| 1. |
- Altai, Mohamed, et al.
(författare)
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Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting
- 2016
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Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:3, s. 431-436
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of Affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal reabsorption of Affibody molecules prevents the use of residualizing radiometals, including several promising low-energy (beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that Affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys. Methods: TCO was conjugated to the anti-human epidermal growth factor receptor 2 (HER2) Affibody molecule Z(2395). DOTA-tetrazine was labeled with In-111 and Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts. Results: I-125-Z(2395)-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 +/- 16 pM. In-111-tetrazine bound specifically and selectively to Z(2325)-TCO pretreated cells. In vivo studies demonstrated HER2-specific I-125-Z(2395)-TCO accumulation in xenografts. TCO-mediated In-111-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z(2395)-TCO. At 1 h after injection, the tumor uptake of In-111-tetrazine and Lu-177-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of In-111 in comparison with direct targeting. Conclusion: The feasibility of Affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pre-targeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.
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| 2. |
- Altai, Mohamed, et al.
(författare)
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Pretargeted Imaging and Therapy
- 2017
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Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:10, s. 1553-1559
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Tidskriftsartikel (refereegranskat)abstract
- In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.
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| 3. |
- Anand, Aseem, et al.
(författare)
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A preanalytic validation study of automated bone scan index : Effect on accuracy and reproducibility due to the procedural variabilities in bone scan image acquisition
- 2016
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 57:12, s. 1865-1871
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Tidskriftsartikel (refereegranskat)abstract
- The effect of the procedural variability in image acquisition on the quantitative assessment of bone scan is unknown. Here, we have developed and performed preanalytical studies to assess the impact of the variability in scanning speed and in vendor-specific γ-camera on reproducibility and accuracy of the automated bone scan index (BSI). Methods: Two separate preanalytical studies were performed: a patient study and a simulation study. In the patient study, to evaluate the effect on BSI reproducibility, repeated bone scans were prospectively obtained from metastatic prostate cancer patients enrolled in 3 groups (Grp). In Grp1, the repeated scan speed and the γ-camera vendor were the same as that of the original scan. In Grp2, the repeated scan was twice the speed of the original scan. In Grp3, the repeated scan used a different γ-camera vendor than that used in the original scan. In the simulation study, to evaluate the effect on BSI accuracy, bone scans of a virtual phantom with predefined skeletal tumor burden (phantom-BSI) were simulated against the range of image counts (0.2, 0.5, 1.0, and 1.5 million) and separately against the resolution settings of the γ-cameras. The automated BSI was measured with a computer-automated platform. Reproducibility was measured as the absolute difference between the repeated BSI values, and accuracy was measured as the absolute difference between the observed BSI and the phantom-BSI values. Descriptive statistics were used to compare the generated data. Results: In the patient study, 75 patients, 25 in each group, were enrolled. The reproducibility of Grp2 (mean ± SD, 0.35 ± 0.59) was observed to be significantly lower than that of Grp1 (mean ± SD, 0.10 ± 0.13; P < 0.0001) and that of Grp3 (mean ± SD, 0.09 ± 0.10; P < 0.0001). However, no significant difference was observed between the reproducibility of Grp3 and Grp1 (P = 0.388). In the simulation study, the accuracy at 0.5 million counts (mean ± SD, 0.57 ± 0.38) and at 0.2 million counts (mean ± SD, 4.67 ± 0.85) was significantly lower than that observed at 1.5 million counts (mean ± SD, 0.20 ± 0.26; P < 0.0001). No significant difference was observed in the accuracy data of the simulation study with vendor-specific γ-cameras (P 5 0.266). Conclusion: In this study, we observed that the automated BSI accuracy and reproducibility were dependent on scanning speed but not on the vendor-specific γ-cameras. Prospective BSI studies should standardize scanning speed of bone scans to obtain image counts at or above 1.5 million.
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| 4. |
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| 5. |
- Andersson, Charlotte, et al.
(författare)
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Recombinant alpha(1)-Microglobulin Is a Potential Kidney Protector in Lu-177-Octreotate Treatment of Neuroendocrine Tumors
- 2019
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 60:11, s. 1600-1604
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of neuroendocrine tumors with Lu-177-octreotate results in prolonged survival and improved quality of life for the patient. However, the treatment is today limited by side effects on kidney and bone marrow, and complete tumor remission is rarely seen. A possible way to minimize dose-limiting toxicity and to optimize this treatment method is to use radioprotectors in conjunction with radiotherapy. A recombinant form of alpha(1)-microglobulin ( rA1M) was recently shown to preserve kidney structure and function after Lu-177-octreotate injection in mice and was suggested as a radioprotector in peptide receptor radionuclide therapy. The aims of this work were to investigate the influence of rA1M on the in vivo biokinetics of Lu-177-octreotate, with a focus on tumor tissue, and to study the impact of rA1M on the therapeutic response in tumor tissue subjected to Lu-177-octreotate treatment. Methods: The biodistribution of Lu-177-octreotate was examined in BALB/c nude mice with GOT2 tumors 1-168 h after injection with either Lu-177-octreotate or coadministration of 177Lu-octreotate and rA1M. The effects of rA1M on the tumor response after Lu-177-octreotate treatment were studied in BALB/c nude mice with GOT1 tumors. Three groups of mice were administered rA1M, Lu-177-octreotate, or both. Another group served as untreated controls. Tumor volume was measured to follow the treatment effects. Results: No statistically significant difference in biodistribution of Lu-177 was observed between the groups receiving Lu-177-octreotate or coinjection of Lu-177-octreotate and rA1M. The therapy study showed a decrease in mean tumor volume during the first 2 wk for both the Lu-177-octreotate group and the coadministration group, followed by tumor regrowth. No statistically significant difference between the groups was found. Conclusion: rA1M did not negatively impact absorbed dose to tumor or therapeutic response in combination with Lu-177-octreotate and may be a promising kidney protector during Lu-177-octreotate treatment of patients with neuroendocrine tumors.
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| 6. |
- Appel, Lieuwe, et al.
(författare)
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Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders
- 2015
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 56:2, s. 234-242
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Tidskriftsartikel (refereegranskat)abstract
- In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET.Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses.Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, respectively. Regional C-11-PE2I R-1 values were moderately to highly correlated with normalized F-18-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between C-11-PE2I BPND and I-123-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using I-123-FP-CIT and F-18-FDG images. Substantial differences were found between clinical diagnosis and both neuro-imaging diagnoses.Conclusion: A single, dynamic C-11-PE2I PET investigation is a powerful alternative to a dual examination with I-123-FP-CIT SPECT and F-18-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathologic patterns in overall brain functional activity for various parkinsonian disorders.
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| 7. |
- Bergström, Mats
(författare)
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The Use of Microdosing in the Development of Small Organic and Protein Therapeutics
- 2017
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Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:8, s. 1188-1195
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Tidskriftsartikel (refereegranskat)abstract
- Microdosing as a regulatory concept was introduced to facilitate exploratory studies in humans. The concept involves the use of very low doses of a radionuclide-labeled compound for imaging studies or for assessing plasma pharmacokinetics using equipment that has a highly sensitive readout. The supporting principle is that use of these low doses for a limited time in well-controlled, small populations will limit exposure and have a low risk of adverse effects. Microdosing regulations specify a reduced preclinical toxicology-assessment package in order to shorten the route to human studies and reduce its cost. However, for extrapolation to therapeutically relevant doses and plasma concentrations, there are specific aspects of the use of these low doses and low plasma concentrations that require special attention. These specific aspects are reviewed in this article, with separate attention being paid to small organic molecules and protein therapeutics. The indications for microdosing in drug development are discussed in terms of the 3 pillars of survival in drug development, the first of which is characterization of tissue distribution and access to the site of action; the second, engagement of the target; and the third, induction of tissue responses relevant to a therapeutic response.
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| 8. |
- Borgquist, Rasmus, et al.
(författare)
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An electrophysiologist perspective on risk stratification in heart failure: can better understanding of the condition of the cardiac sympathetic nervous system help?
- 2015
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 56:Suppl 4, s. 59-64
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure is often complicated by arrhythmias that can adversely affect the quality of life and increase the risk for sudden cardiac death. Current risk stratification strategies for sudden cardiac death in the heart failure patient are not ideal, with much potential for further refinement. Overactivation of the sympathetic nervous system has been shown to be associated with worsening heart failure as well as arrhythmic events. Recent advances in our understanding of the autonomic nervous system and new methods for quantification of the pathologic activation of the sympathetic nerves have triggered increasing interest in this field. This viewpoint focuses on the need for and challenges of risk stratification of sudden death in the heart failure patient and discusses the potential value of measuring sympathetic nervous system activity to better stratify risk and to select patients with heart failure for implantable cardioverter defibrillator therapy.
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| 9. |
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| 10. |
- Bäck, Tom, 1964, et al.
(författare)
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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated alpha-Radioimmunotherapy with At-211-MX35-F(ab')(2): Influence of Absorbed Tumor Dose and Effect on Long-Term Survival
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:4, s. 598-604
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Tidskriftsartikel (refereegranskat)abstract
- The goal of this study was to investigate whether targeted a-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of alpha-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm(3), NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with At-211-MX35-F (ab')(2) at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from bio-distribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated alpha-radioimmunotherapy with 211At-MX35-F(ab')(2) was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after a-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted alpha-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.
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