scholarly journals Comparing Gly11/dAla11-Replacement vs. the in-Situ Neprilysin-Inhibition Approach on the Tumor-targeting Efficacy of the 111In-SB3/111In-SB4 Radiotracer Pair

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1015 ◽  
Author(s):  
Emmanouil Lymperis ◽  
Aikaterini Kaloudi ◽  
Panagiotis Kanellopoulos ◽  
Marion de Jong ◽  
Eric Krenning ◽  
...  
Keyword(s):  
Animal Models ◽  
Tumor Targeting ◽  
Cell Uptake ◽  
Tumor Uptake ◽  
Biological Profile ◽  
Biological Responses ◽  
Grpr Antagonist ◽  
The Cost

Background: The GRPR-antagonist 68Ga-SB3 visualized prostate cancer lesions in animal models and in patients. Switching radiometal from 68Ga to 111In impaired tumor targeting in mice, but coinjection of the neprilysin (NEP)-inhibitor phosphoramidon (PA) stabilized 111In-SB3 in circulation and remarkably increased tumor uptake. We herein report on the biological profile of 111In-SB4: 111In-[dAla11]SB3. Methods: The biological responses of 111In-SB3/SB4 were compared in PC-3 cells and animal models. Results: Gly11/dAla11-replacement deteriorated GRPR-affinity (SB4 IC50: 10.7 ± 0.9 nM vs. SB3 IC50: 4.6 ± 0.3 nM) and uptake in PC-3 cells (111In-SB4: 1.3 ± 0.4% vs. 111In-SB3 16.2 ± 0.8% at 1 h). 111In-SB4 was more stable than 111In-SB3, but PA-coinjection stabilized both radiotracers in peripheral mice blood. Unmodified 111In-SB3 showed higher uptake in PC-3 xenografts (8.8 ± 3.0%ID/g) vs. 111In-SB4 (3.1 ± 1.1%ID/g) at 4 h pi. PA-coinjection improved tumor uptake, with 111In-SB3 still showing superior tumor targeting (38.3 ± 7.9%ID/g vs. 7.4 ± 0.3%ID/g for 111In-SB4). Conclusions: Replacement of Gly11 by dAla11 improved in vivo stability, however, at the cost of GRPR-affinity and cell uptake, eventually translating into inferior tumor uptake of 111In-SB4 vs. unmodified 111In-SB3. On the other hand, in-situ NEP-inhibition turned out to be a more efficient and direct strategy to optimize the in vivo profile of 111In-SB3, and potentially other peptide radiotracers.

scholarly journals Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 528
Author(s):  
Panagiotis Kanellopoulos ◽  
Aikaterini Kaloudi ◽  
Marion de Jong ◽  
Eric P. Krenning ◽  
Berthold A. Nock ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Ace Inhibitor ◽  
Tumor Imaging ◽  
Colon Adenocarcinoma ◽  
Ace Inhibition ◽  
Tumor Uptake ◽  
Protease Inhibition ◽  
Structural Modifications

Neurotensin subtype 1 receptors (NTS1R) represent attractive molecular targets for directing radiolabeled neurotensin (NT) analogs to tumor lesions for diagnostic and therapeutic purposes. This approach has been largely undermined by the rapid in vivo degradation of linear NT-based radioligands. Herein, we aim to increase the tumor targeting of three 99mTc-labeled NT analogs by the in-situ inhibition of two key proteases involved in their catabolism. DT1 ([N4-Gly7]NT(7-13)), DT5 ([N4-βAla7,Dab9]NT(7-13)), and DT6 ([N4-βAla7,Dab9,Tle12]]NT(7-13)) were labeled with 99mTc. Their profiles were investigated in NTS1R-positive colon adenocarcinoma WiDr cells and mice treated or not with the neprilysin (NEP)-inhibitor phosphoramidon (PA) and/or the angiotensin converting enzyme (ACE)-inhibitor lisinopril (Lis). Structural modifications led to the partial stabilization of 99mTc-DT6 in peripheral mice blood (55.1 ± 3.9% intact), whereas 99mTc-DT1 and 99mTc-DT5 were totally degraded within 5 min. Coinjection of PA and/or Lis significantly stabilized all three analogs, leading to a remarkable enhancement of tumor uptake for 99mTc-DT1 and 99mTc-DT5, but was less effective in the case of poorly internalizing 99mTc-DT6. In conclusion, NEP and/or ACE inhibition represents a powerful tool to improve tumor targeting and the overall pharmacokinetics of NT-based radioligands, and warrants further validation in the field of NTS1R-targeted tumor imaging and therapy.

In situlow-immunogenic albumin-conjugating-corona guiding nanoparticles for tumor-targeting chemotherapy

2018 ◽  
Vol 6 (10) ◽  
pp. 2681-2693 ◽  
Author(s):  
Zhenbao Li ◽  
Dan Li ◽  
Qingsong Li ◽  
Cong Luo ◽  
Jing Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Targeting

Thein siturecruited albumin corona enables NPs' tumor-targeting and enhanced antitumor activityin vivo.

scholarly journals One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [99mTc]Tc-DB4 and [111In]In-SG4 in Mice Treated with Entresto

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1145
Author(s):  
Panagiotis Kanellopoulos ◽  
Aikaterini Kaloudi ◽  
Maritina Rouchota ◽  
George Loudos ◽  
Marion de Jong ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Metabolic Stability ◽  
Clinical Translation ◽  
Tumor Uptake ◽  
Gastrin Releasing Peptide ◽  
Cognate Receptor ◽  
One Step ◽  
The Stability ◽  
The Impact

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach.

scholarly journals Model Affitin and PEG modifications onto siRNA lipid nanocapsules: cell uptake and in vivo biodistribution improvements

RSC Advances ◽  
2019 ◽  
Vol 9 (47) ◽  
pp. 27264-27278
Author(s):  
Pauline Resnier ◽  
Elise Lepeltier ◽  
Anthea Lucrezia Emina ◽  
Natacha Galopin ◽  
Jérôme Bejaud ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Tumor Targeting ◽  
Surface Modifications ◽  
Cell Uptake ◽  
Lipid Nanocapsules ◽  
In Vivo Biodistribution

Surface modifications of siRNA LNCs were assessed with innovative TE-PEG polymers and an Affitin model, in comparison to classic DSPE-PEG LNCs, in order to evaluate the potential tumor targeting of siRNA after intravenous administration.

scholarly journals Estimation of Growth Rates of Escherichia coli BJ4 in Streptomycin-Treated and Previously Germfree Mice by In Situ rRNA Hybridization

1999 ◽  
Vol 6 (3) ◽  
pp. 434-436 ◽  
Author(s):  
Camilla U. Rang ◽  
Tine Rask Licht ◽  
Tore Midtvedt ◽  
Patricia L. Conway ◽  
Lin Chao ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Animal Models ◽  
Growth Rates ◽  
Treated Mouse ◽  
23S Rrna ◽  
Growth Physiology ◽  
E Coli ◽  
Bacterial Growth Rates

ABSTRACT The growth physiology of Escherichia coli during colonization of the intestinal tract was studied with four animal models: the streptomycin-treated mouse carrying a reduced microflora, the monoassociated mouse with no other microflora than the introduced strain, the conventionalized streptomycin-treated mouse, and the conventionalized monoassociated mouse harboring a full microflora. A 23S rRNA fluorescent oligonucleotide probe was used for hybridization to whole E. coli cells fixed directly after being taken from the animals, and the respective growth rates of E. coli BJ4 in the four animal models were estimated by correlating the cellular concentrations of ribosomes with the growth rate of the strain. The growth rates thus estimated from the ribosomal content ofE. coli BJ4 in vivo did not differ in the streptomycin-treated and the monoassociated mice. After conventionalization there was a slight decrease of the bacterial growth rates in both animal models.

scholarly journals NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 381 ◽  
Author(s):  
J. Tyson McDonald ◽  
Robert Stainforth ◽  
Jack Miller ◽  
Thomas Cahill ◽  
Willian A. da Silveira ◽  
...  
Keyword(s):  
Animal Models ◽  
Radiation Exposure ◽  
Biological Response ◽  
Galactic Cosmic Rays ◽  
Low Earth Orbit ◽  
Protective Effects ◽  
Biological Responses ◽  
Spaceflight Experiments

Background: Ionizing radiation from galactic cosmic rays (GCR) is one of the major risk factors that will impact the health of astronauts on extended missions outside the protective effects of the Earth’s magnetic field. The NASA GeneLab project has detailed information on radiation exposure using animal models with curated dosimetry information for spaceflight experiments. Methods: We analyzed multiple GeneLab omics datasets associated with both ground-based and spaceflight radiation studies that included in vivo and in vitro approaches. A range of ions from protons to iron particles with doses from 0.1 to 1.0 Gy for ground studies, as well as samples flown in low Earth orbit (LEO) with total doses of 1.0 mGy to 30 mGy, were utilized. Results: From this analysis, we were able to identify distinct biological signatures associating specific ions with specific biological responses due to radiation exposure in space. For example, we discovered changes in mitochondrial function, ribosomal assembly, and immune pathways as a function of dose. Conclusions: We provided a summary of how the GeneLab’s rich database of omics experiments with animal models can be used to generate novel hypotheses to better understand human health risks from GCR exposures.

scholarly journals [99mTc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3418
Author(s):  
Panagiotis Kanellopoulos ◽  
Emmanouil Lymperis ◽  
Aikaterini Kaloudi ◽  
Marion de Jong ◽  
Eric P. Krenning ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Tumor Uptake ◽  
Single Digit ◽  
Spacer Length ◽  
Uptake Rates ◽  
Specific Uptake ◽  
Immunodeficiency Disease ◽  
Grpr Antagonist ◽  
The Impact

Background: The frequent overexpression of gastrin-releasing peptide receptors (GRPRs) in human cancers provides the rationale for delivering clinically useful radionuclides to tumor sites using peptide carriers. Radiolabeled GRPR antagonists, besides being safer for human use, have often shown higher tumor uptake and faster background clearance than agonists. We herein compared the biological profiles of the GRPR-antagonist-based radiotracers [99mTc]Tc-[N4-PEGx-DPhe6,Leu-NHEt13]BBN(6-13) (N4: 6-(carboxy)-1,4,8,11-tetraazaundecane; PEG: polyethyleneglycol): (i) [99mTc]Tc-DB7 (x = 2), (ii) [99mTc]Tc-DB13 (x = 3), and (iii) [99mTc]Tc-DB14 (x = 4), in GRPR-positive cells and animal models. The impact of in situ neprilysin (NEP)-inhibition on in vivo stability and tumor uptake was also assessed by treatment of mice with phosphoramidon (PA). Methods: The GRPR affinity of DB7/DB13/DB14 was determined in PC-3 cell membranes, and cell binding of the respective [99mTc]Tc-radioligands was assessed in PC-3 cells. Each of [99mTc]Tc-DB7, [99mTc]Tc-DB13, and [99mTc]Tc-DB14 was injected into mice without or with PA coinjection and 5 min blood samples were analyzed by HPLC. Biodistribution was conducted at 4 h postinjection (pi) in severe combined immunodeficiency disease (SCID) mice bearing PC-3 xenografts without or with PA coinjection. Results: DB7, -13, and -14 displayed single-digit nanomolar affinities for GRPR. The uptake rates of [99mTc]Tc-DB7, [99mTc]Tc-DB13, and [99mTc]Tc-DB14 in PC-3 cells was comparable and consistent with a radioantagonist profile. The radiotracers were found to be ≈70% intact in mouse blood and >94% intact after coinjection of PA. Treatment of mice with PA enhanced tumor uptake. Conclusions: The present study showed that increase of PEG-spacer length in the [99mTc]Tc-DB7–[99mTc]Tc-DB13–[99mTc]Tc-DB14 series had little effect on GRPR affinity, specific uptake in PC-3 cells, in vivo stability, or tumor uptake. A significant change in in vivo stability and tumor uptake was observed only after treatment of mice with PA, without compromising the favorably low background radioactivity levels.

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