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Mark Bradley - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis, penetrability and intracellular targeting of fluorescein-tagged peptoids and peptide-peptoid hybrids.
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Asier Unciti-broceta, Franziska Diezmann, Chiung Ying Ou-yang, Mario A. Fara, Mark Bradley
    Abstract:

    Abstract The search for novel, generally applicable and highly efficient delivery tools is a major activity in the biotechnology arena. Using highly optimized microwave based Solid-Phase Chemistry a series of fluorescein-labelled cationic peptoid conjugates were synthesized within 24 h and cellular uptake into HeLa, L929 and K562 cells examined via flow cytometry. As expected, analysis revealed that longer oligomers achieved greater cellular penetration ( 7e (9 mer) >  7d (7 mer) >  7c (5 mer) >  7b (3 mer) >  7a (1 mer)) with the nonamer 7e proving to be a remarkable vehicle for all the cell lines, showing excellent penetrability into K562 and L929 cells and extraordinary cell delivery into HeLa cells. Confocal microscopy showed that the hybrid peptoid-nuclear localizing sequence (PKKKRKV from the simian virus 40 large T antigen) resulted in very high levels of nuclei delivery after 3 h, opening up a range of applications such as nuclei staining of living cells with non-DNA-intercalating fluorescent probes.

  • mechanism and structure activity relationships of norspermidine based peptidic inhibitors of trypanothione reductase
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Mark J. Dixon, Richard I Maurer, Cristina Biggi, Julen Oyarzabal, Jonathan W. Essex, Mark Bradley
    Abstract:

    A library of polyamine-peptide conjugates based around some previously identified inhibitors of trypanothione reductase was synthesised by parallel Solid-Phase Chemistry and screened. Kinetic analysis of library members established that subtle structural changes altered their mechanism of action, switching between competitive and non-competitive inhibition. The mode of action of the non-competitive inhibitors was investigated in detail by a variety of techniques including enzyme kinetic analysis (looking at both NADPH and trypanothione disulfide substrates), gel filtration chromatography and analytical ultracentrifugation, leading to the identification of an allosteric mode of inhibition.

  • influence of resin cross linking on Solid Phase Chemistry
    ACS Combinatorial Science, 2001
    Co-Authors: Sunil Rana, Peter White, Mark Bradley
    Abstract:

    A range of PS-DVB resins were prepared by suspension polymerization with styrene, p-chloromethyl styrene, and DVB. Yields of polymerization increased (from 40% to almost 80%) with increasing cross-linking. The beads exhibited the expected swelling characteristics, with the 0.3% resin swelling to almost 9 times its dry volume in CHCl3. Kinetics of cleavage of the dye Methyl Red from the range of Rink linked resins showed rate enhancements of up to 500% between the 6.0 and the 0.3% cross-linked resins. Total synthesis of Kawaguchipeptin B was carried out on the resins, and their performance during the syntheses was investigated. Contrary to expectations, the purities of the cyclic peptide product increased with increasing resin cross-linking doubling from the 0.3-6.0% resin. A Suzuki reaction showed the half-lives of reaction increased with increasing resin cross-linking with an 11-fold increase in half-life between the 0.3-2.7% resin. Surprisingly, we observed very little reaction in the case of the 3.0 and 6.0% cross-linked resins.

  • optimising inhibitors of trypanothione reductase using Solid Phase Chemistry
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Bordin Chitkul, Mark Bradley
    Abstract:

    Abstract A series of inhibitors of the enzyme trypanothione reductase has been identified using directed Solid-Phase Chemistry. The compounds were based on a series of polyamine scaffolds and used the natural product kukoamine A as the lead structure. A compound with a K i of 76 nM was identified, although somewhat surprisingly the compound appeared to be noncompetitive in nature.

Yasuhiko Tabata - One of the best experts on this subject based on the ideXlab platform.

  • enhanced angiogenesis through controlled release of basic fibroblast growth factor from peptide amphiphile for tissue regeneration
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Hisatoshi Kobayashi, Ali Khademhosseini, Yasuhiko Tabata
    Abstract:

    In the present study, we hypothesized that a novel approach to promote vascularization would be to create injectable threedimensional (3-D) scaffolds with encapsulated growth factor that enhance the sustained release of growth factor and induce the angiogenesis. We demonstrate that a 3-D scaffold can be formed by mixing of peptide-amphiphile (PA) aqueous solution with basic fibroblast growth factor (bFGF) suspension. PA was synthesized by standard Solid Phase Chemistry that ends with the alkylation of the NH2 terminus of the peptide. A 3-D network of nanofibers was formed by mixing bFGF suspensions with dilute aqueous solutions of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. In vitro and in vivo release profile of bFGF from 3-D network of nanofibers was investigated while angiogenesis induced by the released bFGF was assessed. When aqueous solution of PA was subcutaneously injected together with bFGF suspension into the back of mice, a transparent 3-D hydrogel was formed at the injected site and induced significant angiogenesis around the injected site, in marked contrast to bFGF injection alone or PA injection alone. The combination of bFGF-induced angiogenesis is a promising procedure to improve tissue regeneration. r 2006 Elsevier Ltd. All rights reserved.

  • ectopic bone formation in collagen sponge self assembled peptide amphiphile nanofibers hybrid scaffold in a perfusion culture bioreactor
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Furong Tian, Hisatoshi Kobayashi, Yasuhiko Tabata
    Abstract:

    Abstract The objective of this study was to enhance ectopic bone formation in a three-dimensional (3-D) hybrid scaffold in combination with bioreactor perfusion culture system. The hybrid scaffold consists of two biomaterials, a hydrogel formed through self-assembly of peptide–amphiphile (PA) with cell suspensions in media, and a collagen sponge reinforced with poly(glycolic acid) (PGA) fiber incorporation. PA was synthesized by standard Solid-Phase Chemistry that ends with the alkylation of the NH 2 terminus of the peptide. A 3-D network of nanofibers was formed by mixing cell suspensions in media with dilute aqueous solution of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. Osteogenic differentiation of mesenchymal stem cells (MSC) in the hybrid scaffold was greatly influenced by the perfusion culture method compared with static culture method. When the osteoinduction activity of hybrid scaffold was studied following the implantation into the back subcutis of rats in terms of histological and biochemical examinations, significantly homogeneous bone formation was histologically observed throughout the hybrid scaffolds when perfusion culture was used compared with static culture method. The level of alkaline phosphatase activity and osteocalcin content at the implanted sites of hybrid scaffolds were significantly high for the perfusion group compared with those in static culture method. We conclude that combination of MSC-seeded hybrid scaffold and the perfusion method was promising to enhance in vitro osteogenic differentiation of MSC and in vivo ectopic bone formation.

  • osteogenic differentiation of mesenchymal stem cells in self assembled peptide amphiphile nanofibers
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Furong Tian, Hisatoshi Kobayashi, Yasuhiko Tabata
    Abstract:

    The proliferation and differentiation of mesenchymal stem cells (MSC) was investigated in a three dimensional (3-D) network of nanofibers formed by self-assembly of peptide-amphiphile (PA) molecules. PA was synthesized by standard Solid Phase Chemistry that ends with the alkylation of the NH(2) terminus of the peptide. The sequence of arginine-glycine-aspartic acid (RGD) was included in peptide design as well. A 3-D network of nanofibers was formed by mixing cell suspensions in media with dilute aqueous solution of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. When rat MSC were seeded into the PA nanofibers with or without RGD, larger number of cells attached was observed in the PA nanofibers including RGD. When measured to evaluate the osteogenic differentiation of MSC, the alkaline phosphatase (ALP) activity and osteocalcin content became maximum for the PA nanofibers including RGD compared with those without RGD, although both the values were significantly higher compared with those in the static tissue culture plate (2-D culture). We concluded that the attachment, proliferation, and osteogenic differentiation of MSC were influenced by PA nanofibers as the cell scaffold.

Hisatoshi Kobayashi - One of the best experts on this subject based on the ideXlab platform.

  • enhanced angiogenesis through controlled release of basic fibroblast growth factor from peptide amphiphile for tissue regeneration
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Hisatoshi Kobayashi, Ali Khademhosseini, Yasuhiko Tabata
    Abstract:

    In the present study, we hypothesized that a novel approach to promote vascularization would be to create injectable threedimensional (3-D) scaffolds with encapsulated growth factor that enhance the sustained release of growth factor and induce the angiogenesis. We demonstrate that a 3-D scaffold can be formed by mixing of peptide-amphiphile (PA) aqueous solution with basic fibroblast growth factor (bFGF) suspension. PA was synthesized by standard Solid Phase Chemistry that ends with the alkylation of the NH2 terminus of the peptide. A 3-D network of nanofibers was formed by mixing bFGF suspensions with dilute aqueous solutions of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. In vitro and in vivo release profile of bFGF from 3-D network of nanofibers was investigated while angiogenesis induced by the released bFGF was assessed. When aqueous solution of PA was subcutaneously injected together with bFGF suspension into the back of mice, a transparent 3-D hydrogel was formed at the injected site and induced significant angiogenesis around the injected site, in marked contrast to bFGF injection alone or PA injection alone. The combination of bFGF-induced angiogenesis is a promising procedure to improve tissue regeneration. r 2006 Elsevier Ltd. All rights reserved.

  • ectopic bone formation in collagen sponge self assembled peptide amphiphile nanofibers hybrid scaffold in a perfusion culture bioreactor
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Furong Tian, Hisatoshi Kobayashi, Yasuhiko Tabata
    Abstract:

    Abstract The objective of this study was to enhance ectopic bone formation in a three-dimensional (3-D) hybrid scaffold in combination with bioreactor perfusion culture system. The hybrid scaffold consists of two biomaterials, a hydrogel formed through self-assembly of peptide–amphiphile (PA) with cell suspensions in media, and a collagen sponge reinforced with poly(glycolic acid) (PGA) fiber incorporation. PA was synthesized by standard Solid-Phase Chemistry that ends with the alkylation of the NH 2 terminus of the peptide. A 3-D network of nanofibers was formed by mixing cell suspensions in media with dilute aqueous solution of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. Osteogenic differentiation of mesenchymal stem cells (MSC) in the hybrid scaffold was greatly influenced by the perfusion culture method compared with static culture method. When the osteoinduction activity of hybrid scaffold was studied following the implantation into the back subcutis of rats in terms of histological and biochemical examinations, significantly homogeneous bone formation was histologically observed throughout the hybrid scaffolds when perfusion culture was used compared with static culture method. The level of alkaline phosphatase activity and osteocalcin content at the implanted sites of hybrid scaffolds were significantly high for the perfusion group compared with those in static culture method. We conclude that combination of MSC-seeded hybrid scaffold and the perfusion method was promising to enhance in vitro osteogenic differentiation of MSC and in vivo ectopic bone formation.

  • osteogenic differentiation of mesenchymal stem cells in self assembled peptide amphiphile nanofibers
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Furong Tian, Hisatoshi Kobayashi, Yasuhiko Tabata
    Abstract:

    The proliferation and differentiation of mesenchymal stem cells (MSC) was investigated in a three dimensional (3-D) network of nanofibers formed by self-assembly of peptide-amphiphile (PA) molecules. PA was synthesized by standard Solid Phase Chemistry that ends with the alkylation of the NH(2) terminus of the peptide. The sequence of arginine-glycine-aspartic acid (RGD) was included in peptide design as well. A 3-D network of nanofibers was formed by mixing cell suspensions in media with dilute aqueous solution of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. When rat MSC were seeded into the PA nanofibers with or without RGD, larger number of cells attached was observed in the PA nanofibers including RGD. When measured to evaluate the osteogenic differentiation of MSC, the alkaline phosphatase (ALP) activity and osteocalcin content became maximum for the PA nanofibers including RGD compared with those without RGD, although both the values were significantly higher compared with those in the static tissue culture plate (2-D culture). We concluded that the attachment, proliferation, and osteogenic differentiation of MSC were influenced by PA nanofibers as the cell scaffold.

Matthias Eder - One of the best experts on this subject based on the ideXlab platform.

  • preclinical evaluation of 18f psma 1007 a new prostate specific membrane antigen ligand for prostate cancer imaging
    The Journal of Nuclear Medicine, 2017
    Co-Authors: Jens Cardinale, Martin Schafer, Ulrike Bauderwust, Karin Leotta, Uwe Haberkorn, Matthias Eder, Martina Benesova, Oliver C Neels, Frederik L Giesel, Klaus Kopka
    Abstract:

    In recent years, several radiotracers targeting the prostate-specific membrane antigen (PSMA) have been introduced. Some of them have had a high clinical impact on the treatment of patients with prostate cancer. However, the number of 18F-labeled tracers addressing PSMA is still limited. Therefore, we aimed to develop a radiofluorinated molecule resembling the structure of therapeutic PSMA-617. Methods: The nonradioactive reference compound PSMA-1007 and the precursor were produced by Solid-Phase Chemistry. The radioligand 18F-PSMA-1007 was produced by a 2-step procedure with the prosthetic group 6-18F-fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester. The binding affinity of the ligand for PSMA and its internalization properties were evaluated in vitro with PSMA-positive LNCaP (lymph node carcinoma of the prostate) cells. Further, organ distribution studies were performed with mice bearing LNCaP and PC-3 (prostate cancer cell line; PSMA-negative) tumors. Finally, small-animal PET imaging of an LNCaP tumor-bearing mouse was performed. Results: The identified ligand had a binding affinity of 6.7 ± 1.7 nM for PSMA and an exceptionally high internalization ratio (67% ± 13%) in vitro. In organ distribution studies, high and specific tumor uptake (8.0 ± 2.4 percentage injected dose per gram) in LNCaP tumor-bearing mice was observed. In the small-animal PET experiments, LNCaP tumors were clearly visualized. Conclusion: The radiofluorinated PSMA ligand showed promising characteristics in its preclinical evaluation, and the feasibility of prostate cancer imaging was demonstrated by small-animal PET studies. Therefore, we recommend clinical transfer of the radioligand 18F-PSMA-1007 for use as a diagnostic PET tracer in prestaging and monitoring of prostate cancer.

  • a dimerized urea based inhibitor of the prostate specific membrane antigen for 68ga pet imaging of prostate cancer
    EJNMMI research, 2012
    Co-Authors: Martin Schafer, Ulrike Bauderwust, Karin Leotta, Frederic Zoller, Walter Mier, Uwe Haberkorn, Michael Eisenhut, Matthias Eder
    Abstract:

    Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu‐ureido‐Lys via the 68Ga chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics. The peptidomimetic structures were synthesized by Solid-Phase Chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu‐ureido‐Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts. Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5). The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.

Hossein Hosseinkhani - One of the best experts on this subject based on the ideXlab platform.

  • enhanced angiogenesis through controlled release of basic fibroblast growth factor from peptide amphiphile for tissue regeneration
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Hisatoshi Kobayashi, Ali Khademhosseini, Yasuhiko Tabata
    Abstract:

    In the present study, we hypothesized that a novel approach to promote vascularization would be to create injectable threedimensional (3-D) scaffolds with encapsulated growth factor that enhance the sustained release of growth factor and induce the angiogenesis. We demonstrate that a 3-D scaffold can be formed by mixing of peptide-amphiphile (PA) aqueous solution with basic fibroblast growth factor (bFGF) suspension. PA was synthesized by standard Solid Phase Chemistry that ends with the alkylation of the NH2 terminus of the peptide. A 3-D network of nanofibers was formed by mixing bFGF suspensions with dilute aqueous solutions of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. In vitro and in vivo release profile of bFGF from 3-D network of nanofibers was investigated while angiogenesis induced by the released bFGF was assessed. When aqueous solution of PA was subcutaneously injected together with bFGF suspension into the back of mice, a transparent 3-D hydrogel was formed at the injected site and induced significant angiogenesis around the injected site, in marked contrast to bFGF injection alone or PA injection alone. The combination of bFGF-induced angiogenesis is a promising procedure to improve tissue regeneration. r 2006 Elsevier Ltd. All rights reserved.

  • ectopic bone formation in collagen sponge self assembled peptide amphiphile nanofibers hybrid scaffold in a perfusion culture bioreactor
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Furong Tian, Hisatoshi Kobayashi, Yasuhiko Tabata
    Abstract:

    Abstract The objective of this study was to enhance ectopic bone formation in a three-dimensional (3-D) hybrid scaffold in combination with bioreactor perfusion culture system. The hybrid scaffold consists of two biomaterials, a hydrogel formed through self-assembly of peptide–amphiphile (PA) with cell suspensions in media, and a collagen sponge reinforced with poly(glycolic acid) (PGA) fiber incorporation. PA was synthesized by standard Solid-Phase Chemistry that ends with the alkylation of the NH 2 terminus of the peptide. A 3-D network of nanofibers was formed by mixing cell suspensions in media with dilute aqueous solution of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. Osteogenic differentiation of mesenchymal stem cells (MSC) in the hybrid scaffold was greatly influenced by the perfusion culture method compared with static culture method. When the osteoinduction activity of hybrid scaffold was studied following the implantation into the back subcutis of rats in terms of histological and biochemical examinations, significantly homogeneous bone formation was histologically observed throughout the hybrid scaffolds when perfusion culture was used compared with static culture method. The level of alkaline phosphatase activity and osteocalcin content at the implanted sites of hybrid scaffolds were significantly high for the perfusion group compared with those in static culture method. We conclude that combination of MSC-seeded hybrid scaffold and the perfusion method was promising to enhance in vitro osteogenic differentiation of MSC and in vivo ectopic bone formation.

  • osteogenic differentiation of mesenchymal stem cells in self assembled peptide amphiphile nanofibers
    Biomaterials, 2006
    Co-Authors: Hossein Hosseinkhani, Mohsen Hosseinkhani, Furong Tian, Hisatoshi Kobayashi, Yasuhiko Tabata
    Abstract:

    The proliferation and differentiation of mesenchymal stem cells (MSC) was investigated in a three dimensional (3-D) network of nanofibers formed by self-assembly of peptide-amphiphile (PA) molecules. PA was synthesized by standard Solid Phase Chemistry that ends with the alkylation of the NH(2) terminus of the peptide. The sequence of arginine-glycine-aspartic acid (RGD) was included in peptide design as well. A 3-D network of nanofibers was formed by mixing cell suspensions in media with dilute aqueous solution of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. When rat MSC were seeded into the PA nanofibers with or without RGD, larger number of cells attached was observed in the PA nanofibers including RGD. When measured to evaluate the osteogenic differentiation of MSC, the alkaline phosphatase (ALP) activity and osteocalcin content became maximum for the PA nanofibers including RGD compared with those without RGD, although both the values were significantly higher compared with those in the static tissue culture plate (2-D culture). We concluded that the attachment, proliferation, and osteogenic differentiation of MSC were influenced by PA nanofibers as the cell scaffold.