| 1. |
- Elgqvist, Jörgen, et al.
(författare)
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Radiosensitivity of Prostate Cancer Cell Lines for Irradiation from Beta Particle-emitting Radionuclide ¹⁷⁷Lu Compared to Alpha Particles and Gamma Rays
- 2016
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Ingår i: Anticancer research. - 1791-7530. ; 36:1, s. 103-109
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The purpose of the present study was to investigate the radiosensitivity of the prostate cancer cell lines LNCaP, DU145, and PC3 when irradiated with beta particles emitted from (177)Lu, and to compare the effect with irradiation using alpha particles or gamma rays.MATERIALS AND METHODS: Cells were irradiated with beta particles emitted from (177)Lu, alpha particles from (241)Am, or gamma rays from (137)Cs. A non-specific polyclonal antibody was labeled with (177)Lu and used to irradiate cells in suspension with beta particles. A previously described in-house developed alpha-particle irradiator based on a (241)Am source was used to irradiate cells with alpha particles. External gamma-ray irradiation was achieved using a standard (137)Cs irradiator. Cells were irradiated to absorbed doses equal to 0, 0.5, 1, 2, 4, 6, 8, or 10 Gy. The absorbed doses were calculated as mean absorbed doses. For evaluation of cell survival, the tetrazolium-based WST-1 assay was used. After irradiation, WST-1 was added to the cell solutions, incubated, and then measured for level of absorbance at 450 nm, indicating the live and viable cells.RESULTS: LNCaP, DU145, and PC3 cell lines all had similar patterns of survival for the different radiation types. No significant difference in surviving fractions were observed between cells treated with beta-particle and gamma-ray irradiation, represented for example by the surviving fraction values (mean±SD) at 2, 6, and 10 Gy (SF2, SF6, and SF10) for DU145 after beta-particle irradiation: 0.700±0.090, 0.186±0.050 and 0.056±0.010, respectively. A strong radiosensitivity to alpha particles was observed, with SF2 values of 0.048±0.008, 0.018±0.006 and 0.015±0.005 for LNCaP, DU145, and PC3, respectively.CONCLUSION: The surviving fractions after irradiation using beta particles or gamma rays did not differ significantly at the absorbed dose levels and dose rates used. Irradiation using alpha particles led to a high level of cell killing. The results show that the beta-particle emitter (177)Lu as well as alpha-particles are both good candidates for radionuclide-therapy applications in the treatment of prostate cancer.
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| 2. |
- Evans Axelsson, Susan, et al.
(författare)
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Preclinical evaluation of (111)In-DTPA-INCA-X anti-Ku70/Ku80 monoclonal antibody in prostate cancer.
- 2014
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Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 4:4, s. 311-323
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this investigation was to assess the Ku70/Ku80 complex as a potential target for antibody imaging of prostate cancer. We evaluated the in vivo and ex vivo tumor targeting and biodistribution of the (111)In-labeled human internalizing antibody, INCA-X ((111)In-DTPA-INCA-X antibody), in NMRI-nude mice bearing human PC-3, PC-3M-Lu2 or DU145 xenografts. DTPA-conjugated, non-labeled antibody was pre-administered at different time-points followed by a single intravenous injection of (111)In-DTPA-INCA-X. At 48, 72 and 96 h post-injection, tissues were harvested, and the antibody distribution was determined by measuring radioactivity. Preclinical SPECT/CT imaging of mice with and without the predose was performed at 48 hours post-injection of labeled DTPA-INCA-X. Biodistribution of the labeled antibody showed enriched activity in tumor, spleen and liver. Animals pre-administered with DTPA-INCA-X showed increased tumor uptake and blood content of (111)In-DTPA-INCA-X with reduced splenic and liver uptake. The in vitro and in vivo data presented show that the (111)In-labeled INCA-X antibody is internalized into prostate cancer cells and by pre-administering non-labeled DTPA-INCA-X, we were able to significantly reduce the off target binding and increase the (111)In-DTPA-INCA-X mAb uptake in PC-3, PC-3M-Lu2 and DU145 xenografts. The results are encouraging and identifying the Ku70/Ku80 antigen as a target is worth further investigation for functional imaging of prostate cancer.
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| 3. |
- Evans Axelsson, Susan, et al.
(författare)
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Radioimmunotherapy for Prostate Cancer-Current Status and Future Possibilities.
- 2016
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Ingår i: Seminars in Nuclear Medicine. - : Elsevier BV. - 0001-2998. ; 46:2, s. 165-179
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Forskningsöversikt (refereegranskat)abstract
- Prostate cancer (PCa) is one of the most common cancers in men and is the second leading cause of cancer-related deaths in the USA. In the United States, it is the second most frequently diagnosed cancer after skin cancer, and in Europe it is number one. According to the American Cancer Society, approximately 221,000 men in the United States would be diagnosed with PCa during 2015, and approximately 28,000 would die of the disease. According to the International Agency for Research on Cancer, approximately 345,000 men were diagnosed with PCa in Europe during 2012, and despite more emphasis placed on early detection through routine screening, 72,000 men died of the disease. Hence, the need for improved therapy modalities is of utmost importance. And targeted therapies based on radiolabeled specific antibodies or peptides are a very interesting and promising alternative to increase the therapeutic efficacy and overall chance of survival of these patients. There are currently several preclinical and some clinical studies that have been conducted, or are ongoing, to investigate the therapeutic efficacy and toxicity of radioimmunotherapy (RIT) against PCa. One thing that is lacking in a lot of these published studies is the dosimetry data, which are needed to compare results between the studies and the study locations. Given the complicated tumor microenvironment and overall complexity of RIT to PCa, old and new targets and targeting strategies like combination RIT and pretargeting RIT are being improved and assessed along with various therapeutic radionuclides candidates. Given alone or in combination with other therapies, these new and improved strategies and RIT tools further enhance the clinical response to RIT drugs in PCa, making RIT for PCa an increasingly practical clinical tool.
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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. |
- Mellhammar, Emma, et al.
(författare)
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Small-scale dosimetry for alpha particle 241Am source cell irradiation and estimation of γ-H2AX foci distribution in prostate cancer cell line PC3
- 2022
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Ingår i: EJNMMI Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes. Methods: A Monte Carlo simulation model of an 241Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the 241Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF. Results: The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations. Conclusion: Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry.
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| 9. |
- Mellhammar, Emma, et al.
(författare)
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Tumor Control Probability and Small-Scale Monte Carlo Dosimetry : Effects of Heterogenous Intratumoral Activity Distribution in Radiopharmaceutical Therapy
- 2023
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Ingår i: Journal of Nuclear Medicine. - 0161-5505. ; 64:10, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- In radiopharmaceutical therapy, intratumoral uptake of radioactivity usually leads to heterogeneous absorbed dose distribution. The likelihood of treatment success can be estimated with the tumor control probability (TCP), which requires accurate dosimetry, estimating the absorbed dose rate per unit activity to individual tumor cells. Methods: Xenograft cryosections of the prostate cancer cell line LNCaP treated with [177Lu]Lu-PSMA-617 were evaluated with digital autoradiography and stained with hematoxylin and eosin. The digital autoradiography images were used to define the source in a Monte Carlo simulation of the absorbed dose, and the stained sections were used to detect the position of cell nuclei to relate the intratumoral absorbed dose heterogeneity to the cell density. Simulations were performed for 225Ac, 177Lu, and 90Y. TCP was calculated to estimate the mean necessary injected activity for a high TCP. A hypothetical case of activity mainly taken up on the tumor borders was generated and used to simulate the absorbed dose. Results: The absorbed dose per decay to tumor cells was calculated from the staining and simulation results to avoid underestimating the tumor response from low absorbed doses in tumor regions with low cell density. The mean of necessary injected activity to reach a 90% TCP for 225Ac, 177Lu, and 90Y was found to be 18.3 kBq (range, 18–22 kBq), 24.3 MBq (range, 20–29 MBq), and 5.6 MBq (range, 5–6 MBq), respectively. Conclusion: To account for the heterogeneous absorbed dose generated from nonuniform intratumoral activity uptake, dosimetry models can estimate the mean necessary activity to reach a sufficient TCP for treatment response. This approach is necessary to accurately evaluate the efficacy of suggested radiopharmaceuticals for therapy.
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| 10. |
- Reistad, Nina, et al.
(författare)
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Diffuse reflectance spectroscopy of liver tissue
- 2015
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Ingår i: [Host publication title missing]. - : SPIE. - 0277-786X .- 1996-756X. ; 9531, s. 95314-95314
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Konferensbidrag (refereegranskat)abstract
- Diffuse reflectance spectroscopy (DRS) with a fiber-optic contact probe is a cost-effective, rapid, and non-invasive optical method used to extract diagnosis information of tissue. By combining commercially available VIS- and NIR-spectrometers with various fiber-optic contact-probes, we have access to the full wavelength range from around 400 to 1600 nm. Using this flexible and portable spectroscopy system, we have acquired ex-vivo DRS-spectra from murine, porcine, and human liver tissue. For extracting the tissue optical properties from the measured spectra, we have employed and compared predictions from two models for light propagation in tissue, diffusion theory model (DT) and Monte Carlo simulations (MC). The focus in this work is on the capacity of this DRS-technique in discriminating metastatic tumor tissue from normal liver tissue as well as in assessing and characterizing damage to non-malignant liver tissue induced by preoperative chemotherapy for colorectal liver metastases.
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