DOTA is commonly used for radiometal chelation in molecular imaging. Yet in the absence of a radiometal, DOTA is hypothesized to promote renal clearance of F-labeled peptide tracers. In light of an increasing interest in the use of F18 for PET, here the effect of DOTA is evaluated for the first time with an F-labeled tracer and is found to significantly improve the quality of images acquired through positron emission tomography (PET). We chose to image the peptide LLP2A that recognizes the transmembrane protein very-late antigen 4 (VLA-4) that is overexpressed by many cancers. Since it is known that [F]RBF-PEG-LLP2A derivatives gave low tumor uptake values and significant GI tract accumulation, this ligand thus represents an ideal means of testing the additive effects of a DOTA group on clearance while permitting a facile, user-friendly, one-step F-labeling. A newly designed RBF-LLP2A bioconjugate with an appended DOTA moiety increased tumor uptake nearly 3-fold and reduced GI accumulation by more than 10-fold. The DOTA-AMBF-PEG-LLP2A was radiolabeled by isotope exchange and was purified by semiprep HPLC and C18 cartridge elution. Male C57BL/6J mice bearing B16-F10 melanoma tumors that overexpress the VLA-4 target were used to evaluate [F]DOTA-AMBF-PEG-LLP2A using a combination of static and dynamic PET scans, biodistribution studies, and blocking controls at 1 h post injection (p.i.). The precursor peptide was synthesized and F-labeled to provide formulations with mean (±SD) radiochemical purities of 95.9 ± 1.8%, in radiochemical yields of 4.8 ± 2.9% having molar activities of 131.7 ± 50.3 GBq/μmol. In vivo static PET images of [F]DOTA-AMBF-PEG-LLP2A provided clear tumor visualization, and biodistribution studies showed that tumor uptake was 9.46 ± 2.19% injected dose per gram of tissue (%ID/g) with high tumor/muscle and tumor/blood contrast ratios of ∼8 and ∼10, respectively. Blocking confirmed the specificity of [F]DOTA-AMBF-PEG-LLP2A to VLA-4 in the tumor and the bone marrow. Dynamic PET showed clearance of [F]DOTA-AMBF-PEG-LLP2A mainly via the renal pathway, wherein accumulation in the intestines was reduced 10-fold compared to our previously investigated LLP2A's, while spleen uptake was at levels similar to previously reported LLP2A-chelator radiotracers. [F]DOTA-AMBF-PEG-LLP2A represents a promising VLA-4 radiotracer and provides key evidence as to how a DOTA appendage can significantly reduce GI uptake in favor of urinary excretion. Implications for the development of dual-isotope theranostics that exploit the use fluorine-18 for imaging and DOTA to chelate therapeutic metal cations for therapy are discussed.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00146 | DOI Listing |
ACS Nano
January 2025
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China.
Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2).
View Article and Find Full Text PDFBMJ Open
December 2024
National School of Public Health, Universidade NOVA de Lisboa, Lisbon, Portugal.
Objective: To explore the perceptions of migrant women, healthcare professionals and community workers regarding migrant women's knowledge and attitudes about cervical cancer (CC) and screening and how these influence cervical cancer screening (CCS) uptake.
Design: Qualitative study with seven focus groups, using a semistructured guide.
Setting: Five focus groups were conducted online and two in community associations in Lisbon, Portugal.
Clin Nucl Med
January 2025
From the Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Purpose: The aim of this study was to investigate the value of 68Ga-NOTA-RM26 (68Ga-RM26), a gastrin-releasing peptide receptor-targeting antagonist labeled with the radionuclide 68Ga, in the diagnosis of high-grade gliomas and in combination with multiregional biopsies using PET/CT.
Patients And Methods: After institutional review board approval and informed consent, a total of 35 patients with suspected glioma lesions were enrolled in this study. All patients underwent 68Ga-RM26 PET/CT scans within 2 weeks before surgery.
Mol Cancer
January 2025
RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China.
KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis of fatty acids and nucleotides. However, the beyond mechanisms of KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related metabolic alterations in cancer cells and explore the prevalence and significance of KRAS mutation in shaping the tumor microenvironment and influencing epigenetic modification via various molecular activities.
View Article and Find Full Text PDFBMC Health Serv Res
January 2025
Te Aka Whai Ora (Māori Health Authority), Auckland, New Zealand.
Background: Breast cancer screening in Aotearoa New Zealand (NZ) still has persistent inequitable coverage by ethnicity, especially for Indigenous Māori women. This project aimed to undertake systematic data linkage to identify and invite eligible Māori women to participate in breast screening.
Methods: This is a cross-sectional observational study conducted in Northern New Zealand between 1/01/2020 and 30/06/2021.
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