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Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid-selective nonadentate bispidine ligand suitable for 177 Lu 3+ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN 3 ) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [ 177 Lu]Lu-1 + was accomplished in 10 minutes at 40 °C. Subsequent incubation of [ 177 Lu]Lu-1 + with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0-8.3, gave the radiolabelled mAb, [ 177 Lu]Lu-1-azepin-trastuzumab ([ 177 Lu]Lu-1-mAb) in a decay-corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK-OV-3 human ovarian cancer cells confirmed that [ 177 Lu]Lu-1-mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK-OV-3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g -1 vs. 14.8±6.1 %ID g -1 , respectively; P-value=0.037). The data indicate that bispidine-based ligand systems are suitable starting points for constructing novel, high-denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides., (© 2023 Wiley-VCH GmbH.)

Recently, radiotheranostics, which systematically combines diagnosis by nuclear medicine imaging and treatment by internal radiotherapy, constitutes a new modality in cancer treatment, with some clinical reports showing marked effects on cancer. We have been developing multifunctional chelates containing a target recognition unit, a radiation release unit, and a radioactivity pharmacokinetics control unit in the same molecule to develop efficient agents for cancer radiotheranostics based on chemical control of radioactivity pharmacokinetics. Using these compounds, we have achieved improved cancer accumulation and reduced renal accumulation in tumor-bearing mice, and have developed novel hybrid radiotheranostic agents that can be applied to simultaneously perform target-specific molecular imaging using γ-ray emitting radionuclides and internal radiotherapy using α-particle-emitting radionuclides. For example, 111 In/ 225 Ac-labeled PSMA-DA1, which targets prostate-specific membrane antigen (PSMA) for radiotheranostics, achieved clear in vivo imaging of PSMA in tumor-bearing mice and showed marked tumor growth inhibition. In addition to PSMA, this platform for radiotheranostics has also shown efficacy against various cancer target molecules, including carbonic anhydrase IX (CA-IX), which is highly expressed in hypoxic regions of cancer, and glucagon-like peptide-1 receptor (GLP-1R), which is highly expressed in insulinomas. This review presents these recent results of our studies on radiotheranostics for cancer.

Purpose: We have developed probes for multiradionuclides radiotheranostics using RGD peptide ([ 67 Ga]Ga-DOTA-c[RGDf(4-I)K] ([ 67 Ga]1) and Ga-DOTA-[ 211 At]c[RGDf(4-At)K] ([ 211 At]2)) for clinical applications. The introduction of an albumin binding moiety (ABM), such as 4-(4-iodophenyl)-butyric acid (IPBA), that has high affinity with the blood albumin and prolongs the circulation half-life can improve the pharmacokinetics of drugs. To perform more effective targeted alpha therapy (TAT), we designed and synthesized Ga-DOTA-K([ 211 At]APBA)-c(RGDfK) ([ 211 At]5) with 4-(4-astatophenyl)-butyric acid (APBA), which has an astato group instead of an iodo group in IPBA. We evaluated whether APBA functions as ABM and [ 211 At]5 is effective for TAT. In addition, we prepared 67 Ga-labeled RGD peptide without ABM, [ 67 Ga]Ga-DOTA-K-c(RGDfK) ([ 67 Ga]3), and 125 I-labeled RGD peptide with ABM, Ga-DOTA-K([ 125 I]IPBA)-c(RGDfK) ([ 125 I]4), to compare with [ 211 At]5., Methods: Biodistribution experiments of [ 67 Ga]3 without ABM, [ 125 I]4 and [ 211 At]5 with ABM were conducted in normal mice and U-87 MG tumor-bearing mice. In addition, two doses of [ 211 At]5 (370 or 925 kBq) were administered to U-87 MG tumor-bearing mice to confirm the therapeutic effects., Results: The blood retention of [ 125 I]4 and [ 211 At]5 was remarkably increased compared to [ 67 Ga]3. Also, [ 125 I]4 and [ 211 At]5 showed similar biodistribution and significantly greater tumor accumulation and retention compared to [ 67 Ga]3. In addition, [ 211 At]5 inhibited tumor growth in a dose-dependent manner., Conclusion: The functionality of APBA as ABM like IPBA, and the usefulness of [ 211 At]5 as the radionuclide therapy agent for TAT was revealed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: As sigma receptors are abundantly expressed on different types of cancer cells, several radiolabeled sigma receptor ligands have been developed for cancer imaging and therapy. Previously, we synthesized and evaluated radioiodinated aza-vesamicol derivatives, [ 125 I]pIC 3 NV, [ 125 I]mIC 2 N5V, and [ 125 I]mIC 3 N5V. They accumulated in tumors, and [ 125 I]mIC 2 N5V and [ 125 I]mIC 3 N5V showed higher tumor to non-target tissue ratios than [ 125 I]pIC 3 NV. Therefore, we synthesized and evaluated the corresponding 211 At-labeled compounds, [ 211 At]mAtC 2 N5V and [ 211 At]mAtC 3 N5V, for targeted alpha therapy (TAT)., Methods: [ 211 At]mAtC 2 N5V and [ 211 At]mAtC 3 N5V were prepared by the standard method of electrophilic astatodestannylation of the corresponding trimethylstannyl precursors. Cellular uptake experiments, and biodistribution experiments and therapeutic experiments in tumor-bearing mice were performed., Results: The radiochemical yields of [ 211 At]mAtC 2 N5V and [ 211 At]mAtC 3 N5V were 45.5 ± 14.4% and 56.9 ± 13.8%, respectively. After HPLC purification, their radiochemical purities were over 95%. [ 211 At]mAtC 2 N5V and [ 211 At]mAtC 3 N5V showed high uptake in DU-145 cells. They demonstrated high accumulation in tumors (6.9 ± 1.4%injected dose/g and 5.1 ± 1.4%injected dose/g at 1 h, respectively) and similar biodistribution tendencies compared with the corresponding 125 I-labeled compounds. A single injection of [ 211 At]mAtC 2 N5V (0.48 MBq) or [ 211 At]mAtC 3 N5V (0.48 MBq) significantly inhibited tumor growth., Conclusion: These results indicated that [ 211 At]mAtC 2 N5V and [ 211 At]mAtC 3 N5V could be potential candidates for TAT., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Since the first introduction of sodium iodide I-131 for use with thyroid patients almost 80 years ago, more than 50 radiopharmaceuticals have reached the markets for a wide range of diseases, especially cancers. The nuclear medicine paradigm also shifts from solely molecular imaging or radionuclide therapy to imaging-guided radionuclide therapy, which is deemed a vital component of precision cancer therapy and an emerging medical modality for personalized medicine. The imaging-guided radionuclide therapy highlights the systematic integration of targeted nuclear diagnostics and radionuclide therapeutics. Regarding this, nuclear imaging serves to "visualize" the lesions and guide the therapeutic strategy, followed by administration of a precise patient specific dose of radiotherapeutics for treatment according to the absorbed dose to different organs and tumors calculated by dosimetry tools, and finally repeated imaging to predict the prognosis. This strategy leads to significantly enhanced therapeutic efficacy, improved patient outcomes, and manageable adverse events. In this review, we provide an overview of imaging-guided targeted radionuclide therapy for different tumors such as advanced prostate cancer and neuroendocrine tumors, with a focus on development of new radioligands and their preclinical and clinical results, and further discuss about challenges and future perspectives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Probes for radiotheranostics could be produced by introducing radionuclides with similar chemical characteristics into the same precursors. We recently developed an 211 At-labeled RGD peptide and a corresponding radioiodine-labeled RGD peptide. Both labeled peptides accumulated in large quantities in the tumor with similar biodistribution, demonstrating their usefulness for radiotheranostics. In this study, we hypothesized that probes for radiotheranostics combined with multiradionuclides, such as 68 Ga and 211 At, have useful clinical applications. New radiolabeled RGD peptide probes were synthesized via a molecular design approach, with two labeling sites for metal and halogen. These probes were evaluated in biodistribution experiments using tumor-bearing mice. [ 67 Ga]Ga-DOTA-c[RGDf(4-I)K] ([ 67 Ga] 4 ), Ga-DOTA-[ 125 I]c[RGDf(4-I)K] ([ 125 I] 4 ), and Ga-DOTA-[ 211 At]c[RGDf(4-At)K] ([ 211 At] 7 ) showed similar biodistribution, with high and equivalent accumulation in tumors. These results indicate the usefulness of these probes in radiotheranostics with multiradionuclides, such as a radiometal and a radiohalogen, and they could contribute to a personalized medicine regimen.

Hypoxic cells dynamically translocate during tumor growth and after radiotherapy. The most desirable direction for therapy targeting hypoxic cells is combining imaging and therapy (theranostics), which may help realize personalized medicine. Here, we conducted cancer radiotheranostics targeting carbonic anhydrase-IX (CA-IX), which is overexpressed in many kinds of hypoxic cancer cells, using low-molecular-weight 111 In and 90 Y complexes with a bivalent ureidosulfonamide scaffold as the CA-IX-binding moiety ([ 111 In/ 90 Y]US2). Methods: The targeting ability of [ 111 In]US2 was evaluated by in vivo biodistribution study in CA-IX high-expressing (HT-29) tumor-bearing mice. In vivo imaging of HT-29 tumors was carried out using single photon emission computed tomography (SPECT). [ 90 Y]US2 was administered to HT-29 tumor-bearing mice to evaluate cancer therapeutic effects. Results: [ 111 In]US2 highly and selectively accumulated within HT-29 tumors (4.57% injected dose/g tumor at 1 h postinjection), was rapidly cleared from the blood pool and muscle after 4 h based on a biodistribution study, and visualized HT-29 tumor xenografts in mice at 4 h postinjection with SPECT. Radionuclide-based therapy with [ 90 Y]US2 significantly delayed HT-29 tumor growth compared with that of untreated mice ( P = 0.02 on day 28, Student's t -test), without any critical hematological toxicity due to its rapid pharmacokinetics. Conclusion: These results indicate that cancer radiotheranostics with [ 111 In/ 90 Y]US2 provides a novel strategy of theranostics for cancer hypoxia., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.