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  • 1
    Keywords: imaging, molecular, molecular imaging
    Type of Publication: Book chapter
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  • 2
    Keywords: PEPTIDE ; CELLS ; GROWTH ; IN-VITRO ; tumor ; BLOOD ; CELL ; Germany ; IN-VIVO ; MODEL ; THERAPY ; VITRO ; VIVO ; imaging ; screening ; cell line ; ACCUMULATION ; LINES ; NUCLEAR-MEDICINE ; TIME ; SERA ; primary ; BINDING ; CELL-LINES ; SEQUENCE ; SEQUENCES ; ACID ; MOUSE ; ASSAY ; CELL-LINE ; LINE ; DISPLAY ; CELLULAR UPTAKE ; PEPTIDES ; BIODISTRIBUTION ; STABILITY ; HEAD ; NECK ; CLEARANCE ; MOUSE MODEL ; KINETICS ; specificity ; SECONDARY STRUCTURE ; cell lines ; nuclear medicine ; AFFINITY ; PHAGE DISPLAY ; SERUM ; targeting ; radiology ; RE ; INCREASE ; LIBRARIES ; LEVEL ; methods ; TUMOR-CELL ; ASSAYS ; INTERNALIZATION ; NUCLEAR ; MCF-7 CELLS ; technique ; pharmacology ; USA ; uptake ; tumor targeting ; in vivo ; MEDICINE ; TOO ; binding affinity ; MODIFIED PEPTIDE ; CONJUGATION ; BINDING PEPTIDE ; BLOOD-LEVELS ; circular dichroism ; peptide structure
    Abstract: The transfer of peptide sequences identified by screening of phage-displayed libraries to clinical application is often difficult. This study investigated whether coupling of a new peptide, FROP-1, to the chelator 1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid (DOTA) resulted in structural restriction and, consequently, improved binding and stability. Methods: The peptide FROP-1 was coupled to the chelator DOTA and labeled with In-111. The structural changes caused by the addition of the chelator were determined by circular dichroism. The properties of this modified peptide were investigated in in vitro binding assays and monitored for kinetics, competition, and internalization as well as serum stability. A cell-type binding profile was established and the in vivo biodistribution was evaluated in a nude mouse model. Results: When compared with the free peptide without chelator, FROPDOTA revealed different cellular uptake kinetics, reaching a maximum at 2 h in vitro. The cells completely accumulated the tracer, and competition experiments revealed that 99.4% (FRO82-2 cells), 98.6% (MCF-7 cells), or 99.3% (average for 3 primary head and neck tumor cell lines) of tracer accumulation could be suppressed, revealing the specificity of this process. The internalization kinetics determined in MCF-7 cells supported this finding: After an incubation time of 180 min, the major fraction of FROPDOTA was trapped intracellularly. Serum stability experiments revealed an increase in stability due to the chelator, with a half-life of 71 min. Circular dichroism measurements indicated a fixed alpha-helix structure of FROPDOTA representing a strong change in secondary structure. In competition binding experiments, the binding constant (K-D) to FRO82-2 cells was determined to be 494 nM. Despite this avid binding affinity, the binding kinetics were found to be too slow to induce an uptake in vivo before clearance. Consequently, the biodistribution revealed a rapid renal and hepatobiliary clearance, with blood levels dropping from 5.48 +/- 0.26 %lD/g (percentage injected dose per gram) 5 min after injection to 0.77 +/- 0.15 %ID/g at 135 min after injection. Conclusion: This study revealed that peptides that are identified by display techniques may be underrated. Careful alteration of their structure will permit going beyond the possibilities that the limited pool of naturally occurring peptides provide for tumor targeting
    Type of Publication: Journal article published
    PubMed ID: 17704241
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  • 3
    Keywords: CELLS ; CELL ; antibodies ; antibody ; CHEMISTRY ; biological ; biomacromolecules ; CETUXIMAB IMC-C225 ; CHE
    Abstract: Fluorescent probes are of increasing interest in medicinal and biological applications for the elucidation of the structures and functions of healthy as well as tumour cells. The quality of these investigations is determined by the intensity of the fluorescence signal. High dye/carrier ratios give strong signals. However, these are achieved by the occupation of a high number of derivatisation sites and therefore are accompanied by strong structural alterations of the carrier. Hence, polyvalent substances containing a high number of fluorescent dyes would be favourable because they would allow the introduction of many dyes at one position of the Compound to be labelled. A large number of different dyes have been investigated to determine the efficiency of coupling to a dendrimer scaffold and the fluorescence properties of the oligomeric dyes, but compounds that fulfil the requirements of both strong fluorescence signals and reactivities are rare. Herein we describe the synthesis and characterisation of dye oligomers containing dansyl-, 7-nitro-2,1.3-benzoxadiazol-4-yl- (NBD), coumarin-343. 5(6)-carboxyfluorescein and sulforhodamine 132 moieties based on polyamidoamine (PAMAM) dendrimers. The PAMAM dendrimers were synthesised by ail improved protocol that yielded highly homogeneous scaffolds with up to 128 conjugation sites, When comparing the 0 fluorescent properties of the dye oligomers it was found that only the dansylated dendrimers met the requirements of enhanced fluorescence signals. The dendrimer containing 16 fluorescent dyes was conjugated to the anti-epidermal-growth-factor receptor (EGFR) antibody hMAb425 as a model compound to show the applicability of the dye multimer compounds. This conjugate revealed a preserved immunoreactivity of 54%. We demonstrate the applicability of the dye oligomers to the efficient and applicable labelling of proteins and other large molecules that enables high dye concentrations and therefore high contrasts in fluorescence applications
    Type of Publication: Journal article published
    PubMed ID: 18752247
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