- Two bifunctional desferrioxamine chelators for bioorthogonal labeling of biovectors with zirconium-89
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We report two bifunctional chelators, DFO-Cys and DFO-CBT, to label biovectors with zirconium-89 according to the 2-cyanobenzothiazole/1,2-aminothiol cycloaddition. Their features are high labeling yields, rapid and efficient bioconjugation, metabolically stable luciferin-based end products, and applicability to orthogonal two-step labeling of sensitive biomolecules.
- Gao,Ieritano,Chen,Dias,Rousseau,Bénard,Seimbille
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- Efficient Triplet-Triplet Annihilation-Based Upconversion for Nanoparticle Phototargeting
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High-efficiency upconverted light would be a desirable stimulus for triggered drug delivery. Here we present a general strategy to achieve photoreactions based on triplet-triplet annihilation upconversion (TTA-UC) and F?rster resonance energy transfer (FRET). We designed PLA-PEG micellar nanoparticles containing in their cores hydrophobic photosensitizer and annihilator molecules which, when stimulated with green light, would undergo TTA-UC. The upconverted energy was then transferred by FRET to a hydrophobic photocleavable group (DEACM), also in the core. The DEACM was bonded to (and thus inactivated) the cell-binding peptide cyclo-(RGDfK), which was bound to the PLA-PEG chain. Cleavage of DEACM by FRET reactivated the PLA-PEG-bound peptide and allowed it to move from the particle core to the surface. TTA-UC followed by FRET allowed photocontrolled binding of cell adhesion with green light LED irradiation at low irradiance for short periods. These are attractive properties in phototriggered systems.
- Wang, Weiping,Liu, Qian,Zhan, Changyou,Barhoumi, Aoune,Yang, Tianshe,Wylie, Ryan G.,Armstrong, Patrick A.,Kohane, Daniel S.
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- Photoactivatable caged cyclic RGD peptide for triggering integrin binding and cell adhesion to surfaces
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We report the synthesis and properties of a photoactivatable caged RGD peptide and its application for phototriggering integrin- and cell-binding to surfaces. We analysed in detail 1) the differences in the integrin-binding affinity of the caged and uncaged forms by quartz crystal microbalance (QCM) studies, 2) the efficiency and yield of the photolytic uncaging reaction, 3) the biocompatibility of the photolysis by-products and irradiation conditions, 4) the possibility of site, temporal and density control of integrin-binding and therefore human cell attachment, and 5) the possibility of in situ generation of cell patterns and cell gradients by controlling the UV exposure. These studies provide a clear picture of the potential and limitations of caged RGD for integrin-mediated cell adhesion and demonstrate the application of this approach to the control and study of cell interactions and responses.
- Wirkner, Melanie,Weis, Simone,San Miguel, Veronica,Alvarez, Marta,Gropeanu, Radu A.,Salierno, Marcelo,Sartoris, Anne,Unger, Ronald E.,Kirkpatrick, C. James,del Campo, Aranzazu
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- Design and synthesis of novel dual-cyclic RGD peptides for αvβ3 integrin targeting
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The specific binding of RGD cyclic peptide with integrin αvβ3 attracts great research interest for tumor-targeting drug delivery. Herein, we designed and synthesized a series of dual-ring RGD-peptide derivatives as a drug carrier for αvβ3 targeting. Three novel peptides showed excellent cell adhesion inhibition effect, in which, P3 exhibited 7-fold enhancement in IC50 compared with cyclo(RGDfK). Drug-loaded cytotoxicity experiment and imaging experiment indicated that such dual-cyclic RGD peptides have good tumor targeting effects. This work provides a new strategy for the design of novel RGD peptides.
- Liu, Junjie,Cheng, Xiaozhong,Tian, Xiaobo,Guan, Dongliang,Ao, Jiwei,Wu, Zhimeng,Huang, Wei,Le, Zhiping
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- A Stable Precursor for Bioorthogonally Removable 3-Isocyanopropyloxycarbonyl (ICPrc) Protecting Groups
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Studies have established 3-isocyanopropyloxycarbonyl (ICPrc) moieties as bioorthogonally removable protecting groups. However, reagents to prepare ICPrc-protected amines are unstable, which critically limits the practical implementation of this chemistry. Here we report 3-isocyanopropyl (pentafluorophenyl) carbonates as bench-stable precursors for the synthesis of ICPrc-protected primary and secondary amines. The utility of the chemistry for bioconjugation applications is demonstrated by reversibly masking a lysine residue on a bioactive peptide.
- Tu, Julian,Xu, Minghao,Franzini, Raphael M.
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- Comparison of radioiodine- or radiobromine-labeled rgd peptides between direct and indirect labeling methods
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Radiolabeled cyclic peptides containing the (Arg-Gly-Asp) RGD sequence for use in positron emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, and targeted radionuclide therapy of cancer have been reported. In this study, RGD was used as a model carrier peptide for diagnosis and therapy of cancer. To evaluate the characteristics of radiohalogen-labeled peptides, several kinds of labeled RGD peptides [125I-c(RGDyK), 77Br-c(RGDyK), [125I]SIB-c(RGDfK), [77Br]SBrB-c(RGDfK), [125I]SIB-EG2-c(RGDfK), and [77Br]SBrB-EG2-c(RGDfK)] were designed, prepared, and evaluated. In these initial studies, 77Br (t1/2=57.0h) and 125I (t1/2=59.4d) were used because of their longer half-lives. Precursor peptides were synthesized using a standard 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase methodology. Radiolabeled peptides were prepared by chloramine-T method or conjugation of RGD peptides with [125I]N-succinimidyl 3-iodobenzoate ([125I]SIB) or [77Br]N-succinimidyl 3-bromobenzoate ([77Br]SBrB). Measurement of the partition coefficients, integrin binding assay, and biodistribution experiments in tumor-bearing mice were performed. 125I and 77Br labeling were successfully performed using similar methods, and in vitro characteristics and biodistributions were similar between the 125I-labeled and corresponding 77Br-labeled peptides. [125I]SIB- and [77Br]SBrB-conjugated RGD peptides showed higher partition coefficients, lower tumor uptakes, and higher intestinal uptake than 125I-c(RGDyK) and 77Br-c(RGDyK). [125I]SIB-EG2-c(RGDfK) and [77Br]SBrB-EG2-c(RGDfK), which possess an ethylene glycol linker, decreased lipophilicity and uptake in intestine compared with [125I]SIB-c(RGDfK) and [77Br]SBrB-c(RGDfK), which possess no linker. However, the improvement in biodistribution of [125I]SIB-EG2-c(RGDfK) and [77Br]SBrB-EG2-c(RGDfK)] was insufficient. In conclusion, directly radiohalogenated c(RGDyK) peptides are potentially more useful for tumor imaging and therapy than indirectly radiohalogenated ones.
- Ogawa, Kazuma,Takeda, Takuya,Yokokawa, Masaru,Yu, Jing,Makino, Akira,Kiyono, Yasushi,Shiba, Kazuhiro,Kinuya, Seigo,Odani, Akira
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p. 651 - 659
(2018/06/11)
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- Synthesis and Biological Evaluation of Paclitaxel Conjugates Involving Linkers Cleavable by Lysosomal Enzymes and αVβ3-Integrin Ligands for Tumor Targeting
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Two cyclo[DKP-RGD]-PTX (PTX = paclitaxel) and two cyclo[RGDfK]-PTX conjugates containing the Gly-Phe-Leu-Gly (GFLG) linker, which is cleavable by lysosomal enzymes, were synthesized and compared to two cyclo[DKP-RGD]-Val-Ala-PTX conjugates. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the isolated αvβ3 receptor, retaining good binding affinity, in the same nanomolar range of the free ligands. Cell viability assays were performed for the six conjugates in the αvβ3+ U87 and in the αvβ3– HT29 cell lines. Loss of potency was observed for all the conjugates, attenuated by the presence of a tetraethylene glycol (PEG-4) spacer. A good Targeting Index (TI = Relative Potency in the αvβ3+ U87/Relative Potency in the αvβ3– HT29) was displayed by the conjugates, in particular by cyclo[DKP-RGD]-PEG-4-Val-Ala-PTX 9 (TI = 533). This conjugate was tested in the αvβ3+ U87 cell line in the presence of 50-fold excess free cyclo[DKP-RGD] ligand 2. In this competition experiment, a fivefold decrease of the conjugate cytotoxicity was calculated, suggesting that the conjugate is possibly internalized by an αvβ3 integrin-mediated process.
- López Rivas, Paula,Ran?elovi?, Ivan,Raposo Moreira Dias, André,Pina, Arianna,Arosio, Daniela,Tóvári, József,Mez?, Gábor,Dal Corso, Alberto,Pignataro, Luca,Gennari, Cesare
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supporting information
p. 2902 - 2909
(2018/06/27)
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- Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11C-Acetylation of Peptides
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A mild and effective method is described for 11C-labeling of peptides selectively at the N-terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium–methyl complexes and their high reactivity towards amino-carbonylation of amine groups in the presence [11C]carbon monoxide. The protocol facilitates the production of native N-11C-acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.
- Andersen, Thomas L.,Nordeman, Patrik,Christoffersen, Heidi F.,Audrain, Hélène,Antoni, Gunnar,Skrydstrup, Troels
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supporting information
p. 4549 - 4553
(2017/04/13)
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- A rapid and clean synthetic approach to cyclic peptides: Via micro-flow peptide chain elongation and photochemical cyclization: Synthesis of a cyclic RGD peptide
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A cyclic RGD peptide was efficiently synthesized based on micro-flow, triphosgene-mediated peptide chain elongation and micro-flow photochemical macrolactamization. Our approach enabled a rapid (amidation for peptide chain elongation 5 s, macrolactamization 5 min) and clean (only one column chromatographic separation) synthesis of a cyclic peptide.
- Mifune, Yuto,Nakamura, Hiroyuki,Fuse, Shinichiro
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p. 11244 - 11249
(2016/12/09)
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- Site-selective three-component reaction for dual-functionalization of peptides
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A site-selective dual-functionalization of peptides is presented, involving readily available maleimides as well as N-hydroxylamines. The modification proceeds through a three component 1,3-dipolar cycloaddition, forming a stable product. This was exemplified by the one-pot attachment of two molecular imaging moieties to a tumor binding cyclic peptide, and was extended to the conjugation of a DOTA chelator to a 12 kDa protein. The Royal Society of Chemistry 2013.
- Munch, Henrik K.,Rasmussen, Jakob E.,Popa, Gina,Christensen, J?rn B.,Jensen, Knud J.
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supporting information
p. 1936 - 1938
(2013/04/10)
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- Multimerization of cRGD peptides by click chemistry: Synthetic strategies, chemical limitations, and influence on biological properties
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Integrin αvβ3 is overexpressed on endothelial cells of growing vessels as well as on several tumor types, and so integrin-binding radiolabeled cyclic RGD pentapeptides have attracted increasing interest for in vivo imaging of αvβ3 integrin expression by positron emission tomography (PET). Of the cRGD derivatives available for imaging applications, systems comprising multiple cRGD moieties have recently been shown to exhibit highly favorable properties in relation to monomers. To assess the synthetic limits of the cRGD-multimerization approach and thus the maximum multimer size achievable by using different efficient conjugation reactions, we prepared a variety of multimers that were further investigated in vitro with regard to their avidities to integrin αvβ3. The synthesized peptide multimers containing increasing numbers of cRGD moieties on PAMAM dendrimer scaffolds were prepared by different click chemistry coupling strategies. A cRGD hexadecimer was the largest construct that could be synthesized under optimized reaction conditions, thus identifying the current synthetic limitations for cRGD multimerization. The obtained multimeric systems were conjugated to a new DOTA-based chelator developed for the derivatization of sterically demanding structures and successfully labeled with 68Ga for a potential in vivo application. The evaluated multimers showed very high avidities-increasing with the number of cRGD moieties-in in vitro studies on immobilized αvβ3 integrin and U87MG cells, of up to 131-and 124-fold, respectively, relative to the underivatized monomer.
- Waengler, Carmen,Maschauer, Simone,Prante, Olaf,Schaefer, Martin,Schirrmacher, Ralf,Bartenstein, Peter,Eisenhut, Michael,Waengler, Bjoern
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experimental part
p. 2168 - 2181
(2011/12/15)
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- Targeting a homogeneously glycosylated antibody Fc to bind cancer cells using a synthetic receptor ligand
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(Chemical Equation Presented) The targeting of a glycosylated antibody Fc fragment to bind to cancer cells by site-selective incorporation of a synthetic ligand is described. Homogeneously glycosylated immunoglobulin G subclass 1 fragment crystallizable (
- Xiao, Junpeng,Chen, Rui,Pawlicki, Mark A.,Tolbert, Thomas J.
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supporting information; experimental part
p. 13616 - 13618
(2010/01/06)
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- Phototriggering of cell adhesion by caged cyclic RGD peptides
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Restrained potential: A caged cyclic peptide attached to a surface is able to trigger cell attachment to the surface with spatiotemporal definition upon exposure to light (λ = 351 nm). The peptide shows no integrin-binding activity in its caged form, but mediates cell adhesion effectively after irradiation (see optical microscopy image of cells on a surface irradiated through a mask in bands 100 μm in width). (Figure Presented).
- Petersen, Svea,Alonso, Jose Maria,Specht, Alexandre,Duodu, Portia,Goeldner, Maurice,Del Campo, Aranzazu
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p. 3192 - 3195
(2008/12/23)
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- A convenient access to αVβ3/αVβ5 integrin ligand conjugates: Regioselective solid-phase functionalisation of an RGD based peptide
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The cyclopeptide (-RGDfK-) is a potent and selective αVβ3/αVβ5 integrin ligand. A methodology for the conjugation of cyclo(-RGDfK-) through the regioselective derivatisation of lysine side chains, either in solution or directly on the solid support, is described. This provides a rapid and flexible chemical entry to conjugated integrin ligands bearing reporter groups for biological investigations or reactive chemical functions for the preparation of new vector systems.
- Boturyn, Didier,Dumy, Pascal
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p. 2787 - 2790
(2007/10/03)
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