| 1. |
- Evans Axelsson, Susan, et al.
(författare)
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Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone
- 2012
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 27:4, s. 243-251
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected 125I-labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting 125I-labeled PSA30. Tissue uptake of 125I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, 18F-fluoro-deoxy-glucose (18F-FDG) or 18F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high 125I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either 18F-FDG or 18F-choline. Biodistribution of 125I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24–48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa.
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| 2. |
- Abouzayed, Ayman, et al.
(författare)
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Co-injection of anti-HER2 antibody Trastuzumab does not increase efficacy of [Lu-177]Lu-PSMA-617 therapy in an animal model of prostate cancer
- 2023
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Ingår i: American Journal of Nuclear Medicine and Molecular Imaging. - : E-CENTURY PUBLISHING CORP. - 2160-8407. ; 13:3, s. 107-
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Tidskriftsartikel (refereegranskat)abstract
- One novel option for treating metastatic castration resistant prostate cancer is radionuclide therapy targeting prostate-specific membrane antigen (PSMA), e.g. [Lu-177]Lu-PSMA-617. Overexpression of HER2 has been found in 80% of metastatic cases of prostate cancer. Previous research showed that HER2 is elevated post irradiation in PC-3 prostate cancer cells. Co-treating with anti-HER2 antibody Trastuzumab gave less proliferation of irradiated tumor cells in vitro, and when using radionuclide therapy, also in vivo. The aim of this study is to determine whether the same holds true in PSMA-expressing PC-3 PIP cells using [Lu-177]Lu-PSMA-617 radionuclide therapy. PC-3 PIP and 22Rv1 prostate cancer cells were tested in vitro, treated with 6 Gy of x-rays with or without Trastuzumab incubation. We measured uptake of HER2-targeting affibody [Ga-68]Ga-ABY-025 and cell survival, e.g. using the WST-1 assay. Three groups (n=10 each) of male nude Balb/c mice were inoculated with PC-3 PIP xenograft tumors and treated with just [Lu-177]Lu-PSMA-617 (20 MBq), [Lu-177]Lu-PSMA-617 (20 MBq) and Trastuzumab (4 x 5 mg/kg), or left untreated. Tumor sizes and animal survival was observed. In vitro, x-ray irradiation did reduce survival in 22Rv1 but not PC-3 PIP cells, and there was no significant effect of Trastuzumab treatment. Cells expressed HER2 but not significantly elevated post irradiation. In vivo, mice co-treated with Trastuzumab had significantly longer survival than untreated mice, but not than only [Lu-177]Lu-PSMA-617. Staining of tumor sections showed similar HER2 and PSMA expression across groups. In conclusion, these results give no support for any benefit from co-treatment with anti-HER2 antibody for PSMA-targeted radioligand therapy.
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| 3. |
- Elgström, Erika, et al.
(författare)
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Change in Cell Death Markers During (177)Lu-mAb Radioimmunotherapy-Induced Rejection of Syngeneic Rat Colon Carcinoma.
- 2014
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 29:4, s. 143-152
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Purpose: To monitor cell death in tumors during the rejection process after treatment with an antibody radiolabeled with a β-emitter. Methods: Tumors during rejection after treatment with (177)Lu-labeled antibody BR96 and after administration of unlabeled BR96 were compared with untreated tumors from the same immunocompetent syngeneic rat tumor model. Cell death was monitored with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemical staining of activated caspase-3 and γH2AX. These data were evaluated together with histopathological morphology, BR96-binding antigen expression, and (177)Lu radioactivity distribution imaged by digital autoradiography. Results: The untreated tumors showed staining for all the markers, mainly in and around the necrotic areas. One to 2 days p.i. large areas were stained with anti-γH2AX, followed by a slight decrease. Staining of activated caspase-3 was intense and extensive 1-2 days p.i., while found in and around necrotic areas 3-8 days p.i. TUNEL staining was similar to activated caspase-3 staining 1-2 days p.i. but more extensive than activated caspase-3 staining 3-4 days p.i. Digital autoradiography revealed activity concentration in granulation tissue from 1 day p.i. Conclusion: Following radioimmunotherapy in an immunocompetent syngeneic colon carcinoma model, tumor cells did not only die through caspase-3-dependent apoptosis, but also by other mechanisms.
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| 4. |
- Kristiansson, Amanda, et al.
(författare)
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177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging
- 2021
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Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3-4 days and 3-4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.
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| 5. |
- Kristiansson, Amanda, et al.
(författare)
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Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin
- 2024
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Ingår i: Scientific Reports. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Radioligand therapy with [177Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity. However, there might be a need to reduce toxicity even further with e.g. radioprotectors. The aim of this study was to (i). establish a preclinical mouse model with fractionated high activity therapy of three consecutive doses of 200 MBq [177Lu]Lu-PSMA-617 in which we aimed to (ii). achieve measurable hematotoxicity and nephrotoxicity and to (iii). analyze the potential protective effect of co-injecting recombinant α1-microglobulin (rA1M), a human antioxidant previously shown to have radioprotective effects. In both groups, three cycles resulted in increased albuminuria for each cycle, with large individual variation. Another marker of kidney injury, serum blood urea nitrogen (BUN), was only significantly increased compared to control animals after the third cycle. The number of white and red blood cells decreased significantly and did not reach the levels of control animals during the experiment. rA1M did reduce absorbed dose to kidney but did not show significant protection here, but future studies are warranted due to the recent clinical studies showing a significant renoprotective effect in patients.
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| 6. |
- Kristiansson, Amanda, et al.
(författare)
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Hematological Toxicity in Mice after High Activity Injections of 177Lu-PSMA-617
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer (PC) is one of the most common malignancies affecting men, with poor prognosis after progression to metastatic castration-resistant prostate cancer (mCRPC). Radioligand therapy (RLT) targeting the overexpressed PSMA on PC cells, with, e.g., 177Lu-PSMA-617, has been effective in reducing tumor burden and prolonging survival in mCRPC. However, it is not a curative method with kidney and bone marrow toxicity limiting the activity given to patients. Previous preclinical models have reported transient hematotoxicity for up to 120 MBq. This activity may still be too low to investigate the effect on renal function since it corresponds to an absorbed dose below 10 Gy, whereas the kidneys in a clinical setting usually receive an absorbed dose more than double. Here we investigated the hematotoxicity and recovery after administered activities of 120, 160, and 200 MBq in a 177Lu-PSMA-617 BALB/cAnNRj mouse model. The animals had an initial drop in white blood cells (WBC) starting 4 days post injection, which recovered after 21 days. The effect on red blood cells (RBC) and platelets was detected later; 17 days post-injection levels decreased compared to the control group. The reduction was restored again 32 days post injection. No correlation between injected activity and hematotoxicity was found. Our results suggest that activities up to 200 MBq of 177Lu-PSMA-617 give transient hematotoxicity from which animals recover within a month and no radiation-related deaths. Injecting these high activities could allow animal studies with increased clinical relevance when studying renal toxicity in animal models.
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| 7. |
- Kristiansson, Amanda, et al.
(författare)
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Kidney protection with the radical scavenger α1-microglobulin (A1m) during peptide receptor radionuclide and radioligand therapy
- 2021
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Ingår i: Antioxidants. - : MDPI AG. - 2076-3921. ; 10:8, s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- α1-microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models. In this review, we focus on A1M as a radioprotector of the kidneys during peptide receptor radionuclide/radioligand therapy (PRRT/RLT). Patients with, e.g., neuroendocrine tumors or castration resistant prostate cancer can be treated by administration of radiolabeled small molecules which target and therefore enable the irradiation and killing of cancer cells through specific receptor interaction. The treatment is not curative, and kidney toxicity has been reported as a side effect since the small, radiolabeled substances are retained and excreted through the kidneys. In recent studies, A1M was shown to have radioprotective effects on cell cultures as well as having a similar biodistribution as the somatostatin analogue peptide177Lu-DOTA-TATE after intravenous infusion in mice. Therefore, several animal studies were conducted to investigate the in vivo radioprotective potential of A1M towards kidneys. The results of these studies demonstrated that A1M co-infusion yielded protection against kidney toxicity and improved overall survival in mouse models. Moreover, two different mouse studies reported that A1M did not interfere with tumor treatment itself. Here, we give an overview of radionuclide therapy, the A1M physiology and the results from the radioprotector studies of the protein.
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| 8. |
- Mahmutovic Persson, Irma, et al.
(författare)
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Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- A large number of systemically administered drugs have the potential to cause drug-induced interstitial lung disease (DIILD). We aim to characterize a model of DIILD in the rat and develop imaging biomarkers (IBs) for detection and quantification of DIILD. In this study, Sprague–Dawley rats received one single dose of intratracheal (i.t.) bleomycin and were longitudinally imaged at day 0, 3, 7, 14, 21, and 28 post dosing, applying the imaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT). Bronchoalveolar lavage fluid (BALF) was analyzed for total protein and inflammatory cells. Lungs were saved for further evaluation by gene analysis using quantitative-PCR and by histology. Lung sections were stained with Masson’s-Trichrome staining and evaluated by modified Ashcroft score. Gene expression profiling of inflammatory and fibrotic markers was performed on lung tissue homogenates. Bleomycin induced significant increase in total protein concentration and total cell count in bronchoalveolar lavage (BAL), peaking at day 3 (p > 0.001) and day 7 (p > 0.001) compared to control, respectively. Lesions measured by MRI and PET signal in the lungs of bleomycin challenged rats were significantly increased during days 3–14, peaking at day 7. Two subgroups of animals were identified as low- and high-responders by their different change in total lung volume. Both groups showed signs of inflammation initially, while at later time points, the low-responder group recovered toward control, and the high-responder group showed sustained lung volume increase, and significant increase of lesion volume (p < 0.001) compared to control. Lastly, important inflammatory and pro-fibrotic markers were assessed from lung tissue, linking observed imaging pathological changes to gene expression patterns. In conclusion, bleomycin-induced lung injury is an adequate animal model for DIILD studies and for translational lung injury assessment by MRI and PET imaging. The scenario comprised disease responses, with different fractions of inflammation and fibrosis. Thereby, this study improved the understanding of imaging and biological biomarkers in DIILD and lung injury.
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| 9. |
- Mahmutovic Persson, Irma, et al.
(författare)
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In vivo MRI and PET imaging in a translational ILD mouse model expressing non-resolving fibrosis and bronchiectasis-like pathology after repeated systemic exposure to bleomycin
- 2024
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Ingår i: Frontiers in Medicine. - 2296-858X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Methods: Drug-induced interstitial lung disease (ILD) is crucial to detect early to achieve the best treatment outcome. Optimally, non-invasive imaging biomarkers can be used for early detection of disease progression and treatment follow-up. Therefore, reliable in vivo models are warranted in new imaging biomarker development to accelerate better-targeted treatment options. Single-dose bleomycin models have, for a long time, served as a reference model in fibrosis and lung injury research. Here, we aimed to use a clinically more relevant animal model by systemic exposure to bleomycin and assessing disease progression over time by combined magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging.C57BL/6 mice received bleomycin (i.p. 35iU/kg) or saline as control twice per week for 4 weeks. Mice were monitored until 2 weeks after cessation of bleomycin administration (w4 + 1 and w4 + 2), referred to as the resting period. MRI scans were performed in weeks 3 and 4 and during the resting weeks. [18F]FDG-PET was performed at the last week of dosing (w4) and 2 weeks after the last dosing (w4 + 2). Lung tissue sections were stained with Masson’s trichrome and evaluated by modified Ashcroft scoring. Lung volume and lesion volumes were assessed using MRI, as well as 3D mapping of the central airways.Results and discussion: Bleomycin-challenged mice showed increased lung weights (p < 0.05), while total lung volume was unchanged (w4 and onward). Histology analysis demonstrated fibrotic lesions emanating from the distal parts of the lung. Fibrosis progression was visualized by MRI with significantly increased high signal in bleomycin-exposed lungs compared to controls (p < 0.05). In addition, a significant increase in central airway diameter (p < 0.01) was displayed in bleomycin-exposed animals compared to controls and further continued to dilate as the disease progressed, comparing the bleomycin groups over time (p < 0.05–0.001). Lung [18F]FDG uptake was significantly elevated in bleomycin-exposed mice compared to controls (p < 0.05).Conclusion: Non-invasive imaging displayed progressing lesions in the lungs of bleomycin-exposed mice, using two distinct MRI sequences and [18F]FDG-PET. With observed fibrosis progression emanating from distal lung areas, dilation of the central airways was evident. Taken together, this chronic bleomycin-exposure model is translationally more relevant for studying lung injury in ILD and particularly in the context of DIILD.
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| 10. |
- Mahmutovic Persson, Irma, et al.
(författare)
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Longitudinal Imaging Using PET/CT with Collagen-I PET-Tracer and MRI for Assessment of Fibrotic and Inflammatory Lesions in a Rat Lung Injury Model
- 2020
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 9:11, s. 1-21
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Tidskriftsartikel (refereegranskat)abstract
- Non-invasive imaging biomarkers (IBs) are warranted to enable improved diagnostics and follow-up monitoring of interstitial lung disease (ILD) including drug-induced ILD (DIILD). Of special interest are IB, which can characterize and differentiate acute inflammation from fibrosis. The aim of the present study was to evaluate a PET-tracer specific for Collagen-I, combined with multi-echo MRI, in a rat model of DIILD. Rats were challenged intratracheally with bleomycin, and subsequently followed by MRI and PET/CT for four weeks. PET imaging demonstrated a significantly increased uptake of the collagen tracer in the lungs of challenged rats compared to controls. This was confirmed by MRI characterization of the lesions as edema or fibrotic tissue. The uptake of tracer did not show complete spatial overlap with the lesions identified by MRI. Instead, the tracer signal appeared at the borderline between lesion and healthy tissue. Histological tissue staining, fibrosis scoring, lysyl oxidase activity measurements, and gene expression markers all confirmed establishing fibrosis over time. In conclusion, the novel PET tracer for Collagen-I combined with multi-echo MRI, were successfully able to monitor fibrotic changes in bleomycin-induced lung injury. The translational approach of using non-invasive imaging techniques show potential also from a clinical perspective.
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