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Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt's lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38-targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr-89 and Lu-177 for theranostic applications. As the diagnostic component, the Zr-89-labeled mAb is highly specific in delineating CD38-positive lymphoma via positron emission tomography (PET) imaging, while the Lu-177-labeled mAb serves well as the therapeutic component to suppress tumor growth after a one-time administration. These results strongly suggest that CD38 is a lymphoma-specific marker and prove that 89 Zr/ 177 Lu-labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38-targeted theranostics may be of significant help in lymphoma patient stratification and management., Competing Interests: Weibo Cai is scientific advisor, stockholder, and grantee of Focus‐X Therapeutics, Inc. The other authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

44 Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc 3+ ion with nonmacrocyclic chelator H 4 pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques ( 1 H, 13 C, 1 H- 13 C HSQC, 1 H- 13 C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)] - presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)] - was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)] - (24.7) and [Sc(DOTA)] - (23.9). In radiolabeling, [ 44 Sc][Sc(pypa)] - formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H 4 pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.

Radio-nanomedicine, or the use of radiolabeled nanoparticles in nuclear medicine, has attracted much attention in the last few decades. Since the discovery of Cerenkov radiation and its employment in Cerenkov luminescence imaging, the combination of nanomaterials and Cerenkov radiation emitters has been revolutionizing the way nanomaterials are perceived in the field: from simple inert carriers of radioactivity to activatable nanomaterials for both diagnostic and therapeutic applications. Herein, we provide a comprehensive review on the types of nanomaterials that have been used to interact with Cerenkov radiation and the gamma and beta scintillation of radionuclides, as well as on their biological applications., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Recent advances in molecular characterization of tumors have made possible the emergence of new types of cancer therapies where traditional cytotoxic drugs and nonspecific chemotherapy can be complemented with targeted molecular therapies. One of the main revolutionary treatments is the use of monoclonal antibodies (mAbs) that selectively target the disseminated tumor cells while sparing normal tissues. mAbs and related therapeutics can be efficiently radiolabeled with a wide range of radionuclides to facilitate preclinical and clinical studies. Non-invasive molecular imaging techniques, such as Positron Emission Tomography (PET), using radiolabeled mAbs provide useful information on the whole-body distribution of the biomolecules, which may enable patient stratification, diagnosis, selection of targeted therapies, evaluation of treatment response, and prediction of dose limiting tissue and adverse effects. In addition, when mAbs are labeled with therapeutic radionuclides, the combination of immunological and radiobiological cytotoxicity may result in enhanced treatment efficacy. The pharmacokinetic profile of antibodies demands the use of long half-life isotopes for longitudinal scrutiny of mAb biodistribution and precludes the use of well-stablished short half-life isotopes. Herein, we review the most promising PET radiometals with chemical and physical characteristics that make the appealing for mAb labeling, highlighting those with theranostic radioisotopes., (Copyright © 2018 John Wiley & Sons, Ltd.)

The benefits to intracellular drug delivery from nanomedicine have been limited by biological barriers and to some extent by targeting capability. We investigated a size-controlled, dual tumor-mitochondria-targeted theranostic nanoplatform (Porphyrin-PEG Nanocomplexes, PPNs). The maximum tumor accumulation (15.6 %ID g -1 , 72 h p.i.) and ideal tumor-to-muscle ratio (16.6, 72 h p.i.) was achieved using an optimized PPN particle size of approximately 10 nm, as measured by using PET imaging tracing. The stable coordination of PPNs with 177 Lu enables the integration of fluorescence imaging (FL) and photodynamic therapy (PDT) with positron emission tomography (PET) imaging and internal radiotherapy (RT). Furthermore, the efficient tumor and mitochondrial uptake of 177 Lu-PPNs greatly enhanced the efficacies of RT and/or PDT. This work developed a facile approach for the fabrication of tumor-targeted multi-modal nanotheranostic agents, which enables precision and radionuclide-based combination tumor therapy., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy., Methods: The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177 Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177 Lu only, TRC105 only, 177 Lu-DTPA-IgG (a nonspecific antibody), 177 Lu-DTPA-TRC105 low-dose, and 177 Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177 Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177 Lu-DTPA-TRC105., Results: Biodistribution studies indicated steady uptake of 177 Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses., Conclusion: 177 Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.

Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. Additionally, high TF expression was shown to strongly correlate with poor prognoses and decreased survival in pancreatic cancer patients. Herein, we exploited the potential targeting of TF for positron emission tomography (PET) imaging of pancreatic cancer. The TF-targeted tracer was developed through radiolabeling of the anti-human TF monoclonal antibody (ALT-836) with 89 Zr. The tracer was characterized by fluorescence microscopy and flow cytometry assays in BXPC-3 and PANC-1 cells, two pancreatic cancer cell lines with high and low TF expression levels, respectively. Non-invasive PET scans were acquired in tumor-bearing mice injected with 89 Zr-Df-ALT-836. Additionally, ex vivo biodistribution, blocking, and histological studies were performed to establish the affinity and specificity of 89 Zr-Df-ALT-836 for TF in vivo. 89 Zr-labeling of Df-ALT-836 was achieved in high yield and good specific activity. Flow cytometry and microscopy studies revealed no detectable difference in TF-binding affinity between ALT-836 and Df-ALT-836 in vitro. Longitudinal PET scans unveiled a lasting and prominent 89 Zr-Df-ALT-836 uptake in BXPC-3 tumors (peak at 31.5±6.0%ID/g at 48h post-injection; n=3), which was significantly abrogated (2.3±0.5%ID/g at 48h post-injection; n=3) when mice were pre-injected with a blocking dose (50mg/kg) of unlabeled ALT-836. Ex vivo biodistribution data confirmed the accuracy of the PET results, and histological analysis correlated high tumor uptake with in situ TF expression. Taken together, these results attest to the excellent affinity and TF-specificity of 89 Zr-Df-ALT-836. With elevated, persistent, and specific accumulation in TF-positive BXPC-3 tumors, PET imaging using 89 Zr-Df-ALT-836 promises to open new avenues for improving future diagnosis, stratification, and treatment response assessment in pancreatic cancer patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Manganese has long been employed as a T 1 -shortening agent in magnetic resonance imaging (MRI) applications, but these techniques are limited by the biotoxicity of bulk-manganese. Positron emission tomography (PET) offers superior contrast sensitivity compared with MRI, and recent preclinical PET studies employing 52g Mn (t 1/2 : 5.6 d, β + : 29%) show promise for a variety of applications including cell tracking, neural tract tracing, immunoPET, and functional β-cell mass quantification. The half-life and confounding gamma emissions of 52g Mn are prohibitive to clinical translation, but the short-lived 51 Mn (t 1/2 : 46 min, β + : 97%) represents a viable alternative. This work develops methods to produce 51 Mn on low-energy medical cyclotrons, characterizes the in vivo behavior of 51 MnCl 2 in mice, and performs preliminary human dosimetry predictions. 51 Mn was produced by proton irradiation of electrodeposited isotopically-enriched 54 Fe targets. Radiochemically isolated 51 MnCl 2 was intravenously administered to ICR mice which were scanned by dynamic and static PET, followed by ex vivo gamma counting. Rapid blood clearance was observed with stable uptake in the pancreas, kidneys, liver, heart, and salivary gland. Dosimetry calculations predict that 370 MBq of 51 Mn in an adult human male would yield an effective dose equivalent of approximately 13.5 mSv, roughly equivalent to a clinical [ 18 F]-FDG procedure.

Titanium-45 ( 45 Ti) with a three-hour half-life (t 1/2 =3.08 h), low maximum positron energy and high positron emission branching ratio, is a suitable positron emission tomography (PET) isotope whose potential has not yet been fully explored. Complicated radiochemistry and rapid hydrolysis continue to be major challenges to the development of 45 Ti compounds based on a traditional chelator-based radiolabeling strategy. In this study we introduced an intrinsic (or chelator-free) radiolabeling technique for the successful labeling of 45 Ti using mesoporous silica nanoparticle (MSN). We synthesized uniform MSN with an average particle size of ∼150 nm in diameter. The intrinsic 45 Ti-labeling was accomplished through strong interactions between 45 Ti (hard Lewis acid) and hard oxygen donors (hard Lewis bases), the deprotonated silanol groups (-Si-O-) from the outer surface and inner meso-channels of MSN. In vivo tumor-targeted PET imaging of as-developed PEGylated [ 45 Ti]MSN was further demonstrated in the 4T1 murine breast tumor-bearing mice. This MSN-based intrinsic radiolabeling strategy could open up new possibilities and speed up the biomedical applications of 45 Ti in the future.

Pretargeted radioimmunotherapy (PRIT) with the β-emitting radionuclide 177 Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such as 213 Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of 213 Bi and 177 Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213 Bi-IMP288 were compared with those of 177 Lu-IMP288. Tumor targeting of 213 Bi-IMP288 and 177 Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of 213 Bi-IMP288 (6, 12, or 17 MBq) and 177 Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213 Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of 177 Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of 213 Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g). 213 Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of 213 Bi-IMP288 was comparable to that of 177 Lu-IMP288. Mice treated with a single dose of 213 Bi-IMP288 or 177 Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq 213 Bi-IMP288, 12 MBq 213 Bi-IMP288, and 60 MBq 177 Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq 213 Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213 Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: To our knowledge, this study shows for the first time that PRIT with TF2 and 213 Bi-IMP288 is feasible and at least as effective as 177 Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Pembrolizumab is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1) found on T and pro-B cells. Pembrolizumab prevents PD-1 ligation by both PD-L1 and PD-L2, preventing the immune dysregulation that otherwise occurs when T-cells encounter cells expressing these ligands. Clinically, PD-1 blockade elicits potent antitumor immune responses, and antibodies blocking PD-1 ligation, including pembrolizumab, have recently received Food and Drug Administration approval for the treatment of advanced melanoma, renal cell cancer, and non-small cell lung cancer., Methods: In this study, we evaluated the pharmacokinetics, biodistribution, and dosimetry of pembrolizumab in vivo, accomplished through radiolabeling with the positron emitter 89 Zr. PET imaging was used to evaluate the whole-body distribution of 89 Zr-deferoxamine (Df)-pembrolizumab in two rodent models (mice and rats). Data obtained from PET scans and biodistribution studies were extrapolated to humans to estimate the dosimetry of the tracer. As a proof of concept, the biodistribution of 89 Zr-Df-pembrolizumab was further investigated in a humanized murine model., Results: The tracer remained stable in blood circulation throughout the study and accumulated the greatest in liver and spleen tissues. Both mice and rats showed similar biodistribution and pharmacokinetics of 89 Zr-Df-pembrolizumab. In the humanized mouse model, T-cell infiltration into the salivary and lacrimal glands could be successfully visualized., Conclusion: These data will augment our understanding of the pharmacokinetics and biodistribution of radiolabeled pembrolizumab in vivo, while providing detailed dosimetry data that may lead to better dosing strategies in the future. These findings further demonstrate the utility of noninvasive in vivo PET imaging to dynamically track T-cell checkpoint receptor expression and localization in a humanized mouse model., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Despite the large interest in nuclear/optical multimodality imaging, the effect of radiation on the fluorescence of fluorophores remains largely unexplored. Herein, we report on the radiobleaching of cyanine fluorophores and describe conditions to provide robust radioprotection under practical (pre)clinical settings. We determined the radiosensitivity of several cyanine fluorescent compounds, including IRDye 800CW (800CW) and a dual modality imaging tetrapeptide containing DOTA as chelator and Dylight 800 as fluorophore, exposed to increasing activities of 111 In, 68 Ga, or 213 Bi (γ, EC/β, and α emitter, respectively). An activity and type of radiation-dependent radiation-induced loss of fluorescence, radiobleaching, of 800CW was observed upon incubation with escalating activities of 111 In, 68 Ga, or 213 Bi. 68 Ga showed the largest radiolytic effect, followed by 111 In and 213 Bi. The addition of oxygen radical scavengers including ethanol, gentisic acid, and ascorbic acid (AA), provided a concentration dependent radioprotective effect. These results supported the hypothesis of a free radical-mediated radiobleaching mechanism. AA provided the most robust radioprotection over a wide range of concentrations and preserved fluorescence at much higher radioactivity levels. Overall, both near-infrared fluorescent compounds displayed similar sensitivity, except for 213 Bi-irradiated solutions, where the dual modality construct exhibited enhanced radiolysis, presumably due to direct radiation damage from α particles. Concurrently, AA was not able to preserve fluorescence of the dual-modality molecule labeled with 213 Bi. Our findings have important consequences for several research areas including ROS sensing, radiation-mediated drug release (uncaging), fluorescent dosimetry, and in the preparation of dual-modality radiopharmaceuticals., Competing Interests: The authors have declared that no competing interest exists.

While position emission tomography (PET) is an important molecular imaging technique for both preclinical research and clinical disease diagnosis/prognosis, chelator-free radiolabeling has emerged as a promising alternative approach to label biomolecules or nanoprobes in a facile way. Herein, starting from bottom-up synthesized WS 2 nanoflakes, this study fabricates a unique type of WS 2 /WO x nanodots, which can function as inherent hard oxygen donor for stable radiolabeling with Zirconium-89 isotope ( 89 Zr). Upon simply mixing, 89 Zr can be anchored on the surface of polyethylene glycol (PEG) modified WS 2 /WO x (WS 2 /WO x -PEG) nanodots via a chelator-free method with surprisingly high labeling yield and great stability. A higher degree of oxidation in the WS 2 /WO x -PEG sample (WS 2 /WO x (0.4)) produces more electron pairs, which would be beneficial for chelator-free labeling of 89 Zr with higher yields, suggesting the importance of surface chemistry and particle composition to the efficiency of chelator-free radiolabeling. Such 89 Zr-WS 2 /WO x (0.4)-PEG nanodots are found to be an excellent PET contrast agent for in vivo imaging of tumors upon intravenous administration, or mapping of draining lymph nodes after local injection., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The engineering of a novel dual-modality imaging probe is reported here by intrinsically labeling zirconium-89 ((89) Zr, a positron emission radioisotope with a half-life of 78.4 h) to PEGylated Gd2 O2 S:Eu nanophorphors, forming [(89) Zr]Gd2 O2 S:Eu@PEG for in vivo positron emission tomography/radioluminescence lymph node mapping., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched (72)Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure (72)As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming (72)Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation.

Traditional chelator-based radio-labeled nanoparticles and positron emission tomography (PET) imaging are playing vital roles in the field of nano-oncology. However, their long-term in vivo integrity and potential mismatch of the biodistribution patterns between nanoparticles and radio-isotopes are two major concerns for this approach. Here, we present a chelator-free zirconium-89 ((89)Zr, t1/2 = 78.4 h) labeling of mesoporous silica nanoparticle (MSN) with significantly enhanced in vivo long-term (>20 days) stability. Successful radio-labeling and in vivo stability are demonstrated to be highly dependent on both the concentration and location of deprotonated silanol groups (-Si-O(-)) from two types of silica nanoparticles investigated. This work reports (89)Zr-labeled MSN with a detailed labeling mechanism investigation and long-term stability study. With its attractive radio-stability and the simplicity of chelator-free radio-labeling, (89)Zr-MSN offers a novel, simple, and accurate way for studying the in vivo long-term fate and PET image-guided drug delivery of MSN in the near future.

There is a growing demand for long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions. This work develops the production of (52)Mn and establishes proof of concept for the use of divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain. (52)Mn was produced via proton irradiation of a natural chromium target. In a comparison of two (52)Mn separation methods, solvent-solvent extraction was preferred over ion exchange chromatography because of reduced chromium impurities and higher (52)Mn recovery. In vitro uptake of Mn-based PET and MRI contrast agents ((52)Mn(2+) and Mn(2+), respectively) was enhanced in DMT1 over-expressing human neural progenitor cells (hNPC-DMT1) compared to wild-type control cells (hNPC-WT). After cell transplantation in the rat striatum, increased uptake of Mn-based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese-enhanced MRI (MEMRI) and ex vivo PET and autoradiography. These initial studies indicate that this approach holds promise for dual-modality PET/MR tracking of transplanted stem cells in the central nervous system and prompt further investigation into the clinical applicability of this technique.

Intrinsically germanium-69-labeled super-paramagnetic iron oxide nanoparticles are synthesized via a newly developed, fast and highly specific chelator-free approach. The biodistribution pattern and the feasibility of (69) Ge-SPION@PEG for in vivo dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging and lymph-node mapping are investigated, which represents the first example of the successful utilization of a (69) Ge-based agent for PET/MR imaging., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The overexpression of integrin αvβ3 has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine-glycine-aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin αvβ3 expression and for targeted radionuclide therapy. In this study, we aim to develop a (44)Sc-labeled RGD-based peptide for in vivo positron emission tomography (PET) imaging of integrin αvβ3 expression in a preclinical cancer model. High quality (44)Sc (t1/2, 3.97 h; β(+) branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated (44)Sc-DOTA-(cRGD)2 uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17, and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (n = 3), which were validated by ex vivo biodistribution experiments. The integrin αvβ3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with (64)Cu or (68)Ga. Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.

Purpose: High tumor microvessel density correlates with a poor prognosis in multiple solid tumor types. The clinical gold standard for assessing microvessel density is CD105 immunohistochemistry on paraffin-embedded tumor specimens. The goal of this study was to develop an (89)Zr-based PET tracer for noninvasive imaging of CD105 expression., Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) and labeled with (89)Zr. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and Df-TRC105. PET imaging, biodistribution, blocking, and ex-vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the pharmacokinetics and tumor-targeting of (89)Zr-Df-TRC105. Another chimeric antibody, cetuximab, was used as an isotype-matched control., Results: FACS analysis of HUVECs revealed no difference in CD105 binding affinity between TRC105 and Df-TRC105, which was further validated by fluorescence microscopy. (89)Zr labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of (89)Zr-Df-TRC105 was 6.1 ± 1.2, 14.3 ± 1.2, 12.4 ± 1.5, 7.1 ± 0.9, and 5.2 ± 0.3 %ID/g at 5, 24, 48, 72, and 96 h after injection, respectively (n = 4), higher than all organs starting from 24 h after injection, which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with (89)Zr-Df-cetuximab, and ex-vivo histology all confirmed the in vivo target specificity of (89)Zr-Df-TRC105., Conclusion: We report here the first successful PET imaging of CD105 expression with (89)Zr as the radiolabel. Rapid, persistent, CD105-specific uptake of (89)Zr-Df-TRC105 in the 4T1 tumor was observed.

Positron emission tomography (PET) imaging with radiolabeled monoclonal antibodies has always been a dynamic area in molecular imaging. With decay half-life (3.3 d) well matched to the circulation half-lives of antibodies (usually on the order of days), (89)Zr has been extensively studied over the last decade. This review article will give a brief overview on (89)Zr isotope production, the radiochemistry generally used for (89)Zr-labeling, and the PET tracers that have been developed using (89)Zr. To date, (89)Zr-based PET imaging has been investigated for a wide variety of cancer-related targets, which include human epidermal growth factor receptor 2, epidermal growth factor receptor, prostate-specific membrane antigen, splice variant v6 of CD44, vascular endothelial growth factor, carbonic anhydrase IX, insulin-like growth factor 1 receptor, among others. With well-developed radiochemistry, commercial availability of chelating agents for (89)Zr labeling, increasingly widely available isotope supply, as well as successful proof-of-principle in pilot human studies, it is expected that PET imaging with (89)Zr-based tracers will be a constantly evolving and highly vibrant field in the near future.

In this study, radiolabeled FAPI-46-F1D (IC SB 50 sb = 157.8 ± 14.5 pM) and FAPI-46-Ibu (IC SB 50 sb = 39.4 ± 16.1 pM) showed enhanced inhibitory activity, while FAPI-46-EB (IC SB 50 sb = 634.3 ± 102.3 pM) and FAP-2286 (IC SB 50 sb = 247.6 ± 71.1 pM) showed reduced or very similar inhibitory activity compared to FAPI-46 (IC SB 50 sb = 247.0 ± 17 pM). The first approach is multimerization of high-affinity FAPI ligands to enhance residence time in FAP-positive tumors [[10]], such as dimeric FAPI ligands that offer better chances of rebinding to their target, with slower off-rates than are seen with their monovalent counterparts [[9]-[11]]. While the potential of these radiolabeled FAPIs as SPECT/PET imaging agents is incontestable, their suitability for therapy is impaired by their short tumor retention leading to suboptimal radiation doses to the tumor [[2], [8]]. [Extracted from the article]

Purpose: This review aims to provide a comprehensive overview of the latest literature on personalized lung cancer management using different ligands and radionuclide-based tumor-targeting agents. Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Due to the heterogeneity of lung cancer, advances in precision medicine may enhance the disease management landscape. More recently, theranostics using the same molecule labeled with two different radionuclides for imaging and treatment has emerged as a promising strategy for systemic cancer management. In radionuclide-based theranostics, the target, ligand, and radionuclide should all be carefully considered to achieve an accurate diagnosis and optimal therapeutic effects for lung cancer. Methods: We summarize the latest radiotracers and radioligand therapeutic agents used in diagnosing and treating lung cancer. In addition, we discuss the potential clinical applications and limitations associated with target-dependent radiotracers as well as therapeutic radionuclides. Finally, we provide our views on the perspectives for future development in this field. Conclusions: Radionuclide-based theranostics show great potential in tailored medical care. We expect that this review can provide an understanding of the latest advances in radionuclide therapy for lung cancer and promote the application of radioligand theranostics in personalized medicine. [ABSTRACT FROM AUTHOR]

Radio‐nanomedicine, or the use of radiolabeled nanoparticles in nuclear medicine, has attracted much attention in the last few decades. Since the discovery of Cerenkov radiation and its employment in Cerenkov luminescence imaging, the combination of nanomaterials and Cerenkov radiation emitters has been revolutionizing the way nanomaterials are perceived in the field: from simple inert carriers of radioactivity to activatable nanomaterials for both diagnostic and therapeutic applications. Herein, we provide a comprehensive review on the types of nanomaterials that have been used to interact with Cerenkov radiation and the gamma and beta scintillation of radionuclides, as well as on their biological applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most commonly diagnosed malignant tumors, possessing high incidence and mortality rates that threaten women's health. Thus, early and effective breast cancer diagnosis is crucial for enhancing the survival rate. Radionuclide molecular imaging displays its advantages for detecting breast cancer from a functional perspective. Noninvasive visualization of biological processes with radionuclide-labeled small metabolic compounds helps elucidate the metabolic state of breast cancer, while radionuclide-labeled ligands/antibodies for receptor-targeted radionuclide molecular imaging is sensitive and specific for visualization of the overexpressed molecular markers in breast cancer. This review focuses on the most recent developments of novel radiotracers as promising tools for early breast cancer diagnosis. Breast cancer is a malignant tumor that can affect women worldwide and endanger their health and wellbeing. Early detection of breast cancer can significantly improve the prognosis and survival rate of patients, but with traditional anatomical imagine methods, it is difficult to detect lesions before morphological changes occur. Radionuclide-based molecular imaging based on positron emission tomography (PET) and single-photon emission computed tomography (SPECT) displays its advantages for detecting breast cancer from a functional perspective. Radionuclide labeling of small metabolic compounds can be used for imaging biological processes, while radionuclide labeling of ligands/antibodies can be used for imaging receptors. Noninvasive visualization of biological processes helps elucidate the metabolic state of breast cancer, while receptor-targeted radionuclide molecular imaging is sensitive and specific for visualization of the overexpressed molecular markers in breast cancer, contributing to early diagnosis and better management of cancer patients. The rapid development of radionuclide probes aids the diagnosis of breast cancer in various aspects. These probes target metabolism, amino acid transporters, cell proliferation, hypoxia, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), gastrin-releasing peptide receptor (GRPR) and so on. This article provides an overview of the development of radionuclide molecular imaging techniques present in preclinical or clinical studies, which are used as tools for early breast cancer diagnosis. [ABSTRACT FROM AUTHOR]

Layered double hydroxide (LDH) nanomaterial has emerged as a novel delivery agent for biomedical applications due to its unique structure and properties. However, in vivo positron emission tomography (PET) imaging with LDH nanoparticles has not been achieved. The aim of this study is to explore chelator-free labeling of LDH nanoparticles with radioisotopes for in vivo PET imaging. Bivalent cation 64Cu2+ and trivalent cation 44Sc3+ were found to readily label LDH nanoparticles with excellent labeling efficiency and stability, whereas tetravalent cation 89Zr4+ could not label LDH since it does not fit into the LDH crystal structure. PET imaging shows that prominent tumor uptake was achieved in 4T1 breast cancer with 64Cu-LDH-BSA via passive targeting alone (7.7 ± 0.1%ID/g at 16 h post-injection; n = 3). These results support that LDH is a versatile platform that can be labeled with various bivalent and trivalent radiometals without comprising the native properties, highly desirable for PET image-guided drug delivery. [ABSTRACT FROM AUTHOR]