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- Abouzayed, Ayman, et al.
(författare)
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Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer
- 2020
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923 .- 1999-4923. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of In-nat-DOTA-ABD-RM26 in the presence of human serum albumin was 49 +/- 5 nM. [In-111]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.
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| 5. |
- Altai, Mohamed, et al.
(författare)
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Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting : Development of an optimized conjugation protocol and 177Lu labeling
- 2017
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Ingår i: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 54, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Introduction We have previously developed a pretargeting approach for affibody-mediated cancer therapy based on PNA–PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, ZHER2:342-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide 177Lu. We also studied the biodistribution profile of 177Lu-HP2 in mice, and evaluated pretargeting with 177Lu-HP2 in vitro and in vivo. Methods The biodistribution profile of 177Lu-HP2 was evaluated in NMRI mice and compared to the previously studied 111In-HP2. Pretargeting using 177Lu-HP2 was studied in vitro using the HER2-expressing cell lines BT‐474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts. Results and conclusion Using an optimized production protocol for ZHER2:342-SR-HP1 the ligation time was reduced from 15 h to 30 min, and the yield increased from 45% to 70%. 177Lu-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with ZHER2:342-SR-HP1. 177Lu-HP2 was shown to have a more rapid blood clearance compared to 111In-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22 ± 0.1 and 0.68 ± 0.07%ID/g for 177Lu- and 111In-HP2, respectively, at 1 h p.i. In contrast, no significant difference in kidney uptake was observed (4.47 ± 1.17 and 3.94 ± 0.58%ID/g for 177Lu- and 111In-HP2, respectively, at 1 h p.i.). Co-injection with either Gelofusine or lysine significantly reduced the kidney uptake for 177Lu-HP2 (1.0 ± 0.1 and 1.6 ± 0.2, respectively, vs. 2.97 ± 0.87%ID/g in controls at 4 h p.i.). 177Lu-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of ZHER2:342-SR-HP1. Without pre-injection of ZHER2:342-SR-HP1, the uptake of 177Lu-HP2 was about 90-fold lower in tumor (0.23 ± 0.08 vs. 20.7 ± 3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with ZHER2:342-SR-HP1. In conclusion, 177Lu-HP2 was shown to be a promising secondary agent for affibody-mediated tumor pretargeting in vivo.
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| 6. |
- Altai, Mohamed, et al.
(författare)
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Preparation of Conjugates for Affibody-Based PNA-Mediated Pretargeting.
- 2020
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Ingår i: Methods in Molecular Biology. - New York, NY : Springer US. - 1064-3745 .- 1940-6029. ; 2105, s. 283-304, s. 283-304
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are small engineered scaffold proteins suitable for in vivo tumor targeting. Radionuclide molecular imaging using directly radiolabelled affibody molecules provides excellent imaging. However, affibody molecules have a high renal reabsorption, which complicates their use for radionuclide therapy. The high renal reabsorption is a common problem for the use of engineered scaffold proteins for radionuclide therapy. Affibody-based PNA-mediated pretargeting reduces dramatically the absorbed dose to the kidneys and makes affibody-based radionuclide therapy possible. This methodology might, hopefully, solve the problem of high renal reabsorption for radionuclide therapy mediated by other engineered scaffold proteins.
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| 8. |
- Amedjkouh, Mohamed, 1966, et al.
(författare)
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Self-reproduction of chirality on alpha-aminophosphonates: asymmetric synthesis of alpha-alkylated diethyl pyrrolidin-2-yl-phosphonate
- 2004
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Ingår i: Tetrahedron Letters. - : Elsevier BV. - 0040-4039. ; 45:26, s. 5175-5177
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Tidskriftsartikel (refereegranskat)abstract
- A simple method for the asymmetric synthesis of alpha-substituted diethyl pyrrolidin-2-yl-phosphonate is described. The chiral oxazolopyrrolidine phosphonate was alkylated diastereospecifically with an alkyl halide. The key intermediate is an alpha-phosphonate-stabilized carbanion that can be alkylated without loss of optical activity and a single enantiomer of product was formed exclusively in 10-80% yield. The configurational assignment of the products relied on H-1-H-1 NOESY analysis of the alkylated oxazolopyrrolidine phosphonates. This represents an unprecedented case of self-regeneration of stereocenters (SRS) of cyclic aminophosphonates. The enantiomerically pure alpha-aminophosphonate dietlhyl-(2S)-(2-methylpyrrolidin-2-yl)-phosphonate, a surrogate of 2-methyl proline, was obtained upon hydrogenolysis of the chiral auxiliary in 83% yield. (C) 2004 Elsevier Ltd. All rights reserved.
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| 10. |
- Blomqvist, Sandra, et al.
(författare)
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Labor market exit around retirement age in Sweden and trajectories of psychotropic drugs in a context of downsizing
- 2020
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background A maintained psychological wellbeing is important in order to continue working longer and remain active into older age. However, little is known about impact of different organizational factors, such as downsizing, on the mental health of older workers exiting the labor market. The aim in this study was to investigate trajectories of purchases of psychotropic drugs in relation to labor market exit later in life in a context with and without downsizing. Method People living in Sweden, born 1941-1951, exiting paid work via unemployment, sickness absence/disability pension, or old-age pension were followed from 2005 to 2013 regarding purchases of psychotropic drugs. Individuals employed at a workplace closing down or downsizing with >= 18% between two subsequent years were compared to employees exiting from workplaces without downsizing or workplace closure. Generalized estimating equations was applied to derive trajectories of annual prevalence of purchased antidepressants, sedatives and anxiolytics from 4 years before to 4 years after a labour market exit. Results During the period around the exit, old-age retirees experiencing a downsizing/workplace closure did not decrease their purchases of sedatives (OR 1.01 95% CI 0.95-1.07) while the unexposed decreased their purchases during this period (OR 0.95 95% CI 0.92-0.98). Similar differences concerning sedatives and antidepressants between exposed and unexposed were seen for those exiting via sickness absence or disability pension. Furthermore, a significant difference in purchases of anxiolytics was observed between those exposed to downsizing (OR 1.10 95% CI 0.97-1.24) and the unexposed (OR 0.98 95% CI 0.91-1.06) exiting via old-age retirement during the time before the exit. Conclusion Downsizing or workplace closure, although weakly, was associated with higher prevalence of psychotropic drugs certain years around the labor market exit. The results support the idea that involuntary labor market exit in mature adulthood may negatively affect the development of mental health.
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