| 1. |
- Ahlstedt, Jonas, et al.
(författare)
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Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.
- 2015
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Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 5:4, s. 333-347
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Tidskriftsartikel (refereegranskat)abstract
- Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.
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| 2. |
- 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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| 3. |
- Timmermand, Oskar Vilhelmsson, et al.
(författare)
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Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics
- 2019
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 9:8, s. 2129-2142
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Tidskriftsartikel (refereegranskat)abstract
- Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint.
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| 4. |
- Ahlstedt, Jonas, et al.
(författare)
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Human Anti-Oxidation Protein A1M-A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.
- 2015
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 16:12, s. 30309-30320
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Forskningsöversikt (refereegranskat)abstract
- Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.
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| 5. |
- Dahlbom, Magnus, et al.
(författare)
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Effects of high photon fluence rate from therapeutic radionuclides on preclinical and clinical PET systems
- 2016
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Ingår i: 2014 IEEE Nuclear Science Symposium and Medical Imaging Conference, NSS/MIC 2014. - 9781479960972
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Konferensbidrag (refereegranskat)abstract
- Tumor response in radionuclide therapy can be monitored with PET/CT and/or PET/MR. A high background photon fluence from a therapy radionuclide may influence both image quality and quantification, when imaging is performed intra-therapeutically, i.e. with high activity of the therapeutic radionuclide present. Here, count losses and image distortion have been investigated for preclinical and clinical PET systems with different detector designs. The effect on the spatial resolution was studied with a point source of 22Na in a background of 99mTc, where 99mTc emulated the photon emission from a therapeutic radionuclide. An in-house made mouse phantom with silicon tubes filled with 99mTc with a centrally placed 22Na point source was used. For the clinical systems, a 70 cm long NEMA PET Scatter Phantom was used, with a 22Na point source placed at the center whereas the off-center silicon tube was filled with 99mTc. In addition, image quality was also evaluated in the presence of different levels of 99mTc with a 18F-filled NEMA image quality phantom on the preclinical systems and a 18F-filled Jaszczak phantom on the clinical system. Preclinical PET systems with different detector geometries showed that the addition of 99mTc affected the count rate capability considerably, especially those with a low number of read-out channels. The coincidence rate for was significantly reduced when high activities of 99mTc were present. The clinical PET system also showed an effect of reduced coincidence rate with increased photon fluence rate. At high 99mTc activities, the spatial resolution was degraded for both the preclinical and the clinical systems. The quantitative capability of PET systems used intra-therapeutically is significantly affected by the additional high photon fluence rate. The dead-time correction implemented on some of the investigated PET systems, was able to accurately compensate for the coincidence count losses. The reduced spatial resolution at high photon fluence rate, however, remains a potentially limiting factor.
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| 6. |
- 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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| 7. |
- Evertsson, Maria, et al.
(författare)
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Combined Magnetomotive ultrasound, PET/CT, and MR imaging of (68)Ga-labelled superparamagnetic iron oxide nanoparticles in rat sentinel lymph nodes in vivo
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff. This study investigates a hypothetical clinical scenario of pre-operative PET imaging, combined with intra-operative MMUS imaging, implemented in a sentinel lymph node (SLN) rat model. At one-hour post injection of (68)Ga-labelled magnetic nanoparticles, six animals were imaged with combined PET/CT. After two or four days, the same animals were imaged with MMUS. In addition, ex-vivo MRI was used to evaluate the amount of nanoparticles in each single SLN. All SLNs were detectable by PET. Four out of six SLNs could be detected with MMUS, and for these MMUS and MRI measurements were in close agreement. The MRI measurements revealed that the two SLNs undetectable with MMUS contained the lowest nanoparticle concentrations. This study shows that MMUS can complement standard pre-operative imaging by providing bedside real-time images with high spatial resolution.
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| 8. |
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| 9. |
- Kjellman, Pontus, et al.
(författare)
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Size-dependent lymphatic uptake of nanoscale-tailored particles as tumor mass increases
- 2015
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Ingår i: Future science OA. - : Future Science Ltd. - 2056-5623. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the size-dependent lymphatic uptake of nanoparticles in mice with rapidly growing syngeneic tumors.MATERIALS & METHODS: Mice were inoculated subcutaneously with EL4 lymphoma cells and on day 5 or day 6 of tumor growth, injected peritumorally with either 29 nm or 58 nm of ultra-small superparamagnetic iron oxide nanoparticles. Twenty-four hours later the animals were imaged using MRI.RESULTS & CONCLUSION: The larger of the two particles can only be detected in the lymph node when injected in animals with 6-day-old tumors while the 29 nm ultra-small superparamagnetic iron oxide nanoparticle is observed on both time points. Tumor mass greatly impacts the size of particles that are transported to the lymph nodes.
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| 10. |
- Kristiansson, Amanda, et al.
(författare)
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Protection of Kidney Function with Human Antioxidation Protein α 1 -Microglobulin in a Mouse 177 Lu-DOTATATE Radiation Therapy Model
- 2019
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Ingår i: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1523-0864 .- 1557-7716. ; 30:14, s. 1746-1759
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α 1 -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 ( 177 Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177 Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177 Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment. © Amanda Kristiansson et al. 2018; Published by Mary Ann Liebert, Inc.
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