scholarly journals PET Imaging Using [18F]olaparib in Mouse Models of Malignant Glioma: Considerations for Molecular Imaging and Radionuclide Therapy Targeting PARP

2021 ◽  
Author(s):  
Chung Ying Chan ◽  
Samantha L. Hopkins ◽  
Florian Guibbal ◽  
Anna Pacelli ◽  
Julia Baguña Torres ◽  
...  
Keyword(s):  
Cancer Diagnosis ◽  
Normal Tissue ◽  
Radionuclide Therapy ◽  
Ex Vivo ◽  
Parp Inhibitor ◽  
Systematic Evaluation ◽  
Human Glioblastoma ◽  
Tumour Uptake ◽  
Molar Activity

Abstract PurposeRadiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [18F]olaparib and the injected mass of [TotalF]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models.Methods[18F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [TotalF]olaparib (varying injected mass: 0.04-8.0 µg, and molar activity: 1-320 GBq/μmol).ResultsSelective uptake of [18F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [TotalF]olaparib (µg), but not the molar activity per sé. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [TotalF]olaparib resulted in lower relative tumour uptake (%ID/g; P<0.05). Ex vivo analysis of U87MG xenograft sections showed that the heterogeneity in [18F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [TotalF]olaparib (>0.5 µg).ConclusionOur findings show that the injected mass of [TotalF]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.

Comparison of in vivo skin and in vitro blood lymphocyte models for the prediction of late normal tissue responses in breast radiotherapy (RT) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11116-11116
Author(s):  
Melvin Chua ◽  
Navita Somaiah ◽  
Sue Davies ◽  
Lone Gothard ◽  
Kai Rothkamm ◽  
...  
Keyword(s):  
Late Effects ◽  
Normal Tissue ◽  
Ex Vivo ◽  
Predictive Marker ◽  
Dermal Fibroblasts ◽  
Clinical Severity ◽  
Breast Size ◽  
Dsb Repair

11116 Background: Critical opinions for the lack of success of DNA double-strand break (DSB) repair as a predictive marker of normal tissue radiosensitivity include the argument that in vitro cellular responses correlate poorly with in vivo responses due to the modifying influence of tissue environment. In this study, we test the hypothesis that a DNA damage assay based on in vivo irradiated skin tissues better predicts clinical responses in human skin, as opposed to the same assay performed in ex vivo irradiated lymphocytes. Methods: DSB levels (24 h post-4 Gy) were quantified using γH2AX/53BP1 immunostaining in irradiated skin tissues and G0 lymphocytes of 35 breast RT patients. Patients were selected on the basis of late RT effects in their breast and individuals with marked or minimal effects were classified as cases and controls, respectively. Risk factors of late effects established from multivariate analyses of outcomes of two breast RT trials were also considered in patient selection. They were 1) total RT dose, 2) RT dosimetry, 3) tumour bed boost, 4) breast size, 5) surgical cavity, and 6) axillary treatment. Results: Clinical parameters were balanced in both patient groups. Residual foci levels in skin epidermis and dermis were comparable between cases (n = 20) and controls (n = 15). Mean foci per cell were 3.29 in cases, 2.80 in controls for dermal fibroblasts (p = 0.07); 3.28 in cases, 2.60 in controls for endothelial cells (p = 0.08); 2.87 in cases, 2.41 in controls for superficial keratinocytes (p = 0.45); 2.32 in cases, 2.35 in controls for basal keratinocytes (p = 0.27). Residual foci levels in lymphocytes were however significantly higher among cases (foci per cell = 12.1) compared to controls (foci per cell = 10.3, p = 0.01). Of the different cell types, only residual foci levels of dermal fibroblasts and lymphocytes correlated with clinical severity (R = 0.722, p < 0.001; 0.593, p = 0.01, respectively). Interestingly, foci levels were not correlated between skin cells and lymphocytes of the same patients. Conclusions: DSB repair of ex vivo irradiated lymphocytes appears to be a better predictive marker of late effects to breast RT than DSB repair of in vivo irradiated skin.

IN VIVO NEAR-INFRARED FLUORESCENCE IMAGING OF HUMAN COLON ADENOCARCINOMA BY SPECIFIC IMMUNOTARGETING OF A TUMOR-ASSOCIATED MUCIN

2009 ◽  
Vol 02 (04) ◽  
pp. 407-422 ◽  
Author(s):  
RALPH S. DACOSTA ◽  
YING TANG ◽  
TUULA KALLIOMAKI ◽  
RAYMOND M. REILLY ◽  
ROBERT WEERSINK ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Fluorescence Imaging ◽  
Normal Tissue ◽  
Near Infrared ◽  
Ex Vivo ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Human Colon Adenocarcinoma

Background and Aims: Accurate endoscopic detection of premalignant lesions and early cancers in the colon is essential for cure, since prognosis is closely related to lesion size and stage. Although it has great clinical potential, autofluorescence endoscopy has limited tumor-to-normal tissue image contrast for detecting small preneoplastic lesions. We have developed a molecularly specific, near-infrared fluorescent monoclonal antibody (CC49) bioconjugate which targets tumor-associated glycoprotein 72 (TAG72), as a contrast agent to improve fluorescence-based endoscopy of colon cancer. Methods: The fluorescent anti-TAG72 conjugate was evaluated in vitro and in vivo in athymic nude mice bearing human colon adenocarcinoma (LS174T) subcutaneous tumors. Autofluorescence, a fluorescent but irrelevant antibody and the free fluorescent dye served as controls. Fluorescent agents were injected intravenously, and in vivo whole body fluorescence imaging was performed at various time points to determine pharmacokinetics, followed by ex vivo tissue analysis by confocal fluorescence microscopy and histology. Results: Fluorescence microscopy and histology confirmed specific LS174T cell membrane targeting of labeled CC49 in vitro and ex vivo. In vivo fluorescence imaging demonstrated significant tumor-to-normal tissue contrast enhancement with labeled-CC49 at three hours post injection, with maximum contrast after 48 h. Accumulation of tumor fluorescence demonstrated that modification of CC49 antibodies did not alter their specific tumor-localizing properties, and was antibody-dependent since controls did not produce detectable tumor fluorescence. Conclusions: These results show proof-of-principle that our near-infrared fluorescent-antibody probe targeting a tumor-associated mucin detects colonic tumors at the molecular level in real time, and offer a basis for future improvement of image contrast during clinical fluorescence endoscopy.

scholarly journals Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0212455 ◽  
Author(s):  
Yoshitaka Tanaka ◽  
Tsutomu Nakazawa ◽  
Mitsutoshi Nakamura ◽  
Fumihiko Nishimura ◽  
Ryosuke Matsuda ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Ex Vivo ◽  
Glioblastoma Cells ◽  
Antitumor Effects ◽  
Killer Cells ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cells

scholarly journals In vivo quantitative assessment of therapeutic response to bortezomib therapy in disseminated animal models of multiple myeloma with [18F]FDG and [64Cu]Cu-LLP2A PET

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anchal Ghai ◽  
Nikki Fettig ◽  
Francesca Fontana ◽  
John DiPersio ◽  
Mike Rettig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Therapeutic Response ◽  
Plasma Cells ◽  
Fluorescent Protein ◽  
Ex Vivo ◽  
Molar Activity ◽  
Quantitative Pet

Abstract Background Multiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow. Imaging-based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4, CD49d/CD29) is overexpressed in MM cells. Here, we evaluated [18F]FDG and VLA4 targeted [64Cu]Cu-LLP2A for quantitative PET imaging in disseminated MM models of variable VLA4 expression, following bortezomib therapy. Methods In vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (C: luciferase and G: green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1 mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no tumor) were longitudinally imaged with [18F]FDG (7.4–8.0 MBq) and [64Cu]Cu-LLP2A (2–3 MBq; Molar Activity: 44.14 ± 1.40 MBq/nmol) PET, respectively. Results Flow cytometry confirmed high expression of CD49d in U266 cells (> 99%) and moderate expression in MM.1S cells (~ 52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [64Cu]Cu-LLP2A localized with a significantly higher SUVmean in spine (0.58 versus 0.31, p < 0.01) and femur (0.72 versus 0.39, p < 0.05) at week 4 post-tumor inoculation. There was a four-fold higher uptake of [64Cu]Cu-LLP2A (SUVmean) in untreated U266-CG mice compared to treated mice at 3 weeks post-treatment. Compared to [64Cu]Cu-LLP2A, [18F]FDG PET detected treatment-related changes at later time points. Conclusion [64Cu]Cu-LLP2A is a promising tracer for timely in vivo assessment of therapeutic response in disseminated models of MM.

scholarly journals In Vivo Quantitative Assessment of Therapeutic Response to Bortezomib Therapy in Disseminated Animal Models of Multiple Myeloma With [18F]FDG and [64Cu]LLP2A PET

2021 ◽  
Author(s):  
Anchal Ghai ◽  
Nikki Fettig ◽  
Francesca Fontana ◽  
John DiPersio ◽  
Mike Rettig ◽  
...  
Keyword(s):  
Therapeutic Response ◽  
Plasma Cells ◽  
Fluorescent Protein ◽  
Ex Vivo ◽  
Molar Activity ◽  
Quantitative Pet ◽  
Late Antigen ◽  
Green Fluorescent

Abstract BackgroundMultiple myeloma (MM) is a disease of cancerous plasma cells. Current treatments have improved the survival rate; however, most MM patients relapse. Imaging based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4) is over expressed in MM cells. Here, we evaluated [18F]FDG and VLA4 targeted [64Cu]LLP2A for quantitative PET imaging in MM models of variable VLA4 expression, and following bortezomib therapy.MethodsIn vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (CG: luciferase and green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no-tumor) were longitudinally imaged with [64Cu]LLP2A (2-3 MBq; Molar Activity: 44.14±1.40 MBq/nmol) and [18F]FDG (7.4-8.0 MBq) PET respectively.ResultsFlow cytometry confirmed high expression of CD49d in U266 cells (>99%) and moderate expression in MM.1S cells (~52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [64Cu]LLP2A localized with a significantly higher SUVmean in spine (0.58 versus 0.31) and femur (0.72 versus 0.39) at week 4 post tumor inoculation. In U266-CG treated versus untreated mice, there was a 4-time percent [64Cu]LLP2A increase in spine at week 3. Compared to [64Cu]LLP2A, [18F]FDG PET detected treatment related changes at later time points.Conclusion[64Cu]LLP2A is a promising tracer for in vivo assessment of therapeutic response in disseminated models of MM.

scholarly journals Synthesis and Biological Evaluation of a Radiolabeled PET Probe for Visualization of In Vivo α-Fucosidase Expression

2021 ◽  
Vol 14 (8) ◽  
pp. 745
Author(s):  
Jonathan Cotton ◽  
Chris Marc Goehring ◽  
Anna Kuehn ◽  
Andreas Maurer ◽  
Kerstin Fuchs ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Sodium Hydride ◽  
Biological Evaluation ◽  
Tracer Uptake ◽  
Mouse Serum ◽  
Molar Activity ◽  
Pet Tracer ◽  
Positron Emission

The acidic hydrolase α-fucosidase (AF) is a biomarker for maladies such as cancer and inflammation. The most advanced probes for α-fucosidase are unfortunately constrained to ex vivo or in vitro applications. The in vivo detection and quantification of AF using positron emission tomography would allow for better discovery and diagnosis of disease as well as provide better understanding of disease progression. We synthesized, characterized, and evaluated a radiolabeled small molecule inhibitor of AF based on a known molecule. The radiosynthesis involved the 11C methylation of a phenoxide, which was generated in situ by ultrasonification of the precursor with sodium hydride. The tracer was produced with a decay corrected yield of 41.7 ± 16.5% and had a molar activity of 65.4 ± 30.3 GBq/μmol. The tracer was shown to be stable in mouse serum at 60 min. To test the new tracer, HCT116 colorectal carcinoma cells were engineered to overexpress human AF. In vitro evaluation revealed 3.5-fold higher uptake in HCT116AF cells compared to HCT116 controls (26.4 ± 7.8 vs. 7.5 ± 1.0 kBq/106 cells). Static PET scans 50 min post injection revealed 2.5-fold higher tracer uptake in the HCT116AF tumors (3.0 ± 0.8%ID/cc (n = 6)) compared with the controls (1.2 ± 0.8 (n = 5)). Dynamic scans showed higher uptake in the HCT116AF tumors at all time-points (n = 2). Ex vivo analysis of the tumors, utilizing fluorescent DDK2 antibodies, confirmed the expression of human AF in the HCT116AF xenografts. We have developed a novel PET tracer to image AF in vivo and will now apply this to relevant disease models.

Analysis of phosphatidylcholines alterations in human glioblastoma multiform tissues ex vivo

2021 ◽  
Vol 67 (1) ◽  
pp. 81-87
Author(s):  
S.I. Pekov ◽  
A.A. Sorokin ◽  
A.A. Kuzin ◽  
K.V. Bocharov ◽  
D.S. Bormotov ◽  
...  
Keyword(s):  
Fatty Acids ◽  
De Novo ◽  
Ex Vivo ◽  
Lipid Synthesis ◽  
Beta Oxidation ◽  
Secondary Glioblastoma ◽  
Human Glioblastoma ◽  
Glioblastoma Multiform ◽  
Process Energy

Significant metabolism alteration is accompanying the cell malignization process. Energy metabolism disturbance leads to the activation of de novo synthesis and beta-oxidation processes of lipids and fatty acids in a cancer cell, which becomes an indicator of pathological processes inside the cell. The majority of studies dealing with lipid metabolism alterations in glial tumors are performed using the cell lines in vitro or animal models. However, such conditions do not entirely represent the physiological conditions of cell growth or possible cells natural variability. This work presents the results of the data obtained by applying ambient mass spectrometry to human glioblastoma multiform tissues. By analyzing a relatively large cohort of primary and secondary glioblastoma samples, we identify the alterations in cells lipid composition, which accompanied the development of grade IV brain tumors. We demonstrate that primary glioblastomas, as well as ones developed from astrocytomas, are enriched with mono- and diunsaturated phosphatidylcholines (PC 26:1, 30:2, 32:1, 32:2, 34:1, 34:2). Simultaneously, the saturated and polyunsaturated phosphatidylcholines and phosphatidylethanolamines decrease. These alterations are obviously linked to the availability of the polyunsaturated fatty acids and activation of the de novo lipid synthesis and beta-oxidation pathways under the anaerobic conditions in the tumor core.

scholarly journals Feasibility of interstitial ex-vivo mammary autofluorescne microendoscopy

2021 ◽  
Author(s):  
Dena Monjazebi
Keyword(s):  
Breast Cancer ◽  
Cancer Diagnosis ◽  
Gold Standard ◽  
Normal Tissue ◽  
Ex Vivo ◽  
Target Tissue ◽  
Breast Cancer Imaging ◽  
Imaging Diagnostics ◽  
The Past ◽  
Breast Tissues

In the past decades our knowledge of breast cancer has been rapidly evolving yet the basic paradigm of diagnosis and treatment of cancer has not. In cancer diagnosis, presentation of breast cancer can be a palpable lump or a suspicious mass on screening imaging, namely a mammogram. However, malignancy will be ascertained by tissue biopsy if needed. Biopsy is the gold standard breast cancer diagnostic test. Biopsy sampling is invasive, painful and costly. In addition, when the interpretation of current imaging modalities is not concordant with pathology results the biopsies may have to be repeated. Microendoscopy autofluorescence (AM) is a method of acquiring images directly from the tissues that contain fluorescent susceptible molecules (fluorophore). Studies of endoscopy in colon and esophagus showed that AM imaging is capable to recognize malignancy and can be utilized to discriminate between normal tissue and tumor. Additionally, it has been shown that, AM was able to differentiate cancer versus normal cells when a microendoscope was inserted into a breast duct. The main purpose of this study is to investigate if the same contrast exists if AM applied interstitially into the ex-vivo mastectomy breast tissues. This is a feasibility study to explore if interstitial AM has the potential to be coupled with breast cancer imaging diagnostics to provide better discrimination of the characteristics of the target tissue inside. The success in this approach could significantly reduce the number of required tissue biopsies to confirm the diagnosis.

scholarly journals Feasibility of interstitial ex-vivo mammary autofluorescne microendoscopy

2021 ◽  
Author(s):  
Dena Monjazebi
Keyword(s):  
Breast Cancer ◽  
Cancer Diagnosis ◽  
Gold Standard ◽  
Normal Tissue ◽  
Ex Vivo ◽  
Target Tissue ◽  
Breast Cancer Imaging ◽  
Imaging Diagnostics ◽  
The Past ◽  
Breast Tissues

In the past decades our knowledge of breast cancer has been rapidly evolving yet the basic paradigm of diagnosis and treatment of cancer has not. In cancer diagnosis, presentation of breast cancer can be a palpable lump or a suspicious mass on screening imaging, namely a mammogram. However, malignancy will be ascertained by tissue biopsy if needed. Biopsy is the gold standard breast cancer diagnostic test. Biopsy sampling is invasive, painful and costly. In addition, when the interpretation of current imaging modalities is not concordant with pathology results the biopsies may have to be repeated. Microendoscopy autofluorescence (AM) is a method of acquiring images directly from the tissues that contain fluorescent susceptible molecules (fluorophore). Studies of endoscopy in colon and esophagus showed that AM imaging is capable to recognize malignancy and can be utilized to discriminate between normal tissue and tumor. Additionally, it has been shown that, AM was able to differentiate cancer versus normal cells when a microendoscope was inserted into a breast duct. The main purpose of this study is to investigate if the same contrast exists if AM applied interstitially into the ex-vivo mastectomy breast tissues. This is a feasibility study to explore if interstitial AM has the potential to be coupled with breast cancer imaging diagnostics to provide better discrimination of the characteristics of the target tissue inside. The success in this approach could significantly reduce the number of required tissue biopsies to confirm the diagnosis.

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