177 results on '"Nimmagadda, Sridhar"'
Search Results
152. Gallium-68-labeled Peptide PET Quantifies Tumor Exposure of PD-L1 Therapeutics.
- Author
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Mishra A, Kumar D, Gupta K, Lofland G, Sharma AK, Banka DS, Hobbs RF, Dannals RF, Rowe SP, Gabrielson E, and Nimmagadda S
- Subjects
- Humans, Positron-Emission Tomography methods, B7-H1 Antigen metabolism, Peptides, Carcinoma, Transitional Cell, Urinary Bladder Neoplasms
- Abstract
Purpose: Immune checkpoint therapy (ICT) is currently ineffective in a majority of patients. Tumor drug exposure measurements can provide vital insights into mechanisms involved in the resistance of solid tumors to those therapeutics; however, tools to quantify in situ drug exposure are few. We have investigated the potential of programmed death-ligand 1 (PD-L1) pharmacodynamics, quantified using PET, to inform on the tumor exposure of anti-PD-L1 (aPD-L1) therapeutics., Experimental Design: To noninvasively quantify PD-L1 levels, we first developed a novel peptide-based gallium-68-labeled binder, [68Ga]Ga-DK223, and evaluated its in vivo distribution, pharmacokinetics, and PD-L1 specificity in preclinical models of triple-negative breast cancer and urothelial carcinoma with variable PD-L1 expression. We then quantified baseline and accessible PD-L1 levels in tumors as a noninvasive pharmacodynamic measure to assess tumor exposure to two aPD-L1 antibodies (avelumab and durvalumab)., Results: DK223 exhibited a KD of 1.01±0.83 nmol/L for PD-L1 and inhibited the PD-1:PD-L1 interaction in a dose-dependent manner. [68Ga]Ga-DK223 provides high-contrast PET images within 60 minutes of administration and detects PD-L1 in an expression-dependent manner in xenograft models. PD-L1 pharmacodynamics measured using [68Ga]Ga-DK223-PET revealed that avelumab and durvalumab had similar exposure early during therapy, but only durvalumab exhibited sustained exposure at the tumor., Conclusions: [68Ga]Ga-DK223 detected variable PD-L1 levels and exhibited salient features required for clinical translation. [68Ga]Ga-DK223-PET could be useful for quantifying total PD-L1 levels at baseline and accessible PD-L1 levels during therapy to understand drug exposure at the tumor, thus supporting its use for guiding and optimizing ICT., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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153. Imaging PD-L1 Expression in Melanoma Brain Metastases.
- Author
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Nimmagadda S
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- B7-H1 Antigen metabolism, Fluorodeoxyglucose F18, Humans, Positron-Emission Tomography methods, Radiopharmaceuticals, Brain Neoplasms diagnostic imaging, Melanoma diagnostic imaging, Melanoma pathology
- Published
- 2022
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154. First-in-Humans Evaluation of a PD-L1-Binding Peptide PET Radiotracer in Non-Small Cell Lung Cancer Patients.
- Author
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Zhou X, Jiang J, Yang X, Liu T, Ding J, Nimmagadda S, Pomper MG, Zhu H, Zhao J, Yang Z, and Li N
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- Animals, B7-H1 Antigen metabolism, Humans, Mice, Peptides metabolism, Positron Emission Tomography Computed Tomography, Tissue Distribution, Carcinoma, Non-Small-Cell Lung diagnostic imaging, Lung Neoplasms diagnostic imaging
- Abstract
68 Ga-NOTA-WL12 is a peptide-based PET imaging agent. We conducted a first-in-human study of68 Ga-NOTA-WL12 for PET to study the in vivo biodistribution, metabolism, radiation dosimetry, safety, and potential for quantifying programmed death ligand-1 (PD-L1) expression levels in patients with advanced non-small cell lung cancer (NSCLC). Methods: In vitro assessment of the PD-L1 expression and cellular uptake of68 Ga-NOTA-WL12 was performed, followed by in vivo evaluation of68 Ga-NOTA-WL12 uptake in mouse models with tumors. Nine patients with NSCLC with lesions expressing PD-L1 were enrolled and monitored for adverse events during the study.68 Ga-NOTA-WL12 and paired18 F-FDG PET/CT imaging were performed. Uptake (SUV, SUL [SUVlean ], and kBq/mL) values of tumors and normal organs were obtained. Radiopharmaceutical biodistribution, radiation dosimetry, and the relationship of tumor uptake to PD-L1 expression were evaluated. Follow-up18 F-FDG PET/CT was performed in patients who had undergone treatment with a combination of pembrolizumab with chemotherapy. Results:68 Ga-NOTA-WL12 exhibited PD-L1-specific uptake in vitro and in PD-L1-positive tumors in vivo.68 Ga-NOTA-WL12 PET imaging proved safe with acceptable radiation dosimetry. Physiologic tracer uptake was mainly visible in the liver, spleen, small intestine, and kidney. Tumors were clearly visible, particularly in the lungs, with a tumor-to-lung ratio of 4.45 ± 1.89 at 1 h. One hour was a suitable time point for image acquisition because no significant differences were noted in tumor-to-background ratios between 1 and 2 h. A strong, positive correlation was found between tumor uptake (SUVpeak ) and PD-L1 immunohistochemistry results ( r = 0.9349; P = 0.002).68 Ga-NOTA-WL12 and18 F-FDG PET studies suggest that PD-L1 PET before therapy may indicate the therapeutic efficacy of pembrolizumab plus chemotherapy combination treatment. Conclusion: Our first-in-human findings demonstrate the safety and feasibility of68 Ga-NOTA-WL12 for noninvasive, in vivo detection of tumor PD-L1 expression levels, indicating potential benefits for clinical PD-L1 therapy., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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155. PD-L1 near Infrared Photoimmunotherapy of Ovarian Cancer Model.
- Author
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Jin J, Sivakumar I, Mironchik Y, Krishnamachary B, Wildes F, Barnett JD, Hung CF, Nimmagadda S, Kobayashi H, Bhujwalla ZM, and Penet MF
- Abstract
(1) Background: Despite advances in surgical approaches and drug development, ovarian cancer is still a leading cause of death from gynecological malignancies. Patients diagnosed with late-stage disease are treated with aggressive surgical resection and chemotherapy, but recurrence with resistant disease is often observed following treatment. There is a critical need for effective therapy for late-stage ovarian cancer. Photoimmunotherapy (PIT), using an antibody conjugated to a near infrared (NIR) dye, constitutes an effective theranostic strategy to detect and selectively eliminate targeted cell populations. (2) Methods: Here, we are targeting program death ligand 1 (PD-L1) using NIR-PIT in a syngeneic mouse model of ovarian cancer. PD-L1 PIT-mediated cytotoxicity was quantified in RAW264.7 macrophages and ID8-Defb29-VEGF cells in culture, and in vivo with orthotopic ID8-Defb29-VEGF tumors. (3) Results: Treatment efficacy was observed both in vitro and in vivo. (4) Conclusions: Our data highlight the need for further investigations to assess the potential of using NIR-PIT for ovarian cancer therapy to improve the treatment outcome of ovarian cancer.
- Published
- 2022
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156. Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.
- Author
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Kumar D, Mishra A, Lisok A, Kureshi R, Shelake S, Plyku D, Sen R, Doucet M, De Silva RA, Mease RC, Forde PM, Jaffee EM, Desai P, Ganguly S, Gabrielson E, Vaidya D, Spangler JB, and Nimmagadda S
- Subjects
- Animals, Apoptosis, Breast Neoplasms diagnostic imaging, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation, Female, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Radiopharmaceuticals pharmacokinetics, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological pharmacology, B7-H1 Antigen antagonists & inhibitors, Breast Neoplasms drug therapy, Fluorine Radioisotopes pharmacokinetics, Peptide Fragments pharmacokinetics, Positron-Emission Tomography methods, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1). For PD-L1 quantification, we first developed a small peptide-based fluorine-18-labeled PET imaging agent, [
18 F]DK222, which provided high-contrast images in preclinical models. We then quantified accessible PD-L1 levels in the tumor bed during treatment with anti-PD-1 and anti-PD-L1 mAbs. Applying mixed-effects models to these data, we found subtle differences in the pharmacodynamic effects of two anti-PD-1 mAbs (nivolumab and pembrolizumab). In contrast, we observed starkly divergent target engagement with anti-PD-L1 mAbs (atezolizumab, avelumab, and durvalumab) that were administered at equivalent doses, correlating with differential effects on tumor growth. Thus, we show that measuring PD-L1 pharmacodynamics informs mechanistic understanding of therapeutic mAbs targeting PD-L1 and PD-1. These findings demonstrate the value of quantifying target pharmacodynamics to elucidate the pharmacologic activity of mAbs, independent of mAb biophysical properties and inclusive of all physiological variables, which are highly heterogeneous within and across tumors and patients., Competing Interests: Competing interest statement: D.K. and S.N. are coinventors on a pending US patent covering [18F]DK222 and as such are entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. S.N. is a consultant for and receives funding from Precision Molecular, Inc.- Published
- 2021
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157. Process validation, current good manufacturing practice production, dosimetry, and toxicity studies of the carbonic anhydrase IX imaging agent [ 111 In]In-XYIMSR-01 for phase I regulatory approval.
- Author
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De Silva RA, Gorin MA, Mease RC, Minn I, Lisok A, Plyku D, Nimmagadda S, Allaf ME, Yang X, Sgouros G, Rowe SP, and Pomper MG
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- Animals, Humans, Radiometry, Indium Radioisotopes, Rats, Female, Radiopharmaceuticals chemistry, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Male, Drug Approval, Rats, Sprague-Dawley, Clinical Trials, Phase I as Topic, Antigens, Neoplasm, Carbonic Anhydrase IX metabolism
- Abstract
[
111 In]In-XYIMSR-01 is a promising single-photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [111 In]In-XYIMSR-01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing, and controls component of a standard regulatory application. The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters <823> and <825>, FDA 21 CFR Part 212. Toxicity was evaluated by using nonradioactive [113/115 In]In-XYIMSR-01 according to 21 CFR Part 58 guidelines. Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was used to calculate the maximum single dose for human studies. Three process validation runs at starting radioactivities of ~800 MBq were completed with a minimum concentration of 407 MBq/ml and radiochemical purity of ≥99% at the end of synthesis. A single intravenous dose of 55 μg/ml of [113/115 In]In-XYIMSR-01 was well tolerated in male and female Sprague-Dawley rats. The calculated maximum single dose for human injection from dosimetry studies was 390.35 MBq of [111 In]In-XYIMSR-01. We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [111 In]In-XYIMSR-01 in a phase I clinical trial., (© 2021 John Wiley & Sons, Ltd.)- Published
- 2021
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158. Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.
- Author
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Slania SL, Das D, Lisok A, Du Y, Jiang Z, Mease RC, Rowe SP, Nimmagadda S, Yang X, and Pomper MG
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- Animals, Cell Line, Tumor, Endopeptidases, Fluorescent Dyes chemical synthesis, Fluorometry, Heterografts metabolism, Humans, Male, Mice, Inbred NOD, Mice, SCID, Pyrrolidines chemical synthesis, Pyrrolidines chemistry, Quinolines chemical synthesis, Quinolines chemistry, Mice, Fibroblasts metabolism, Fluorescent Dyes chemistry, Gelatinases metabolism, Membrane Proteins metabolism, Neoplasms metabolism, Serine Endopeptidases metabolism
- Abstract
Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, QCP01 and [
111 In] QCP02 , using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226). Mouse xenograft models were developed with FAP-positive U87 and FAP-negative PC3 cells to test pharmacokinetics and binding specificity in vivo . QCP01 and [111 In] QCP02 demonstrated nanomolar inhibition of FAP at Ki values of 1.26 and 16.20 nM, respectively. Both were selective for FAP over DPP-IV, a related serine protease. Both enabled imaging of FAP-expressing tumors specifically in vivo . [111 In] QCP02 showed high uptake at 18.2 percent injected dose per gram in the U87 tumor at 30 min post-administration.- Published
- 2021
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159. Comparison of skeletal and soft tissue pericytes identifies CXCR4 + bone forming mural cells in human tissues.
- Author
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Xu J, Li D, Hsu CY, Tian Y, Zhang L, Wang Y, Tower RJ, Chang L, Meyers CA, Gao Y, Broderick K, Morris C, Hooper JE, Nimmagadda S, Péault B, and James AW
- Abstract
Human osteogenic progenitors are not precisely defined, being primarily studied as heterogeneous multipotent cell populations and termed mesenchymal stem cells (MSCs). Notably, select human pericytes can develop into bone-forming osteoblasts. Here, we sought to define the differentiation potential of CD146
+ human pericytes from skeletal and soft tissue sources, with the underlying goal of defining cell surface markers that typify an osteoblastogenic pericyte. CD146+ CD31- CD45- pericytes were derived by fluorescence-activated cell sorting from human periosteum, adipose, or dermal tissue. Periosteal CD146+ CD31- CD45- cells retained canonical features of pericytes/MSC. Periosteal pericytes demonstrated a striking tendency to undergo osteoblastogenesis in vitro and skeletogenesis in vivo, while soft tissue pericytes did not readily. Transcriptome analysis revealed higher CXCR4 signaling among periosteal pericytes in comparison to their soft tissue counterparts, and CXCR4 chemical inhibition abrogated ectopic ossification by periosteal pericytes. Conversely, enrichment of CXCR4+ pericytes or stromal cells identified an osteoblastic/non-adipocytic precursor cell. In sum, human skeletal and soft tissue pericytes differ in their basal abilities to form bone. Diversity exists in soft tissue pericytes, however, and CXCR4+ pericytes represent an osteoblastogenic, non-adipocytic cell precursor. Indeed, enrichment for CXCR4-expressing stromal cells is a potential new tactic for skeletal tissue engineering., Competing Interests: Competing interestsA.W.J. is on the scientific advisory board for Novadip Biosciences, receives funding for unrelated research from MTF Biologics, and is on the editorial board of American Journal of Pathology and Bone Research. B.P. is the inventor of perivascular stem cell-related patents held by the UC Regents and is on the editorial board of Stem Cells., (© The Author(s) 2020.)- Published
- 2020
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160. SNP2SIM: a modular workflow for standardizing molecular simulation and functional analysis of protein variants.
- Author
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McCoy MD, Shivakumar V, Nimmagadda S, Jafri MS, and Madhavan S
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- Humans, Ligands, Molecular Dynamics Simulation, Mutation, Missense, Protein Conformation, Software, Workflow, Molecular Docking Simulation methods, Mutant Proteins chemistry
- Abstract
Background: Molecular simulations are used to provide insight into protein structure and dynamics, and have the potential to provide important context when predicting the impact of sequence variation on protein function. In addition to understanding molecular mechanisms and interactions on the atomic scale, translational applications of those approaches include drug screening, development of novel molecular therapies, and targeted treatment planning. Supporting the continued development of these applications, we have developed the SNP2SIM workflow that generates reproducible molecular dynamics and molecular docking simulations for downstream functional variant analysis. The Python workflow utilizes molecular dynamics software (NAMD (Phillips et al., J Comput Chem 26(16):1781-802, 2005), VMD (Humphrey et al., J Mol Graph 14(1):33-8, 27-8, 1996)) to generate variant specific scaffolds for simulated small molecule docking (AutoDock Vina (Trott and Olson, J Comput Chem 31(2):455-61, 2010))., Results: SNP2SIM is composed of three independent modules that can be used sequentially to generate the variant scaffolds of missense protein variants from the wildtype protein structure. The workflow first generates the mutant structure and configuration files required to execute molecular dynamics simulations of solvated protein variant structures. The resulting trajectories are clustered based on the structural diversity of residues involved in ligand binding to produce one or more variant scaffolds of the protein structure. Finally, these unique structural conformations are bound to small molecule ligand libraries to predict variant induced changes to drug binding relative to the wildtype protein structure., Conclusions: SNP2SIM provides a platform to apply molecular simulation based functional analysis of sequence variation in the protein targets of small molecule therapies. In addition to simplifying the simulation of variant specific drug interactions, the workflow enables large scale computational mutagenesis by controlling the parameterization of molecular simulations across multiple users or distributed computing infrastructures. This enables the parallelization of the computationally intensive molecular simulations to be aggregated for downstream functional analysis, and facilitates comparing various simulation options, such as the specific residues used to define structural variant clusters. The Python scripts that implement the SNP2SIM workflow are available (SNP2SIM Repository. https://github.com/mccoymd/SNP2SIM , Accessed 2019 February ), and individual SNP2SIM modules are available as apps on the Seven Bridges Cancer Genomics Cloud (Lau et al., Cancer Res 77(21):e3-e6, 2017; Cancer Genomics Cloud [ www.cancergenomicscloud.org ; Accessed 2018 November]).
- Published
- 2019
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161. Peptide-based PET quantifies target engagement of PD-L1 therapeutics.
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Kumar D, Lisok A, Dahmane E, McCoy M, Shelake S, Chatterjee S, Allaj V, Sysa-Shah P, Wharram B, Lesniak WG, Tully E, Gabrielson E, Jaffee EM, Poirier JT, Rudin CM, Gobburu JV, Pomper MG, and Nimmagadda S
- Subjects
- A549 Cells, Animals, CHO Cells, Copper Radioisotopes, Cricetulus, Female, Humans, Male, Mice, Mice, Inbred NOD, Antineoplastic Agents, Immunological pharmacology, B7-H1 Antigen antagonists & inhibitors, Models, Biological, Neoplasm Proteins antagonists & inhibitors, Neoplasms, Experimental diagnostic imaging, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Peptides chemistry, Peptides pharmacokinetics, Peptides pharmacology, Positron-Emission Tomography, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Radiopharmaceuticals pharmacology
- Abstract
Immune checkpoint therapies have shown tremendous promise in cancer therapy. However, tools to assess their target engagement, and hence the ability to predict their efficacy, have been lacking. Here, we show that target engagement and tumor-residence kinetics of antibody therapeutics targeting programmed death ligand-1 (PD-L1) can be quantified noninvasively. In computational docking studies, we observed that PD-L1-targeted monoclonal antibodies (atezolizumab, avelumab, and durvalumab) and a high-affinity PD-L1-binding peptide, WL12, have common interaction sites on PD-L1. Using the peptide radiotracer [64Cu]WL12 in vivo, we employed positron emission tomography (PET) imaging and biodistribution studies in multiple xenograft models and demonstrated that variable PD-L1 expression and its saturation by atezolizumab, avelumab, and durvalumab can be quantified independently of biophysical properties and pharmacokinetics of antibodies. Next, we used [64Cu]WL12 to evaluate the impact of time and dose on the unoccupied fraction of tumor PD-L1 during treatment. These quantitative measures enabled, by mathematical modeling, prediction of antibody doses needed to achieve therapeutically effective occupancy (defined as >90%). Thus, we show that peptide-based PET is a promising tool for optimizing dose and therapeutic regimens employing PD-L1 checkpoint antibodies, and can be used for improving therapeutic efficacy.
- Published
- 2019
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162. Peptide-Based 68 Ga-PET Radiotracer for Imaging PD-L1 Expression in Cancer.
- Author
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De Silva RA, Kumar D, Lisok A, Chatterjee S, Wharram B, Venkateswara Rao K, Mease R, Dannals RF, Pomper MG, and Nimmagadda S
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- Animals, CHO Cells, Cricetulus, Female, Flow Cytometry, Immunohistochemistry, Mice, B7-H1 Antigen metabolism, Gallium Radioisotopes chemistry, Peptides chemistry, Positron-Emission Tomography methods, Triple Negative Breast Neoplasms diagnostic imaging, Triple Negative Breast Neoplasms metabolism
- Abstract
Tumors create and maintain an immunosuppressive microenvironment that promotes cancer cell escape from immune surveillance. The immune checkpoint protein programmed death-ligand 1 (PD-L1) is expressed in many cancers and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy. Guidance of anti-PD-L1 therapy is currently effected through measurement of PD-L1 through biopsy and immunohistochemistry. Here, we report a peptide-based imaging agent, [
68 Ga]WL12, to detect PD-L1 expression in tumors noninvasively by positron emission tomography (PET). WL12, a cyclic peptide comprising 14 amino acids, binds to PD-L1 with high affinity (IC50≈ 23 nM). Synthesis of [68 Ga]WL12 provided radiochemical purity >99% after purification. Biodistribution in immunocompetent mice demonstrated 11.56 ± 3.18, 4.97 ± 0.8, 1.9 ± 0.1, and 1.33 ± 0.21 percentage of injected dose per gram (%ID/g) in hPD-L1, MDAMB231, SUM149, and CHO tumors, respectively, at 1 h postinjection, with high binding specificity noted with coinjection of excess, nonradiolabeled WL12. PET imaging demonstrated high tissue contrast in all tumor models tested.- Published
- 2018
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163. In vivo Evaluation of an Engineered Cyclotide as Specific CXCR4 Imaging Reagent.
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Lesniak WG, Aboye T, Chatterjee S, Camarero JA, and Nimmagadda S
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- Amino Acid Sequence, Animals, Brain Neoplasms diagnosis, Brain Neoplasms diagnostic imaging, Cell Line, Tumor, Contrast Media chemical synthesis, Contrast Media metabolism, Cyclotides chemical synthesis, Cyclotides metabolism, Female, Humans, Inhibitory Concentration 50, Mice, Mice, Inbred NOD, Mice, SCID, Positron Emission Tomography Computed Tomography, Protein Binding, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals chemistry, Radiopharmaceuticals metabolism, Receptors, CXCR4 antagonists & inhibitors, Tissue Distribution, Transplantation, Heterologous, Contrast Media chemistry, Cyclotides chemistry, Receptors, CXCR4 metabolism
- Abstract
The CXCR4 chemokine receptor plays a key regulatory role in many biological functions, including embryonic development and controlling leukocyte functions during inflammation and immunity. CXCR4 has been also associated with multiple types of cancers where its overexpression/activation promotes metastasis, angiogenesis, and tumor growth and/or survival. Furthermore, CXCR4 is involved in HIV replication, as it is a co-receptor for viral entry into host cells. Altogether, these features make CXCR4 a very attractive target for the development of imaging and therapeutic agents. Here, the in vivo evaluation of the MCoTI-based cyclotide, MCo-CVX-5c, for the development of imaging agents that target CXCR4 is reported. Cyclotide MCo-CVX-5c is a potent CXCR4 antagonist with a remarkable in vivo resistance to biological degradation in serum. A [
64 Cu]-DOTA-labeled version of this cyclotide demonstrated high and significant uptake in U87-stb-CXCR4 tumors compared to the control U87 tumors. Furthermore, protracted imaging studies demonstrated radiotracer retention in the U87-stb-CXCR4 tumor at 24 h post injection. Uptake in U87-stb-CXCR4 tumors could be blocked by unlabeled MCo-CVX-5c, showing high in vivo specificity. These results demonstrate the in vivo specificity and retention of a bioactive molecularly targeted cyclotide and highlight the potential of bioactive cyclotides for the development of new imaging agents that target CXCR4., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
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164. Imaging α4β2 Nicotinic Acetylcholine Receptors (nAChRs) in Baboons with [ 18 F]XTRA, a Radioligand with Improved Specific Binding in Extra-Thalamic Regions.
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Kuwabara H, Gao Y, Stabin M, Coughlin J, Nimmagadda S, Dannals RF, Pomper MG, and Horti AG
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- 2,2'-Dipyridyl analogs & derivatives, 2,2'-Dipyridyl chemistry, Animals, Azabicyclo Compounds chemistry, Male, Mice, Papio, Positron-Emission Tomography, Radiometry, Time Factors, Tissue Distribution, Molecular Imaging methods, Radiopharmaceuticals chemistry, Receptors, Nicotinic metabolism, Thalamus diagnostic imaging
- Abstract
Purpose: Currently available positron-emitting radiotracers for imaging of the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) exhibit high and moderate specific binding in the thalamus and extra-thalamic brain regions, respectively. In many neuropsychiatric disorders, α4β2-nAChRs are altered in the extra-thalamic brain regions, but not necessarily in the thalamus. The purpose of this study was to evaluate [
18 F]XTRA, a new α4β2-nAChR positron emission tomography (PET) radioligand with improved specific binding in extra-thalamic brain regions, in non-human primates., Procedures: The regional distribution of [18 F]XTRA in the brain of Papio anubis baboons was evaluated in baseline and blocking experiments. Various PET modeling procedures were used for determination of volume of distribution (VT ), binding potential (BPND ), and receptor occupancy. Radiation dosimetry for [18 F]XTRA was studied in male CD-1 mice and extrapolated to human dosimetry estimates using OLINDA/EXM software., Results: [18 F]XTRA was synthesized using an automated radiochemistry module with 25 % decay-corrected radiochemical yield. [18 F]XTRA readily enters the baboon brain and specifically labels α4β2-nAChRs. Mathematical modeling demonstrates high binding potential values (BPND = 7 and 1.3 in the thalamus and frontal cortex, respectively). A PET scanning time of 90-120 min was sufficient to obtain stable VT values in the extra-thalamic regions. The extrapolated human effective dose was 0.041 mSv/MBq (0.15 Rem/mCi)., Conclusion: [18 F]XTRA exhibits improved specific binding in the baboon brain including extra-thalamic regions and it is considered radiologically acceptable for human studies. Further evaluations of [18 F]XTRA in human subjects are under way.- Published
- 2017
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165. Heterogeneous expression of PD-L1 in pulmonary squamous cell carcinoma and adenocarcinoma: implications for assessment by small biopsy.
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Gniadek TJ, Li QK, Tully E, Chatterjee S, Nimmagadda S, and Gabrielson E
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- Adenocarcinoma pathology, Biomarkers, Tumor metabolism, Biopsy, Carcinoma, Squamous Cell pathology, Female, Humans, Immunohistochemistry, Lung Neoplasms pathology, Male, Tissue Array Analysis, Adenocarcinoma metabolism, B7-H1 Antigen metabolism, Carcinoma, Squamous Cell metabolism, Lung Neoplasms metabolism
- Abstract
Predicting response to checkpoint blockade therapy for lung cancer has largely focused on measuring programmed death-ligand 1 (PD-L1) expression on tumor cells. PD-L1 expression is geographically heterogeneous within many tumors, however, and we questioned whether small tissue samples, such as biopsies, might be sufficiently representative of PD-L1 expression for evaluating this marker in lung cancer tumors. To evaluate the extent of variability of PD-L1 expression in small tissue samples, and how that variability affects accuracy of overall assessment of PD-L1 in lung cancer, we scored immunohistochemical staining for PD-L1 in tissue microarray cores from a series of 79 squamous cell lung cancers and 71 pulmonary adenocarcinomas. Our study found substantial inconsistencies for the percentages of cells staining positive for PD-L1 among different tissue microarray cores in many cases of both adenocarcinoma and squamous cell carcinoma. This variable scoring was seen at both high levels and low levels of PD-L1 expression, and by further evaluation of cases with discordant results on full-face sections to assess geographic distribution of staining, we found that discordant results among different tissue microarray cores reflected geographic variation of PD-L1 expression in those tumors. Moreover, we found that as a result of heterogeneous expression, the sensitivity of a single small tissue sample can be as low as 85% for detecting PD-L1 expression at scoring thresholds commonly used in clinical practice. Based on these studies, we conclude that many cases of lung cancer could be inaccurately or variably scored for PD-L1 expression with a single biopsy sample. Accordingly, lung cancer patients can be inconsistently classified for PD-L1 expression status, particularly when a threshold for the percentage of positive cells is used to determine eligibility for checkpoint blockade therapy.
- Published
- 2017
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166. A PSMA-targeted theranostic agent for photodynamic therapy.
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Chen Y, Chatterjee S, Lisok A, Minn I, Pullambhatla M, Wharram B, Wang Y, Jin J, Bhujwalla ZM, Nimmagadda S, Mease RC, and Pomper MG
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- Animals, Male, Mice, Mice, Inbred NOD, Mice, SCID, Optical Imaging, Photosensitizing Agents chemical synthesis, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Photochemotherapy, Photosensitizing Agents therapeutic use, Prostatic Neoplasms drug therapy, Theranostic Nanomedicine
- Abstract
Prostate-specific membrane antigen (PSMA) is over-expressed in the epithelium of prostate cancer and in the neovasculature of many non-prostate solid tumors. PSMA has been increasingly used as a target for cancer imaging and therapy. Here we describe a low-molecular-weight theranostic photosensitizer, YC-9, for PSMA-targeted optical imaging and photodynamic therapy (PDT). YC-9 was synthesized by conjugating IRDye700DX N-hydroxysuccinimide (NHS) ester with a PSMA targeting Lys-Glu urea through a lysine-suberate linker in suitable yield. Optical imaging in vivo demonstrated PSMA-specific tumor uptake of YC-9 with rapid clearance from non-target tissues. PSMA-specific cell kill was demonstrated with YC-9in vitro through PDT in PSMA
+ PC3-PIP and PSMA- PC3-flu cells. In vivo PDT in mice bearing PSMA+ PC3-PIP tumors at 4h post-injection of YC-9 (A total of four PDT sessions were performed, 48h apart) resulted in significant tumor growth delay, while tumors in control groups continued to grow. PDT with YC-9 significantly increased the median survival of the PSMA+ PC3-PIP tumor mice (56.5days) compared to control groups [23.5-30.0days, including untreated, light alone, YC-9 alone (without light) and non-targeted IRDye700DX PDT treatment groups], without noticeable toxicity at the doses used. This study proves in principle that YC-9 is a promising therapeutic agent for targeted PDT of PSMA-expressing tissues, such as prostate tumors, and may also be useful against non-prostate tumors by virtue of neovascular PSMA expression., (Copyright © 2016 Elsevier B.V. All rights reserved.)- Published
- 2017
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167. [(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA).
- Author
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Yang X, Mease RC, Pullambhatla M, Lisok A, Chen Y, Foss CA, Wang Y, Shallal H, Edelman H, Hoye AT, Attardo G, Nimmagadda S, and Pomper MG
- Subjects
- Animals, Carbamates pharmacokinetics, Cell Line, Tumor, Drug Stability, Female, Fluorine Radioisotopes, Humans, Kidney diagnostic imaging, Male, Mice, Mice, SCID, Molecular Docking Simulation, Organ Specificity, Prostate diagnostic imaging, Radiopharmaceuticals pharmacokinetics, Tissue Distribution, Xenograft Model Antitumor Assays, Carbamates chemical synthesis, Carbamates pharmacology, Pentanoic Acids chemical synthesis, Pentanoic Acids pharmacology, Positron-Emission Tomography methods, Prostate-Specific Antigen metabolism, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacology
- Abstract
Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four (18)F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[(18)F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [(18)F]23 and 4-iodo-2-[(18)F]fluorobenzoyllysine OPA carbamate [(18)F]24 in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [(18)F]23 is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [(18)F]24, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues.
- Published
- 2016
- Full Text
- View/download PDF
168. ⁶⁴Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer.
- Author
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Banerjee SR, Pullambhatla M, Foss CA, Nimmagadda S, Ferdani R, Anderson CJ, Mease RC, and Pomper MG
- Subjects
- Animals, Cell Line, Tumor, Chelating Agents chemical synthesis, Chelating Agents chemistry, Chromatography, High Pressure Liquid, Copper chemistry, Copper Radioisotopes, Glutamate Carboxypeptidase II metabolism, Humans, Image Processing, Computer-Assisted, Indicators and Reagents, Isotope Labeling methods, Male, Mice, Neoplasm Transplantation, Positron-Emission Tomography, Radiopharmaceuticals pharmacokinetics, Rats, Spectrophotometry, Ultraviolet, Tissue Distribution, Tomography, X-Ray Computed, Whole-Body Counting, Prostate-Specific Antigen antagonists & inhibitors, Prostatic Neoplasms diagnostic imaging, Radiopharmaceuticals chemical synthesis
- Abstract
Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five (64)Cu-labeled inhibitors of PSMA, [(64)Cu]3-7, which are based on the lysine-glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [(64)Cu]3-7 were prepared in high radiochemical yield (60-90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [(64)Cu]3-7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA- PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [(64)Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [(64)Cu]CB-TE2A as compared with [(64)Cu]NOTA, [(64)Cu]PCTA, [(64)Cu]Oxo-DO3A, and [(64)Cu]DOTA chelates in vivo.
- Published
- 2014
- Full Text
- View/download PDF
169. The intricate role of CXCR4 in cancer.
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Chatterjee S, Behnam Azad B, and Nimmagadda S
- Subjects
- Animals, Gene Expression Regulation, Neoplastic, Humans, Receptors, CXCR4 immunology, Antibodies, Monoclonal immunology, Molecular Imaging methods, Neoplasms diagnosis, Neoplasms metabolism, Receptors, CXCR4 metabolism
- Abstract
Chemokines mediate numerous physiological and pathological processes related primarily to cell homing and migration. The chemokine CXCL12, also known as stromal cell-derived factor-1, binds the G-protein-coupled receptor CXCR4, which, through multiple divergent pathways, leads to chemotaxis, enhanced intracellular calcium, cell adhesion, survival, proliferation, and gene transcription. CXCR4, initially discovered for its involvement in HIV entry and leukocytes trafficking, is overexpressed in more than 23 human cancers. Cancer cell CXCR4 overexpression contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. As such, CXCR4 is a target not only for therapeutic intervention but also for noninvasive monitoring of disease progression and therapeutic guidance. This review provides a comprehensive overview of the biological involvement of CXCR4 in human cancers, the current status of CXCR4-based therapeutic approaches, as well as recent advances in noninvasive imaging of CXCR4 expression., (© 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
170. Distribution of cell-free and cell-associated HIV surrogates in the female genital tract after simulated vaginal intercourse.
- Author
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Louissaint NA, Fuchs EJ, Bakshi RP, Nimmagadda S, Du Y, Macura KJ, King KE, Wahl R, Goldsmith AJ, Caffo B, Cao YJ, Anderson J, and Hendrix CW
- Subjects
- Adult, Female, HIV Infections virology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multimodal Imaging, Positron-Emission Tomography, Radioactive Tracers, Radiopharmaceuticals, Semen cytology, Statistics, Nonparametric, Technetium Tc 99m Sulfur Colloid, Time Factors, Tomography, X-Ray Computed, Vagina diagnostic imaging, Vagina physiology, Young Adult, Coitus physiology, HIV Infections transmission, Semen diagnostic imaging, Vagina virology
- Abstract
Background: Rational development of drugs to prevent human immunodeficiency virus (HIV) transmission benefits from an understanding HIV distribution in the female genital tract after intercourse. This study describes HIV distribution using surrogates of cell-free and cell-associated HIV and semen., Methods: Apheresis-derived, autologous, lymphocyte-rich cells radiolabeled with 3.7-MBq (100-μCi) indium 111 ((111)In)-oxine (cell-associated HIV surrogate) and 18.5-MBq (500-μCi) technetium 99m ((99m)Tc)-sulfur colloid (HIV-sized 100-nm particle, cell-free HIV surrogate) were resuspended in 3 mL of hydroxyethylcellulose gel (semen simulant) with gadoteridol and dosed via artificial phallus after simulated intercourse. Postdosing dual-isotope single photon emission computed tomography with computed tomography (SPECT/CT) and magnetic resonance (MR) images were acquired to determine the surrogates' distribution. Seven hours after dosing, vaginal biopsy and luminal samples were collected at discrete locations in 8 subjects., Results: SPECT/CT and MR analysis showed HIV and semen surrogate distribution with highest signal intensity in the vaginal pericervical area, without detectable signal in the uterus. One-third of the administered dose was retained in the female genital tract after 4 hours. Cell-free and cell-associated surrogate distribution coincided., Conclusions: We demonstrate the feasibility of dual-isotope SPECT/CT and MR imaging to determine the distribution of HIV and semen surrogates after simulated intercourse without disrupting vaginal contents. Surrogate distribution suggests topical microbicides do not need to reach the uterus for efficacy.
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- 2012
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- View/download PDF
171. Distribution of cell-free and cell-associated HIV surrogates in the colon after simulated receptive anal intercourse in men who have sex with men.
- Author
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Louissaint NA, Nimmagadda S, Fuchs EJ, Bakshi RP, Cao YJ, Lee LA, Goldsmith J, Caffo BS, Du Y, King KE, Menendez FA, Torbenson MS, and Hendrix CW
- Subjects
- Adult, Anti-Infective Agents administration & dosage, HIV Infections etiology, Humans, Male, Middle Aged, Multimodal Imaging, Positron-Emission Tomography, Radioactive Tracers, Semen cytology, Semen virology, Technetium Tc 99m Sulfur Colloid, Time Factors, Tomography, X-Ray Computed, Colon physiology, Homosexuality, Male, Sexual Behavior physiology
- Abstract
Objectives: Describing the distribution and clearance of HIV surrogates within the gastrointestinal tract to inform rectal microbicide development., Design: Radiolabeled simulated HIV-infected semen was administered, imaged, and biopsied to simulate and measure colonic HIV distribution after anal intercourse., Methods: Healthy male subjects with a history of receptive anal intercourse and experience with the use of anal sex toys were recruited to this study. Apheresis isolated leukocytes were collected before simulated intercourse. These autologous leukocytes, radiolabeled with 9.25 MBq (111)Indium-oxine (cell-associated HIV surrogate), and sulfur colloid particles, labeled with 37 MBq (99m)Technectium (cell-free HIV surrogate), were mixed in 3 mL autologous seminal plasma. This simulated HIV-infected semen was administered to subjects via an artificial phallus with urethra after 5 minutes of simulated intercourse. Postdosing dual isotope Single photon emission computed tomography coupled with traditional computed tomography (SPECT/CT) images were acquired at 1, 4, 8, and 24 hours. At 5 hours postdosing, colon biopsies were collected, CD4 cells were extracted, and samples analyzed for radioactivity., Results: SPECT/CT images showed similar luminal distribution for both surrogates, with migration limited to the rectosigmoid colon in all subjects. SPECT showed at least 75% overlap in distribution of both surrogates up to 4 hours after dosing. Biopsies indicate that 2.4% of CD4 cells extracted from rectosigmoid colon tissue were exogenously administered., Conclusions: Our HIV surrogates stayed within the rectosigmoid colon for 24 hours. Exogenously dosed autologous lymphocytes and HIV-sized particles migrate to similar locations and associate with the colonic tissue in the lumen.
- Published
- 2012
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- View/download PDF
172. Sequential SPECT and optical imaging of experimental models of prostate cancer with a dual modality inhibitor of the prostate-specific membrane antigen.
- Author
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Banerjee SR, Pullambhatla M, Byun Y, Nimmagadda S, Foss CA, Green G, Fox JJ, Lupold SE, Mease RC, and Pomper MG
- Subjects
- Animals, Fluorescent Dyes chemistry, Heterocyclic Compounds, 1-Ring chemistry, Indium Radioisotopes chemistry, Male, Mice, Peptides chemistry, Peptides pharmacokinetics, Porphyrins pharmacokinetics, Prostate-Specific Antigen metabolism, Protease Inhibitors pharmacokinetics, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Transplantation, Heterologous, Porphyrins chemistry, Prostate-Specific Antigen antagonists & inhibitors, Prostatic Neoplasms diagnostic imaging, Protease Inhibitors chemistry
- Published
- 2011
- Full Text
- View/download PDF
173. Effects of recombinant human thyroid-stimulating hormone superagonists on thyroidal uptake of 18F-fluorodeoxyglucose and radioiodide.
- Author
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Reinfelder J, Maschauer S, Foss CA, Nimmagadda S, Fremont V, Wolf V, Weintraub BD, Pomper MG, Szkudlinski MW, Kuwert T, and Prante O
- Subjects
- Animals, Cell Line, Cyclic AMP metabolism, Female, Fluorodeoxyglucose F18, Humans, Mice, Rats, Receptors, Thyrotropin drug effects, Receptors, Thyrotropin metabolism, Sodium Iodide metabolism, Thyrotropin pharmacology, Tissue Distribution, Iodine Radioisotopes, Thyroid Gland metabolism, Thyrotropin agonists, Thyrotropin analogs & derivatives
- Abstract
Background: Superagonist analogs of human thyroid-stimulating hormone (hTSH) may stimulate the uptake of (131)I-iodide and (18)F-fluorodeoxyglucose ((18)F-FDG) in thyroid carcinomas to a greater degree than hTSH. We herein report the potency and efficacy of two hTSH analogs, TR1401 and TR1402, to stimulate radioiodide and (18)F-FDG uptake in FRTL-5 cells and compared the effects of hTSH and TR1401 on radioiodide uptake in the thyroid in vivo in mice., Methods: The effects of hTSH analogs on intracellular levels of cAMP, uptake of (131)I-iodide, and (18)F-FDG were studied in FRTL-5 cells to determine the stimulatory potency and efficacy of the compounds by calculating half-maximum effective concentration (EC(50)) values and maximal stimulatory effects (E(max)). Biodistribution studies (n = 96) and positron emission tomography/computed tomography imaging studies (single animals) on thyroid (125)I/(124)I-iodide uptake were performed with T3-suppressed CD-1 mice in a dose-dependent manner (3, 10, and 30 μg/animal)., Results: The EC(50) values of TR1401 and TR1402 demonstrated a 90-fold or 800-fold higher potency for their capacity to increase intracellular cAMP levels in comparison with hTSH (p < 0.05). Similar results were demonstrated for the stimulation of (18)F-FDG uptake. Bovine TSH, TR1401, and TR1402 were 85%-490% more potent to increase iodide uptake than hTSH (p < 0.05). TR1402 was 30% more efficacious to stimulate iodide uptake than hTSH. The agonist-induced increase in radiotracer uptake was paralleled by increases in NIS and GLUT-1 expression. Ex vivo biodistribution studies showed an increased iodide uptake in the thyroid of TR1401-treated mice at the low dose of 3 μg/animal in comparison with hTSH-treated mice (n = 16, p < 0.05). Positron emission tomography/computed tomography imaging studies confirmed the increased thyroidal iodide uptake in TR1401-treated mice in vivo., Conclusions: TR1401 and TR1402 have considerably higher potency than hTSH to stimulate thyroidal iodide and (18)F-FDG uptake in vitro. Moreover, in vivo studies indicated that at low but not higher doses, TR1401 induced an enhanced ability for the thyroid to concentrate iodide compared with hTSH. These properties makes TR1401 and TR1402 interesting candidates for use in humans to enhance uptake of radioiodine and (18)F-FDG by metastases and recurrences of thyroid carcinoma.
- Published
- 2011
- Full Text
- View/download PDF
174. Herpes simplex virus thymidine kinase imaging in mice with (1-(2'-deoxy-2'-[18F]fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) and metabolite (1-(2'-deoxy-2'-[18F]fluoro-1-β-D-arabinofuranosyl)-5-uracil).
- Author
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Nimmagadda S, Mangner TJ, Lawhorn-Crews JM, Haberkorn U, and Shields AF
- Subjects
- Animals, Arabinofuranosyluracil metabolism, Arabinofuranosyluracil pharmacokinetics, Biological Transport, Cell Line, Tumor, Gene Expression Regulation, Enzymologic, Humans, Male, Mice, Rats, Substrate Specificity, Arabinofuranosyluracil analogs & derivatives, Fluorine Radioisotopes, Molecular Imaging methods, Simplexvirus enzymology, Thymidine Kinase metabolism
- Abstract
Purpose: FIAU, (1-(2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of 18F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of 18F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite 18F-FAU., Methods: CD-1 nu/nu mice with subcutaneous MH3924A and MH3924A-stb-tk+ xenografts on opposite flanks were used for the biodistribution and imaging studies. Mice were injected IV with either 18F-FIAU or 18F-FAU. Mice underwent dynamic imaging with each tracer for 65 min followed by additional static imaging up to 150 min post-injection for some animals. Animals were sacrificed at 60 or 150 min post-injection. Samples of blood and tissue were collected for biodistribution and metabolite analysis. Regions of interest were drawn over the images obtained from both tumors to calculate the time-activity curves., Results: Biodistribution and imaging studies showed the highest uptake of 18F-FIAU in the MH3924A-stb-tk+ tumors. Dynamic imaging studies revealed a continuous accumulation of 18F-FIAU in HSV-TK expressing tumors over 60 min. The mean biodistribution values (SUV ± SE) for MH3924A-stb-tk+ were 2.07 ± 0.40 and 6.15 ± 1.58 and that of MH3924A tumors were 0.19 ± 0.07 and 0.47 ± 0.06 at 60 and 150 min, respectively. In 18F-FIAU injected mice, at 60 min nearly 63% of blood activity was present as its metabolite 18F-FAU. Imaging and biodistribution studies with 18F-FAU demonstrated no specific accumulation in MH3924A-stb-tk+ tumors and SUVs for both the tumors were similar to those observed with muscle., Conclusion: 18F-FIAU shows a continuous accumulation of activity in HSV-TK expressing tumors. 18F-FAU does not show any preferential accumulation in HSV-TK expressing tumors. In the 18F-FIAU treated mice, the 18F-FAU contribution to the total uptake seen in HSV-TK positive tumors is minimal.
- Published
- 2009
- Full Text
- View/download PDF
175. The role of DNA synthesis imaging in cancer in the era of targeted therapeutics.
- Author
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Nimmagadda S and Shields AF
- Subjects
- Animals, Humans, Neoplasms metabolism, Positron-Emission Tomography, Radiopharmaceuticals, Cell Proliferation, DNA Replication, Diagnostic Imaging methods, Neoplasms diagnostic imaging, Neoplasms genetics
- Abstract
Non-specific targets such as DNA and microtubules have been the mainstay of cancer therapeutics and the most effective clinical agents until a decade ago. Advances in genetics, molecular and cellular biology over the past decade led to the development of a new generation of agents that are far more specific and effective. In contrast to progress seen with therapeutic agents, general monitoring targets such as proliferation imaging are just gaining momentum and targeted imaging is still in its infancy. In these paradoxical times, this review assesses the role of proliferation imaging in monitoring the efficacy of targeted therapeutics.
- Published
- 2008
- Full Text
- View/download PDF
176. Biodistribution, PET, and radiation dosimetry estimates of HSV-tk gene expression imaging agent 1-(2'-Deoxy-2'-18F-Fluoro-beta-D-arabinofuranosyl)-5-iodouracil in normal dogs.
- Author
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Nimmagadda S, Mangner TJ, Douglas KA, Muzik O, and Shields AF
- Subjects
- Animals, Arabinofuranosyluracil pharmacokinetics, DNA metabolism, Dogs, Genes, Reporter, Genetic Therapy methods, Kinetics, Liver metabolism, Positron-Emission Tomography methods, Tissue Distribution, Arabinofuranosyluracil analogs & derivatives, Fluorine Radioisotopes pharmacokinetics, Gene Expression Regulation, Radiometry methods, Simplexvirus metabolism, Thymidine Kinase genetics
- Abstract
Unlabelled: FIAU is of interest as a potential reporter probe to monitor herpes simplex virus thymidine kinase (HSV-tk) gene expression and bacterial infections. This study investigates the biodistribution, metabolism, and DNA uptake of 1-(2'-deoxy-2'-(18)F-fluoro-beta-d-arabinofuranosyl)-5-iodouracil ((18)F-FIAU) in normal dogs., Methods: Four normal dogs were intravenously administered (18)F-FIAU. A dynamic PET scan was performed for 60 min over the upper abdomen; this was followed by a whole-body scan for a total of 150 min on 3 dogs. The fourth dog was not scanned and was euthanized at 60 min. Blood and urine samples were collected at stipulated time intervals and analyzed by high-performance liquid chromatography to evaluate tracer clearance and metabolism. Tissue samples collected from various organs were analyzed to evaluate tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. Nondecay-corrected time-activity curves were used for residence time calculation and absorbed dose estimation., Results: At 60 min after injection, unmetabolized FIAU radioactivity in blood and urine samples was greater than 78% and 63%, respectively, demonstrating resistance to metabolism. The tissue-to-muscle ratio derived from image and tissue analysis showed a slightly higher uptake in proliferating organs (mean tissue-to-muscle values: small intestine, 1.97; marrow, 1.70) compared with nonproliferative organs (heart, 1.07; lung, 1.06). A high concentration of activity was seen in the bile (mean, 23.02), demonstrating hepatobiliary excretion of the tracer. Extraction analysis of tissue samples showed that >62% of the activity in the small intestine, 74% in marrow, and <21% in heart, liver, and muscle was incorporated into DNA., Conclusion: These results demonstrate that FIAU is resistant to metabolism and moderately incorporates into DNA in proliferating tissues. These results suggest that incorporation into the DNA of normal tissues may need to be considered when FIAU is used to track reporter gene activity. Studies in humans are needed to determine whether imaging properties differ in patients and are altered as a result of metabolism changes affected by gene therapies.
- Published
- 2007
- Full Text
- View/download PDF
177. Biodistribution and radiation dosimetry estimates of 1-(2'-deoxy-2'-(18)F-Fluoro-1-beta-D-arabinofuranosyl)-5-bromouracil: PET imaging studies in dogs.
- Author
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Nimmagadda S, Mangner TJ, Sun H, Klecker RW Jr, Muzik O, Lawhorn-Crews JM, Douglas KA, Collins JM, and Shields AF
- Subjects
- Animals, Body Burden, Bromouracil pharmacokinetics, Cell Line, Tumor, Dogs, Humans, Organ Specificity, Radiation Dosage, Radiometry, Radiopharmaceuticals pharmacokinetics, Relative Biological Effectiveness, Tissue Distribution, Whole Body Imaging, Whole-Body Counting, Bromouracil analogs & derivatives, Neoplasms diagnostic imaging, Neoplasms metabolism, Positron-Emission Tomography methods
- Abstract
Unlabelled: This study reports on the biodistribution and radiation estimates of 1-(2'-deoxy-2'-(18)F-fluoro-1-beta-d-arabinofuranosyl)-5-bromouracil ((18)F-FBAU), a potential tracer for imaging DNA synthesis., Methods: Three normal dogs were intravenously administered (18)F-FBAU and a dynamic PET scan was performed for 60 min over the upper abdomen followed by a whole-body scan for a total of 150 min. Blood samples were collected at stipulated time intervals to evaluate tracer clearance and metabolism. Tissue samples of various organs were analyzed for tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. The radiation dosimetry of (18)F-FBAU was evaluated using the MIRD method., Results: At 60 min after injection, blood analysis found >90% of the activity in unmetabolized form. At 2 h after injection, (18)F-FBAU uptake was highest in proliferating tissues (mean SUVs: marrow, 2.6; small intestine, 4.0), whereas nonproliferative tissues showed little uptake (mean SUVs: muscle, 0.75; lung, 0.70; heart, 0.85; liver, 1.28). Dynamic image analysis over 60 min showed progressive uptake of the tracer in marrow. Extraction studies demonstrated that most of the activity in proliferative tissues was in the acid-insoluble fraction (marrow, 83%; small intestine, 73%), consistent with incorporation into DNA. In nonproliferative tissue, most of the activity was not found in the acid-insoluble fraction (>84% for heart, muscle, and liver)., Conclusion: These results demonstrate that (18)F-FBAU was resistant to metabolism, readily incorporated into DNA in proliferating tissues, and showed good contrast between organs of variable DNA synthesis. These findings indicate that (18)F-FBAU may find use in measuring DNA synthesis with PET.
- Published
- 2005
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