scholarly journals Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4585
Author(s):  
Anton Amadeus Hörmann ◽  
Maximilian Klingler ◽  
Maliheh Rezaeianpour ◽  
Nikolas Hörmann ◽  
Ronald Gust ◽  
...  
Keyword(s):  
Amino Acid ◽  
Enzymatic Degradation ◽  
Cell Uptake ◽  
Receptor Interaction ◽  
In Vivo Evaluation ◽  
Linear Peptide ◽  
Peptide Analog ◽  
Targeting Peptide

Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 comprising site-specific amino acid substitutions in position 2, 6 and 8 and different possible metabolites thereof were synthesized. The receptor interaction of the peptide and selected metabolites was evaluated in a CCK2R-expressing cell line. The enzymatic stability of the 177Lu-labeled peptide analog was evaluated in vitro in different media as well as in BALB/c mice up to 1 h after injection and the metabolites were identified based on radio-HPLC analysis. The new radiopeptide showed a highly increased stability in vivo with >56% intact radiopeptide in the blood of BALB/c mice 1 h after injection. High CCK2R affinity and cell uptake was confirmed only for the intact peptide, whereas enzymatic cleavage within the receptor specific C-terminal amino acid sequence resulted in complete loss of affinity and cell uptake. A favorable biodistribution profile was observed in BALB/c mice with low background activity, preferential renal excretion and prolonged uptake in CCK2R-expressing tissues. The novel stabilized MG analog shows high potential for diagnostic and therapeutic use. The radiometabolites characterized give new insights into the enzymatic degradation in vivo.

Synthesis of Fragments of the Vasoactive Intestinal Peptide (VIP) and Analysis of Their Residual Biological Activities

1995 ◽  
Vol 60 (7) ◽  
pp. 1229-1235 ◽  
Author(s):  
Ivana Zoulíková ◽  
Ivan Svoboda ◽  
Jiří Velek ◽  
Václav Kašička ◽  
Jiřina Slaninová ◽  
...  
Keyword(s):  
Amino Acid ◽  
Biological Activities ◽  
Residual Activity ◽  
Detailed Examination ◽  
Amino Acid Residues ◽  
Linear Peptide ◽  
Zone Electrophoresis ◽  
Capillary Zone

The vasoactive intestinal (poly)peptide (VIP) is a linear peptide containing 28 amino acid residues, whose primary structure indicates a low metabolic stability. The following VIP fragments, as potential metabolites, and their analogues were prepared by synthesis on a solid: [His(Dnp)1]VIP(1-10), VIP(11-14), [D-Arg12]VIP(11-14), [Lys(Pac)15,21,Arg20]VIP(15-22), and VIP(23-28). After purification, the peptides were characterized by amino acid analysis, mass spectrometry, RP HPLC, and capillary zone electrophoresis. In some tests, detailed examination of the biological activity of the substances in vivo and in vitro gave evidence of a low, residual activity of some fragments, viz. a depressoric activity in vivo for [His(Dnp)1]VIP(1-10) and a stimulating activity for the release of α-amylase in vitro and in vivo for [Lys(Pac)15,21,Arg20]VIP(15-22) and VIP(23-28).

Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vivo evaluation of cyclic amino acid esters

2003 ◽  
Vol 20 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Cosimo Altomare ◽  
Giuseppe Trapani ◽  
Andrea Latrofa ◽  
Mariangela Serra ◽  
Enrico Sanna ◽  
...  
Keyword(s):  
Amino Acid ◽  
Water Soluble ◽  
Anesthetic Agent ◽  
Amino Acid Esters ◽  
In Vivo Evaluation ◽  
Derivatives Of ◽  
Acid Esters

scholarly journals In vivo evaluation of CD38 and CD138 as targets for nanoparticle-based drug delivery in multiple myeloma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
David T. Omstead ◽  
Franklin Mejia ◽  
Jenna Sjoerdsma ◽  
Baksun Kim ◽  
Jaeho Shin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppression ◽  
Synthetic Methods ◽  
Cell Uptake ◽  
In Vivo Evaluation ◽  
Targeted Nanoparticles ◽  
Liposomal Nanoparticles ◽  
Tumor Accumulation

Abstract Background Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies. Methods In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health. Results The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter’s poor selectivity. Conclusion These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.

scholarly journals Cholecystokinin-2 Receptor Targeting with Radiolabeled Peptides: Current Status and Future Directions

2020 ◽  
Vol 27 (41) ◽  
pp. 7112-7132 ◽  
Author(s):  
Maximilian Klingler ◽  
Anton Amadeus Hörmann ◽  
Elisabeth Von Guggenberg
Keyword(s):  
Enzymatic Degradation ◽  
Peptide Sequence ◽  
Current Status ◽  
Tumor Uptake ◽  
Linear Peptide ◽  
Peptide Analogs ◽  
Recent Developments ◽  
Targeting Peptide ◽  
Peptide Probes

A wide variety of radiolabeled peptide analogs for specific targeting of cholecystokinin- 2 receptors (CCK2R) has been developed in the last decades. Peptide probes based on the natural ligands Minigastrin (MG) and Cholecystokinin (CCK) have a high potential for molecular imaging and targeted radiotherapy of different human tumors, such as Medullary Thyroid Carcinoma (MTC) and Small Cell Lung Cancer (SCLC). MG analogs with high persistent uptake in CCK2R expressing tumors have been preferably used for the development of radiolabeled peptide analogs. The clinical translation of CCK2R targeting has been prevented due to high kidney uptake or low metabolic stability of the different radiopeptides developed. Great efforts in radiopharmaceutical development have been undertaken to overcome these limitations. Various modifications in the linear peptide sequence of MG have been introduced mainly with the aim to reduce kidney retention. Furthermore, improved tumor uptake could be obtained by in situ stabilization of the radiopeptide against enzymatic degradation through coinjection of peptidase inhibitors. Recent developments focusing on the stabilization of the Cterminal receptor binding sequence (Trp-Met-Asp-Phe-NH2) have led to new radiolabeled MG analogs with highly improved tumor uptake and tumor-to-kidney ratio. In this review, all the different aspects in the radiopharmaceutical development of CCK2R targeting peptide probes are covered, giving also an overview on the clinical investigations performed so far. The recent development of radiolabeled MG analogs, which are highly stabilized against enzymatic degradation in vivo, promises to have a high impact on the clinical management of patients with CCK2R expressing tumors in the near future.

scholarly journals Feasibility of Developing Radiotracers for MDM2: Synthesis and Preliminary Evaluation of an 18F-Labeled Analogue of the MDM2 Inhibitor SP-141

2021 ◽  
Vol 14 (4) ◽  
pp. 358
Author(s):  
Satish K. Chitneni ◽  
Zhengyuan Zhou ◽  
Brian E. Watts ◽  
Michael R. Zalutsky
Keyword(s):  
Negative Regulator ◽  
Cell Uptake ◽  
Preliminary Evaluation ◽  
In Vivo Evaluation ◽  
Normal Tissues ◽  
Pet Tracer ◽  
Positron Emission ◽  
Mdm2 Expression

Murine double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor protein, is overexpressed in several human cancers. Herein we investigate the feasibility of developing 18F-labeled compounds based on the small molecule inhibitor SP-141 for imaging tumor MDM2 expression levels with positron emission tomography (PET). Three nonradioactive fluorinated SP-141 analogues, 1–3, were synthesized, and their binding to the MDM2 protein was analyzed by surface plasmon resonance (SPR). One of these, a fluoroethoxy analogue, was labeled with fluorine-18 (18F) using 18F-fluorethyl bromide to provide [18F]1 and evaluated in vitro and in vivo. SPR analysis confirmed the binding of the fluorinated analogues to MDM2 at 1.25–20 µM concentrations. Cell uptake studies revealed high uptake (67.5–71.4 %/mg protein) and specificity of [18F]1 in MCF7 and HepG2 cells. The uptake of [18F]1 in these cells could be modulated using 100 µM SP-141, potentially reflecting changes in MDM2 expression because of p53 activation by SP-141. [18F]1 exhibited stable uptake and retention in HepG2 tumor xenografts (~3 %ID/g) in vivo, but poor clearance from blood and other normal tissues, yielding low tumor-to-background ratios (< 2) at 2 h post injection. Our results suggest that [18F]1 has suboptimal characteristics for in vivo evaluation as a PET tracer for MDM2, but warrant radiolabeling and assessment of the other fluorinated analogues synthesized in this work, 2 and 3, and potentially other molecular scaffolds for developing MDM2 targeted radiotracers.

In vitro and in vivo evaluation of improved EGFR targeting peptide-conjugated phthalocyanine photosensitizers for tumor photodynamic therapy

2018 ◽  
Vol 29 (7) ◽  
pp. 1171-1178 ◽  
Author(s):  
Qingle Chen ◽  
Yanhong Ma ◽  
Jisi Zhao ◽  
Mei Zhao ◽  
Wenjing Li ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
In Vivo Evaluation ◽  
Targeting Peptide

In Vitro and In Vivo Evaluation of Amino Acid-Functionalized Cellulose Beads for Whole Blood Hemoperfusion

2005 ◽  
Vol 288-289 ◽  
pp. 393-396 ◽  
Author(s):  
Yong Jian Wang ◽  
Yao Ting Yu
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Whole Blood ◽  
Blood Perfusion ◽  
In Vitro Test ◽  
Rheumatoid Factors ◽  
In Vivo Evaluation ◽  
Vitro Test

Phenylalanine linked to cellulose beads was designed as an adsorbent in whole blood hemoperfusion for the therapy of rheumatoid arthritis. In whole blood perfusion tests, the adsorbent adsorbed rheumatoid factors directly from whole blood. In vitro test showed that the adsorbent had good biocompability properties. No acute systemic toxicity and dermal irritancy with extremely low skin sensitizing activity were observed. In vivo animal test with satisfactory results was perfumed with rabbits. Experimental results show that the adsorbent holds promise as a highly effective and safe hemoadsorbent in clinical therapy for rheumatoid arthritis patients by hemoperfusion.

In Vitro and in Vivo Evaluation of64Cu-Labeled DOTA−Linker−Bombesin(7−14) Analogues Containing Different Amino Acid Linker Moieties

2007 ◽  
Vol 18 (4) ◽  
pp. 1110-1117 ◽  
Author(s):  
Jesse J. Parry ◽  
Thomas S. Kelly ◽  
Rebecca Andrews ◽  
Buck E. Rogers
Keyword(s):  
Amino Acid ◽  
In Vivo Evaluation

In vitro and in vivo evaluation of the anti-inflammatory effects of Arzanol from Helichrysum italicum

Planta Medica ◽  
2010 ◽  
Vol 76 (12) ◽  
Author(s):  
J Bauer ◽  
F Dehm ◽  
A Koeberle ◽  
F Pollastro ◽  
G Appendino ◽  
...  
Keyword(s):  
In Vivo Evaluation ◽  
Anti Inflammatory
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