1,5-dihydroxyisoquinoline, PJ-34, veliparib, talazoparib, Hsp90 inhibitor, androgen receptor inhibitor, capecitabine, temozolomide, sonidegib, NAMPT inhibitor, topotecan, bortezomib, the inhibitor of the P53-MDM2 interaction nutlin-3 and the copper-chelated form of the oxidizing agent disulfiram (DSF:Cu), EBRT | |
Combination with other agents: upregulation of the therapeutic target | Transcriptional, translational, and functional analysis, tracer uptake | Neuroendocrine tumor (SST2) | n.a. | Cell culture | n.a. | – | |
Combination with other agents: chemotherapeutic drugs | Cell viability, biodistribution, tumor volume | Breast cancer | 131I | Cell culture, mouse | < 7.4 MBq/mL in vitro, 7.4 MBq in vivo | Human serum albumin–paclitaxel nanoparticles | [40] |
Combination with other agents: radioprotectant agents | Biodistribution, tumor response | Kidneys | 177Lu | Mouse | 30 MBq | Kidney-preserving agent | [41] |
Tumor radionuclide/receptor distribution | [111In]In-EGF and [111In]In-labeled trastuzumab imaging, autoradiography, immunofluorescence microscopy | Breast cancer (EGFR, HER2), head and neck cancer (EGFR), neuroendocrine tumor (SST2) | 111In, 177Lu | Spheroids, cell culture, mouse, patients (ex vivo) | 1 MBq/mL 177Lu in vitro, 30 MBq 177Lu in vivo | – | |
Molecular profiling | Blood NET transcript analysis | Neuroendocrine tumors (SST2) | 177Lu | Patients | [177Lu]Lu-DOTA-TATE-based PRRT | NETest, PPQ: PRRT predictive quotient (PPQ) | |
Molecular profiling | Whole genome microarray analysis | Neuroendocrine tumor (SST2), thyroid gland, various normal tissues, Kidney | 177Lu, 131I, 211At | Mouse, rat | < 15 MBq 177Lu, < 4.7 MBq 131I, < 42 kBq 211At | – | |
Molecular profiling | Targeted next-generation sequencing of DNA damage-repair associated genes | Prostate cancer | 225Ac | Biopsies | [225Ac]Ac-PSMA-617 therapy | – | [8] |
Relative biological effectiveness | Cell survival | Neuroendocrine tumor (SST2) | 177Lu, 213Bi | Cell culture | < 10 Gy (177Lu), < 5.2 MBq (7 Gy) 213Bi | RBE = 6 | [51] |
Radiation quality effects | Cell survival, cell viability, gene expression, DNA damage, in vivo therapy studies | 131I, 161Tb, 177Lu | Cell culture, mouse | < 9.25 MBq 131I in vitro | – | ||
Cell membrane-mediated non-targeted effects | Cell membrane lipid raft analysis, underlying signaling pathways, cell survival, DNA damage tumor volume | Colon cancer (CEA), vulvar squamous carcinoma (A431 HER2 + CEA), ovarian carcinoma (SKOV3 MISRII), endometrial carcinoma (AN3CA MISRII) | 125I, 212Pb/212Bi, 213Bi | Cell culture, mouse | < 0.5 MBq/ml 212Pb in vitro, 0.5 MBq/mL 213Bi in vitro, < 4 MBq 125I in vitro, 1.48 MBq 212Pb in vivo, 37 MBq 125I in vivo | – | |
Single cell and micrometastases dosimetry | Calculation | Neuroendocrine tumor (SST2) | 177Lu, 161Tb | Cell culture, computed cell model | 2.5 MBq/mL 177Lu in vitro | – | |
Radiobiology, generic dose models | Calculation | Kidneys, tumor | Development of the linear-quadratic model for nuclear medicine | ||||
Thyroid dose-toxicity model | Retrospective calculations of TCP, NTCP | Thyroid treatment | 131I | Patients | < 560 MBq [65] | Retrospective analysis | |
Hepatocellular carcinoma tumor response | Prospective study based on [99mTc]Tc macro-aggregated albumin dosimetry | Liver treatment glass microspheres | 90Y | Patients | > 205 Gy | Prospective study | [67] |
Hepatic dose-toxicity model | BED, TD, EUD | Liver treatment glass and resin microspheres | 90Y | – | < 250 Gy BED50 | Dose-toxicity model | [68] |
Kidney dose-toxicity model | BED, TCP, NTCP | SST2 agonists, treatment of neuroendocrine tumors | 90Y, 177Lu | Patients | 40 Gy BED | Clinical trial | [69] |
Kidneys and red bone marrow toxicity model | BED | Neuroendocrine tumor | 177Lu | Virtual patients | 40 Gy2.5 kidneys BED, 2 Gy15 red bone marrow BED | In silico clinical trial | [70] |
mIBG treatment | Retrospective calculations | Neuroblastoma mIBG treatment | 131I | Patients | 30 GBq | Two fractions | |
Predicting tumor response | BED | Prostate carcinoma | 177Lu | Patients | 7.3 ± 0.3 GBq | Prediction of tumor volume shrinking using PBPK/PD modeling | [73] |