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A recent article in the European Journal of Nuclear Medicine & Molecular Imaging discusses the development of a macrocyclic peptide PET radioligand for PD-L1, a protein involved in immune checkpoint mechanisms. The article highlights the challenges and opportunities in individualizing treatment for patients who could benefit from anti-PD-1/PD-L1 therapy and monitoring their response during therapy. The authors present a study on the discovery and evaluation of a novel fluorine-18 labeled macrocyclic peptide-based PET ligand, [18F]BMS-986229, which demonstrated high affinity for PD-L1 and rapid clearance from non-PD-L1 tissues. The study suggests that this ligand has the potential to facilitate a broader clinical application of PD-L1 PET imaging. [Extracted from the article]

This article discusses the use of radiomics, a method that involves extracting imaging features from radiologic images, to predict lymph node metastasis (LNM) in colorectal cancer (CRC) patients. The study found that radiomics analysis using 2-[18F]FDG PET-based imaging was more effective in predicting LNM compared to traditional CT and PET reports. The study also highlighted the need for standardization in radiomics workflow and the development of automated segmentation tools. While promising, further research and validation in larger clinical trials are needed before radiomics can be integrated into routine clinical practice. [Extracted from the article]

The article discusses the use of positron emission tomography (PET) imaging for the visualization and quantification of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in cancer treatment. The development of small molecule radiotracers for PET imaging of PD-L1 is explored as an alternative to radiolabeled antibodies, with advantages including rapid clearance and improved tissue penetration. Various small molecule tracers, such as WL12, PEG-TPP-1, nanobodies, and D-peptides, are discussed, highlighting their potential for PET imaging of PD-L1 expression in tumors. The article also introduces a novel small-molecule radiotracer called [68Ga]Ga-D-PMED, which shows promise for visualizing PD-L1 expression in vivo. Comparative studies of different tracers can provide insights into their strengths and limitations, aiding in the development of improved PET imaging strategies for personalized immunotherapy in cancer patients. [Extracted from the article]

Purpose: Classical brachytherapy of solid malignant tumors is an invasive procedure which often results in an uneven dose distribution, while requiring surgical removal of sealed radioactive seed sources after a certain period of time. To circumvent these issues, we report the synthesis of intrinsically radiolabeled and gum Arabic glycoprotein functionalized [169Yb]Yb2O3 nanoseeds as a novel nanoscale brachytherapy agent, which could directly be administered via intratumoral injection for tumor therapy. Methods: 169Yb (T½ = 32 days) was produced by neutron irradiation of enriched (15.2% in 168Yb) Yb2O3 target in a nuclear reactor, radiochemically converted to [169Yb]YbCl3 and used for nanoparticle (NP) synthesis. Intrinsically radiolabeled NP were synthesized by controlled hydrolysis of Yb3+ ions in gum Arabic glycoprotein medium. In vivo SPECT/CT imaging, autoradiography, and biodistribution studies were performed after intratumoral injection of radiolabeled NP in B16F10 tumor bearing C57BL/6 mice. Systematic tumor regression studies and histopathological analyses were performed to demonstrate therapeutic efficacy in the same mice model. Results: The nanoformulation was a clear solution having high colloidal and radiochemical stability. Uniform distribution and retention of the radiolabeled nanoformulation in the tumor mass were observed via SPECT/CT imaging and autoradiography studies. In a tumor regression study, tumor growth was significantly arrested with different doses of radiolabeled NP compared to the control and the best treatment effect was observed with ~ 27.8 MBq dose. In histopathological analysis, loss of mitotic cells was apparent in tumor tissue of treated groups, whereas no significant damage in kidney, lungs, and liver tissue morphology was observed. Conclusions: These results hold promise for nanoscale brachytherapy to become a clinically practical treatment modality for unresectable solid cancers. [ABSTRACT FROM AUTHOR]

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]

Incorporation of ABDs into nanobodies will enable the fusion proteins simultaneously binding to endogenous albumin, thereby extending their cycle time and increasing tumor uptake, leading to improved imaging contrast [[21]]. SP 177 sp Lu-MIRC213-709 has demonstrated excellent tumor uptake and prolonged blood circulation time, with a tumor uptake of 6.59 ± 1.67, 27.65 ± 7.66, 30.82 ± 7.29, 19.95 ± 1.76, and 17.61 ± 2.63 %ID/g at 1, 24, 48, 72, and 120 h post-injection, respectively ( I n i = 4). Another promising strategy involves fusing nanobodies with an albumin-binding domain (ABD) to extend their cycle time and increase tumor uptake, leading to improved imaging contrast [[16]]. [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]

PSMA theranostics: review of the current status of PSMA-targeted imaging and radioligand therapy. Astatine-211 for PSMA-targeted -radiation therapy of micrometastatic prostate cancer: a sustainable approach towards precision oncology Biodistribution and dosimetry for combined [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T therapy using multi-isotope quantitative SPECT imaging. Several peptidomimetic inhibitors of PSMA (such as PSMA-11, PSMA-617, PSMA I&T, MIP-1095, DCFPyL, etc.) typically having a Glu-ureido component that serves as the PSMA binding motif have been designed and translated for routine clinical use [[4], [7]-[9]]. [Extracted from the article]

The article focuses on bispecific proteins, particularly bispecific antibodies (BsAbs), and their potential in the treatment of diseases. Topics covered include the advantages and classifications of BsAbs, their application in pancreatic ductal adenocarcinoma (PDAC) treatment using an ultra-small bispecific fusion protein, and the use of bispecific proteins in nuclear medicine for imaging and combination therapies.

An editorial is presented on use of Photodynamic therapy (PDT), a two-step process that utilizes light energy to excite a photosensitizer to generate harmful singlet oxygen, as an effective treatment approach for several types of cancer. It presents the views on comparison of PDT with conventional cancer treatments, such as chemotherapy and surgery.

Objective: Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality rates. In many non-prostate solid tumors such as HCC, prostate-specific membrane antigens (PSMA) are overexpressed in tumor-associated endothelial cells. Therefore, the aim of this study was to evaluate the performance of [68Ga]Ga-PSMA-617 PET imaging on HCC with different animal models, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX), and to explore its mechanisms of function. Methods: [68Ga]Ga-PSMA-617 was prepared. The expression level of PSMA in two human hepatocellular cancer cells (HepG2 and HuH-7) was evaluated, and the cellular uptakes of [68Ga]Ga-PSMA-617 were assayed. HepG2 and HuH-7 subcutaneous xenograft models, HepG2 orthotopic xenograft models, and four different groups of PDX models were prepared. Preclinical pharmacokinetics and performance of [68Ga]Ga-PSMA-617 were evaluated in different types of HCC xenografts models using small animal PET and biodistribution studies. Results: Low PSMA expression level of HepG2 and HuH-7 cells was observed, and the cellular uptake and blocking study confirmed the non-specificity of the PSMA-targeted probe binding to HepG2 and HuH-7 cells. In the subcutaneous xenograft models, the tumor uptakes at 0.5 h were 0.76 ± 0.12%ID/g (HepG2 tumors) and 0.78 ± 0.08%ID/g (HuH-7 tumors), respectively, which were significantly higher than those of the blocking groups (0.23 ± 0.04%ID/g and 0.20 ± 0.04%ID/g, respectively). In the orthotopic xenograft models, PET images clearly displayed the tumor locations based on the preferential accumulation of [68Ga]Ga-PSMA-617 in tumor tissue versus normal liver tissue, suggesting the possibility of using [68Ga]Ga-PSMA-617 PET imaging to detect primary HCC lesions in deep tissue. In the four different groups of HCC PDX models, PET imaging with [68Ga]Ga-PSMA-617 provided clear tumor uptakes with prominent tumor-to-background contrast, further demonstrating its potential for the clinical imaging of PSMA-positive HCC lesions. The staining of tumor tissue sections with CD31- and PSMA-specific antibodies visualized the tumor-associated blood vessels and PSMA expression on endothelial cells in subcutaneous, orthotopic tissues, and PDX tissues, confirming the imaging with [68Ga]Ga-PSMA-617 might be mediated by targeting tumor associated endothelium. Conclusion: In this study, in vivo PET on different types of HCC xenograft models illustrated high uptake within tumors, which confirmed that [68Ga]Ga-PSMA-617 PET may be a promising imaging modality for HCC by targeting tumor associated endothelium. [ABSTRACT FROM AUTHOR]

An editorial is presented on announcing the publication of a European Journal of Nuclear Medicine and Molecular Imaging (EJNMMI). Topics include indicated the ever-increasing global impact and infuence of EJNMMI in the feld of nuclear medicine and molecular imaging; and high-quality manuscripts on any specific focusing topic such as artifcial intelligence, new tracers, fibroblast activation protein inhibitor (FAPI), immunotherapy, and total-body PET.

Fibroblast activation protein (FAP) is a type II membrane-bound glycoprotein which is overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Since the first clinical application of quinoline-based FAP ligands in 2018, FAP inhibitor (FAPI)-based PET imaging and radiotherapy have been investigated for a wide variety of diseases, both cancerous and non-cancerous. As a consequence, promising strides have been made in particular to improve the understanding of FAPI-based PET imaging and the potential value of FAPI-based tumor radiotherapy. Herein, we present a comprehensive review of radiolabeled FAPI, including their clinical translation, in order to clarify the current and potential future role of this class of molecules in nuclear medicine. In particular, this review underlines the value of FAPI radiopharmaceuticals in the diagnosis or therapy of tumors or benign conditions. However, limitations in present studies have hampered a precise evaluation of FAPI radiopharmaceuticals. Despite this, it will likely be worthwhile to further explore the clinical value of FAPI in diagnosis and therapy through better-designed and larger-population clinical trials in the future. [ABSTRACT FROM AUTHOR]

Purpose: Abnormal CD38 expression in some hematologic malignancies, including lymphoma, has made it a biomarker for targeted therapies. Daratumumab (Dara) is the first FDA-approved CD38-specific monoclonal antibody, enabling successfully immunoPET imaging over the past years. Radiolabeled Dara however has a long blood circulation and delayed tumor uptake which can limit its applications. The focus of this study is to develop 64Cu-labeled Dara-F(ab′)2 for the visualization of CD38 in lymphoma models. Methods: F(ab′)2 fragment was prepared from Dara using an IdeS enzyme and purified with Protein A beads. Western blotting, flow cytometry, and surface plasmon resonance (SPR) were performed for in vitro assay. Probes were labeled with 64Cu after the chelation of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Small animal PET imaging and quantitative analysis were performed after injection of 64Cu-labeled Dara-F(ab′)2, IgG-F(ab′)2, and Dara for evaluation in lymphoma models. Results: Flow cytometry and SPR assay proved the specific binding ability of Dara-F(ab′)2 and NOTA-Dara-F(ab′)2 in vitro. Radiolabeling yield of [64Cu]Cu-NOTA-Dara-F(ab′)2 was over 90% and with a specific activity of 4.0 ± 0.6 × 103 MBq/μmol (n = 5). PET imaging showed [64Cu]Cu-NOTA-Dara-F(ab′)2 had a rapid and high tumor uptake as early as 2 h (6.9 ± 1.2%ID/g) and peaked (9.5 ± 0.7%ID/g) at 12 h, whereas [64Cu]Cu-NOTA-Dara reached its tumor uptake peaked at 48 h (8.3 ± 1.4%ID/g, n = 4). In comparison, IgG-F(ab′)2 and HBL-1 control groups found no noticeable tumor uptake. [64Cu]Cu-NOTA-Dara-F(ab′)2 had significantly lower uptake in blood pool, bone, and muscle than [64Cu]Cu-NOTA-Dara and its tumor-to-blood and tumor-to-muscle ratios were significantly higher than controls. Conclusions: [64Cu]Cu-NOTA-Dara-F(ab′)2 showed a rapid and high tumor uptake in CD38-positive lymphoma models with favorable imaging contrast, showing its promise as a potential PET imaging agent for future clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: Without a standard test for pancreatic carcinomas, this highly lethal disease is normally diagnosed at its advanced stage, leading to a low survival rate of patients. Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is associated with cell proliferation and highly expressed in most of solid epithelial tumors, including pancreatic cancer. A non-invasive method of imaging Trop-2 would greatly benefit clinical diagnosis and monitoring of pancreatic cancer. In the current study, 89Zr-labeled anti-Trop-2 antibody (AF650) was recruited for the systemic evaluation of Trop-2 as an immunoPET target for pancreatic cancer imaging. Methods: AF650 was conjugated with desferrioxamine (DFO) and then radiolabeled with 89Zr. Trop-2 expression levels were determined in three pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and AsPC-1) via western blot, flow cytometry, saturation binding assay, and immunofluorescence staining. The targeting capacity of 89Zr-DFO-AF650 was evaluated in mouse models with subcutaneous xenograft of pancreatic cancers via PET imaging and bio-distribution studies. In addition, a Trop-2-positive orthotopic cancer model was recruited for further validating the targeting specificity of 89Zr-DFO-AF650. Results: BxPC-3 cells expressed high levels of Trop-2, while AsPC-1 and MIA PaCa-2 cells expressed low levels of Trop-2. Additionally, 89Zr-DFO-AF650 exhibited high specificity to Trop-2 in BxPC-3 cells (Kd = 22.34 ± 2.509 nM). In subcutaneous xenograft models, about 28.8 ± 7.63%ID/g tracer accumulated in the BxPC-3 tumors at 120 h post injection, which was much higher than those reaching MIA PaCa-2 (6.76 ± 2.08%ID/g) and AsPC-1 (3.51 ± 0.69%ID/g) tumors (n = 4). More importantly, 89Zr-DFO-AF650 could efficiently distinguish primary tumors in the orthotopic BxPC-3 cancer model, showing high correlation between PET imaging and bio-distribution and sensitivity. Conclusions: 89Zr-DFO-AF650 can be effectively used to detect pancreatic cancer via Trop-2-mediated immunoPET in vivo, clearly revealing the great potential of Trop-2-based non-invasive imaging in pancreatic cancer detection and treatment monitoring. [ABSTRACT FROM AUTHOR]

Total-body PET/CT using half-dose FDG and compared with conventional PET/CT using full-dose FDG in lung cancer. The scanner has a 194 cm axial field-of-view for PET imaging provided by > 500,000 detector elements, as well as an 80-row, 160-slice CT scanner for anatomical imaging and PET attenuation correction [[3]], and was later called the uEXPLORER PET/CT scanner (United Imaging Healthcare Co., Ltd.). This CT scan was used for attenuation coefficient (AC) instead of disease diagnosis, with its effective radiation dose (~ 2.4 mSv) being significantly lower than a typical diagnostic body CT exam and the CT component of a typical modern PET/CT exam (~ 5-10 mSv) [[13]-[15]]. [Extracted from the article]

With continued development and optimization of the PET/CT scanner, as well as cost reduction, we believe LAFOV PET/CT scanners will become widely available in the future, just like PET/CT scanners have replaced PET scanners more than a decade ago [[41]]. Although the CT dose was not specifically stated, the effective radiation dose associated with this type of low-dose CT scan is approximately 2-3 mSv, which is significantly lower than a typical diagnostic body CT exam and the CT component of a typical modern PET/CT exam (~ 5-10 mSv) [[21]-[23]]. With the constant advancements of CT tube and detector technologies [[24]], as well as artificial intelligence (AI)-based CT dose reduction technologies (e.g., TrueFidelity Deep Learning Image Reconstruction from GE Healthcare [[25]] and Advanced Intelligent Clear-IQ Engine from Canon Medical Systems USA Inc. [[27]-[29]]), it is very likely that the CT component of LAFOV PET/CT exam will be further reduced to the sub-mSv level in the near future, which means the entire whole-body PET/CT exam with a low dose of injected PET tracer can be achieved below 2 mSv. 10.1007/s00259-021-05357-5. 33866409 20 Tan H, Sui X, Yin H, Yu H, Gu Y, Chen S. Total-body PET/CT using half-dose FDG and compared with conventional PET/CT using full-dose FDG in lung cancer. [Extracted from the article]

A combination of [ SP 18 sp F]-FBY PET with various other imaging techniques or other PET tracers that can better delineate early-stage, low-grade brain tumors may be needed for the sub-population of low-grade cancer patients, since early and accurate detection of brain tumor is crucial for longer survival and better clinical outcome. 1a), were developed and readily labeled with SP 18 sp F for PET imaging, which can serve as general imaging probes for AATs [[24]]. This article is part of the Topical Collection on Radiopharmacy Given the many limitations of [ SP 18 sp F]-FDG in glioma imaging, such as high background uptake in normal brain tissue and significant uptake in inflammation, the quest for better positron emission tomography (PET) tracers for brain tumor imaging has been constant [[1]]. [Extracted from the article]

This article is part of the Topical Collection on Hematology Immunotherapy, a therapeutic approach that activates and utilizes a patient's own immune system, has gathered tremendous attention from both patients and researchers, especially after the 2018 Nobel Prize in Physiology or Medicine was awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation." In addition, multi-color optical imaging and multispectral optoacoustic tomography can serve as complementary imaging modalities for simultaneously imaging different biomarkers, although they are not as sensitive and quantitative as radionuclide-based imaging. Since recruitment of MMR SP + sp tumor-associated macrophages is generally related to poor responsiveness to immunotherapy [[21]], MMR-targeted imaging may be beneficial in predicting and longitudinally monitoring the response of immunotherapy. Towards this goal, [ SP 68 sp Ga]Ga-NOTA-Nb1053-based immunoPET could play an important role in selecting patients who are suitable for anti-CD38 therapy, and predicting and evaluating consequent therapeutic efficacy by longitudinal monitoring of CD38 expression. [Extracted from the article]

Purpose: We dual-labeled an intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb) and evaluated its effectiveness for lesion detection and surgical navigation in pancreatic ductal adenocarcinoma (PDAC) via multiple noninvasive imaging approaches, including positron emission tomography (PET), near-infrared fluorescence (NIRF), and Cerenkov luminescence imaging (CLI). Methods: ICAM-1 expression in PDAC cell lines (BxPC-3 and AsPC-1) was assessed via flow cytometry and immunofluorescent staining. An ICAM-1 mAb labeled by IRDye 800CW and radionuclide zirconium-89 (denoted as [89Zr]Zr-DFO-ICAM-1-IR800) was synthesized. Its performance was validated via in vivo comparative PET/NIRF/CLI and biodistribution (Bio-D) studies in nude mice bearing subcutaneous BxPC-3/AsPC-1 tumors or orthotopic BxPC-3 tumor models using nonspecific IgG as an isotype control tracer. Results: ICAM-1 expression was strong in the BxPC-3 and minimal in the AsPC-1 cell line. Both multimodality imaging and Bio-D data exhibited more prominent uptake of [89Zr]Zr-DFO-ICAM-1-IR800 in BxPC-3 tumors than in AsPC-1 tumors. The uptake of [89Zr]Zr-DFO-IgG-IR800 in BxPC-3 tumors was similar to that of [89Zr]Zr-DFO-ICAM-1-IR800 in AsPC-1 tumors. These results demonstrate the desirable affinity and specificity of [89Zr]Zr-DFO-ICAM-1-IR800 compared to [89Zr]Zr-DFO-IgG-IR800. Orthotopic BxPC-3 tumor foci could also be clearly delineated by [89Zr]Zr-DFO-ICAM-1-IR800. An intermodal match was achieved in the ICAM-1–targeted immunoPET/NIRF/CLI. The positive expression levels of ICAM-1 in BxPC-3 tumor tissue were further confirmed by immunohistopathology. Conclusion: We successfully developed a dual-labeled ICAM-1–targeted tracer for PET/NIRF/CLI of PDAC that can facilitate better diagnosis and intervention of PDAC upon clinical translation. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) by near-infrared (NIR) irradiation is a promising technique for treating various cancers. Here, we reported the development of free-standing wafer-scale Au nanosheets (NSs) that exhibited an impressive PDT effect. The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm. These Au NSs were found very effective in generating singlet oxygen under NIR irradiation. In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology. Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation. This performance is comparable to using 10 times mass loading of Au nanoparticles (NPs). This work suggests that two-dimensional (2D) Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency. [ABSTRACT FROM AUTHOR]

Purpose: Intercellular adhesion molecule-1 (ICAM-1, CD54) is an emerging therapeutic target for a variety of solid tumors including melanoma and anaplastic thyroid cancer (ATC). This study aims to develop an ICAM-1-targeted immuno-positron emission tomography (immunoPET) imaging strategy and assess its diagnostic value in melanoma and ATC models. Methods: Flow cytometry was used to screen ICAM-1-positive melanoma and ATC cell lines. Melanoma and ATC models were established using A375 cell line and THJ-16T cell line, respectively. An ICAM-1-specific monoclonal antibody (R6-5-D6) and a nonspecific human IgG were radiolabeled with 64Cu and the diagnostic efficacies were interrogated in tumor-bearing mouse models. Biodistribution and fluorescent imaging studies were performed to confirm the specificity of the ICAM-1-targeted imaging probes. Results: ICAM-1 was strongly expressed on melanoma and advanced thyroid cancer cell lines. 64Cu-NOTA-ICAM-1 immunoPET imaging efficiently delineated A375 melanomas with a peak tumor uptake of 21.28 ± 6.56 %ID/g (n = 5), significantly higher than that of 64Cu-NOTA-IgG (10.63 ± 2.58 %ID/g, n = 3). Moreover, immunoPET imaging with 64Cu-NOTA-ICAM-1 efficiently visualized subcutaneous and orthotopic ATCs with high clarity and contrast. Fluorescent imaging with IRDye 800CW-ICAM-1 also visualized orthotopic ATCs and the tumor uptake could be blocked by the ICAM-1 parental antibody R6-5-D6, indicating the high specificity of the developed probe. Finally, blocking with the human IgG prolonged the circulation of the 64Cu-NOTA-ICAM-1 in R2G2 mice without compromising the tumor uptake. Conclusion: ICAM-1-targeted immunoPET imaging could characterize ICAM-1 expression in melanoma and ATC, which holds promise for optimizing ICAM-1-targeted therapies in the future. [ABSTRACT FROM AUTHOR]

DNA tetrahedron nanostructure (DTN) is one of the simplest DNA nanostructures and has been successfully applied for biosensing, imaging, and treatment of cancer. To facilitate its biomedical applications and potential clinical translation, fundamental understanding of DTN's transportation among major organs in living organisms becomes increasingly important. Here, we describe the efficient renal clearance of DTN in healthy mice by using positron emission tomography (PET) imaging. The kidney elimination of DTN was later applied for renal function evaluation in murine models of unilateral ureteral obstruction (UUO). We further established a mathematical program of DTN to validate its changes of transportation pattern in healthy and UUO mice. We believe the establishment of pharmacokinetic profiles and mathematical model of DTN may provide insight for future optimization of DNA nanostructures for biomedical applications. [ABSTRACT FROM AUTHOR]

Reactive oxygen and nitrogen species (RONS) are essential for normal physiological processes and play important roles in cell signaling, immunity, and tissue homeostasis. However, excess radical species are implicated in the development and augmented pathogenesis of various diseases. Several antioxidants may restore the chemical balance, but their use is limited by disappointing results of clinical trials. Nanoparticles are an attractive therapeutic alternative because they can change the biodistribution profile of antioxidants, and possess intrinsic ability to scavenge RONS. Herein, we review the types of RONS, how they are implicated in several diseases, and the types of nanoparticles with inherent antioxidant capability, their mechanisms of action, and their biological applications. [ABSTRACT FROM AUTHOR]

Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 (89Zr)-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/shell hybrid nanoparticles for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanoshells to form the yolk/shell-structured hybrid nanoparticles. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody (specific for CD105/endoglin), and 89Zr (a positron-emitting radioisotope), and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1 murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor-targeted imaging and drug delivery. [ABSTRACT FROM AUTHOR]

Purpose: CD38 is considered a potential biomarker for multiple myeloma (MM) and has shown a strong link with chronic lymphocytic leukemia due to high and uniform expression on plasma cells. In vivo evaluation of CD38 expression may provide useful information about lesion detection and prognosis of treatment in MM. In this study, immunoPET imaging with 89Zr-labeled daratumumab was used for differentiation of CD38 expression in murine lymphoma models to provide a potential non-invasive method for monitoring CD38 in the clinic.Methods: Daratumumab was radiolabeled with 89Zr (t1/2 = 78.4 h) via conjugation with desferrioxamine (Df). After Western blot (WB) was used to screen CD38 expression in five lymphoma cell lines, flow cytometry and cellular binding assays were performed to test the binding ability of labeled or conjugated daratumumab with CD38 in vitro. PET imaging and biodistribution studies were performed to evaluate CD38 expression after injection of 89Zr-Df-daratumumab. 89Zr-Df-IgG was also evaluated as a non-specific control group in the Ramos model. Finally, CD38 expression in tumor tissues was verified by histological analysis.Results: Using WB screening, the Ramos cell line was found to express the highest level of CD38 while the HBL-1 cell line had the lowest expression. Df-conjugated and 89Zr-labeled daratumumab displayed similar high binding affinities with Ramos cells. PET imaging of 89Zr-Df-daratumumab showed a high tumor uptake of up to 26.6 ± 8.0 %ID/g for Ramos at 120 h post-injection, and only up to 6.6 ± 2.9 %ID/g for HBL-1 (n = 4). Additionally, 89Zr-Df-IgG demonstrated a low tumor uptake in the Ramos model (only 4.3 ± 0.8 %ID/g at 120 h post-injection). Ex vivo biodistribution studies showed similar trends with imaging results. Immunofluorescence staining of tumor tissues verified higher CD38 expression of Ramos than that of HBL-1.Conclusions: The role of 89Zr-Df-daratumumab was investigated for evaluating CD38 expression in lymphoma models non-invasively and was found to be to a promising imaging agent of CD38-positive hematological diseases such as MM in future clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: Human epidermal growth factor receptor 2 (HER2) is over-expressed in over 30% of ovarian cancer cases, playing an essential role in tumorigenesis and metastasis. Non-invasive imaging of HER2 is of great interest for physicians as a mean to better detect and monitor the progression of ovarian cancer. In this study, HER2 was assessed as a biomarker for ovarian cancer imaging using Cu-labeled pertuzumab for immunoPET imaging. Methods: HER2 expression and binding were examined in three ovarian cancer cell lines (SKOV3, OVCAR3, Caov3) using in vitro techniques, including western blot and saturation binding assays. PET imaging and biodistribution studies in subcutaneous models of ovarian cancer were performed for non-invasive in vivo evaluation of HER2 expression. Additionally, orthotopic models were employed to further validate the imaging capability of Cu-NOTA-pertuzumab. Results: HER2 expression was highest in SKOV3 cells, while OVCAR3 and Caov3 displayed lower HER2 expression. Cu-NOTA-pertuzumab showed high specificity for HER2 (K = 3.1 ± 0.6 nM) in SKOV3. In subcutaneous tumors, PET imaging revealed tumor uptake of 41.8 ± 3.8, 10.5 ± 3.9, and 12.1 ± 2.3%ID/g at 48 h post-injection for SKOV3, OVCAR3, and Caov3, respectively ( n = 3). In orthotopic models, PET imaging with Cu-NOTA-pertuzumab allowed for rapid and clear delineation of both primary and small peritoneal metastases in HER2-expressing ovarian cancer. Conclusions: Cu-NOTA-pertuzumab is an effective PET tracer for the non-invasive imaging of HER2 expression in vivo, rendering it a potential tracer for treatment monitoring and improved patient stratification. [ABSTRACT FROM AUTHOR]

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. [ABSTRACT FROM AUTHOR]

Purpose: Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. We describe the generation of a Cu-labeled CD146-specific antibody and its use for quantitative immunoPET imaging of CD146 expression in six lung cancer models. Methods: The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative western blot studies. The biodistribution and tumor uptake of Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146. Results: Flow cytometry and western blot studies showed similar findings with H460 and H23 cells showing high levels of expression of CD146. Small differences in CD146 expression levels were found among A549, H4006, H522, and H358 cells. Tumor uptake of Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h after injection ( n = 4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h after injection; n = 4), while H4006, A549 and H358 exhibited similar uptake of Cu-NOTA-YY146. A positive correlation was found between tumor uptake of Cu-NOTA-YY146 (%ID/g) and relative CD146 expression ( r = 0.98, p < 0.01). Ex vivo biodistribution confirmed the accuracy of the PET data. Conclusion: The strong correlation between tumor uptake of Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification. [ABSTRACT FROM AUTHOR]

An editorial is presented on predicting the status of PD-1 (programmed death protein 1) and its natural ligand PD-L1 in bladder cancer with F-FDG PET. Topics discussed include immunotherapy as a novel cancer treatment, and relationships between FBP1 expression and FDG uptake in hepatocellular carcinoma.

Purpose: Our goal was to demonstrate that suitably derivatized monomeric RGD peptide-based PET tracers, targeting integrin αβ, may offer advantages in image contrast, time for imaging, and low uptake in nontarget tissues. Methods: Two cyclic RGDfK derivatives, (PEG)-c(RGDfK) and PEG-SAA-c(RGDfK), were constructed and conjugated to NOTA for Cu labeling. Their integrin αβ-binding properties were determined via a competitive cell binding assay. Mice bearing U87MG tumors were intravenously injected with each of the Cu-labeled peptides, and PET scans were acquired during the first 30 min, and 2 and 4 h after injection. Blocking and ex vivo biodistribution studies were carried out to validate the PET data and confirm the specificity of the tracers. Results: The IC values of NOTA-(PEG)-c(RGDfK) and NOTA-PEG-SAA-c(RGDfK) were 444 ± 41 nM and 288 ± 66 nM, respectively. Dynamic PET data of Cu-NOTA-(PEG)-c(RGDfK) and Cu-NOTA-PEG-SAA-c(RGDfK) showed similar circulation t and peak tumor uptake of about 4 %ID/g for both tracers. Due to its marked hydrophilicity, Cu-NOTA-PEG-SAA-c(RGDfK) provided faster clearance from tumor and normal tissues yet maintained excellent tumor-to-background ratios. Static PET scans at later time-points corroborated the enhanced excretion of the tracer, especially from abdominal organs. Ex vivo biodistribution and receptor blocking studies confirmed the accuracy of the PET data and the integrin αβ-specificity of the peptides. Conclusion: Our two novel RGD-based radiotracers with optimized pharmacokinetic properties allowed fast, high-contrast PET imaging of tumor-associated integrin αβ. These tracers may facilitate the imaging of abdominal malignancies, normally precluded by high background uptake. [ABSTRACT FROM AUTHOR]

Amino acid-based tracers have been extensively investigated for positron emission tomography (PET) imaging of brain tumors, and 11C-methionine (11C-MET) is one of the most extensively investigated. However, widespread clinical use of 11C-MET is challenging due to the short half-life of 11C and low radiolabeling yield. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Yang and colleagues report an 18F-labeled boron-derived methionine analog, 18F-B-MET, as a potential substitute for 11C-MET in PET imaging of glioma. The push-button synthesis, highly efficient radiolabeling, and good imaging performance in glioma models make this tracer a promising candidate for future clinical translation. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Clinical summary of fibroblast activation protein inhibitor‑based radiopharmaceuticals: cancer and beyond.

Purpose: To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. Methods: ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of Cu-NOTA-ALT-836-Fab. Results: ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. Conclusion: Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. [ABSTRACT FROM AUTHOR]

There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and provide good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ∼20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1,000). Unlike conventional chromophores, nanonaps exhibit non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole-body imaging. [ABSTRACT FROM AUTHOR]

With many desirable properties, nanoparticles hold tremendous potential for in vivo molecular imaging and improving the efficacy of small-molecule drugs. The pharmacokinetics (PK) and tissue distribution of nanoparticles largely define their in vivo performance and potential toxicity, which are fundamental issues that need to be elucidated. In this review article, we summarized how molecular imaging techniques (e.g., positron emission tomography, fluorescence imaging, etc.) can facilitate the investigation of PK profiles of nanoparticles using carbon nanotubes (CNTs) and quantum dots (QDs) as representative examples. Different imaging techniques can provide useful insights in monitoring the in vivo behavior and tissue distribution of these nanoparticles, and a number of strategies were utilized to optimize the PK profiles of CNTs and QDs. Based on the available literature reports, it can be concluded that chemical/physical properties of the nanoparticles (e.g., surface functionalization, hydrodynamic size, shape, surface charge, etc.), along with the administration routes/doses, can play critical roles in determining the PK and biodistribution pattern of nanoparticles. Robust chemistry for surface modification of nanoparticles is a prerequisite for successful future biomedical/clinical applications. [ABSTRACT FROM AUTHOR]

The goal of this study was to develop a molecular imaging agent that can allow for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of CD105 expression in metastatic breast cancer. TRC105, a chimeric anti-CD105 monoclonal antibody, was labeled with both a NIRF dye (i.e., IRDye 800CW) and Cu to yield Cu-NOTA-TRC105-800CW. Flow cytometry analysis revealed no difference in CD105 binding affinity/specificity between TRC105 and NOTA-TRC105-800CW. Serial bioluminescence imaging (BLI) was carried out to non-invasively monitor the lung tumor burden in BALB/c mice, after intravenous injection of firefly luciferase-transfected 4T1 (i.e., fLuc-4T1) murine breast cancer cells to establish the experimental lung metastasis model. Serial PET imaging revealed that fLuc-4T1 lung tumor uptake of Cu-NOTA-TRC105-800CW was 11.9 ± 1.2, 13.9 ± 3.9, and 13.4 ± 2.1 %ID/g at 4, 24, and 48 h post-injection respectively (n = 3). Biodistribution studies, blocking fLuc-4T1 lung tumor uptake with excess TRC105, control experiments with Cu-NOTA-cetuximab-800CW (which served as an isotype-matched control), ex vivo BLI/PET/NIRF imaging, autoradiography, and histology all confirmed CD105 specificity of Cu-NOTA-TRC105-800CW. Successful PET/NIRF imaging of tumor angiogenesis (i.e., CD105 expression) in the breast cancer experimental lung metastasis model warrants further investigation and clinical translation of dual-labeled TRC105-based agents, which can potentially enable early detection of small metastases and image-guided surgery for tumor removal. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e., endoglin), and investigate its potential for PET imaging of tumor angiogenesis in a small-animal model after Cu labeling. Methods: TRC105-Fab was generated by enzymatic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) conjugation and Cu labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficiency and normal organ distribution of Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression. Results: TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC analysis, and mass spectrometry. Cu labeling of NOTA-TRC105-Fab was achieved with about 50 % yield (specific activity about 44 GBq/μmol). PET imaging revealed rapid uptake of Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 ± 0.4, 4.2 ± 0.5, 4.9 ± 0.3, 4.4 ± 0.7, and 4.6 ± 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h after injection, respectively; n = 4). Since tumor uptake peaked soon after tracer injection, Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h after injection. CD105 specificity of the tracer was confirmed with blocking studies and histological examination. Conclusion: We report PET imaging of CD105 expression using Cu-NOTA-TRC105-Fab, which exhibited prominent and target-specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same-day immunoPET imaging for clinical investigation. [ABSTRACT FROM AUTHOR]