Challenges in Pharmacokinetic Modelling of [F]fluoro-PEG-folate PET/CT Imaging in Epithelial Ovarian Cancer Patients.

Purpose: To describe the pharmacokinetic properties of the [F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC).

Procedures: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v.

Microspheres as a Carrier System for Therapeutic Embolization Procedures: Achievements and Advances.

The targeted delivery of anti-cancer drugs and isotopes is one of the most pursued goals in anti-cancer therapy. One of the prime examples of such an application is the intra-arterial injection of microspheres containing cytostatic drugs or radioisotopes during hepatic embolization procedures. Therapy based on the application of microspheres revolves around vascular occlusion, complemented with local therapy in the form of trans-arterial chemoembolization (TACE) or radioembolization (TARE).

Peptide Antagonists for P-selectin Discriminate between Sulfatide-Dependent Platelet Aggregation and PSGL-1-Mediated Cell Adhesion.

Background: Membrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface under flow indeed depended on sulfatides and that this interaction differed considerably from the interaction of P-selectin with P-selectin Glycoprotein Ligand-1 (PSGL-1), which underlies leukocyte-endothelium adhesion.

Methods And Results: Upon platelet activation, sulfatides were translocated to the platelet surface to form focal hot-spots.

Design and validation of a specific scavenger receptor class AI binding peptide for targeting the inflammatory atherosclerotic plaque.

Objective: Scavenger receptor A (SR-A) is abundantly expressed by macrophage and plays a critical role in foam cell formation and atherogenesis. In search of selective SR-AI antagonists, we have used affinity selection of a phage displayed peptide library on the synthetic extracellular domain of SR-AI.

Methods And Results: Phage selection led to an almost 1,000-fold enrichment of SR-AI binding phage, which bound avidly to human THP-1 cells.

Efficient degradation-aided selection of protease inhibitors by phage display.

In this report, we describe a novel phage display strategy for the identification of dedicated protease inhibiting peptides, based on degradation-aided enrichment of protease resistant phages. Phages were directly incubated with a range of phage-degrading proteases, after which non-degraded phages were used for the next selection round. For proteinase-K we identified after only four selection rounds a peptide (VLIMPVLLGIPLLC) that inhibits proteinase-K activity with an inhibition constant of 4 microM.

Blocking endothelial adhesion molecules: a potential therapeutic strategy to combat atherogenesis.

Purpose Of Review: This review provides a concise update of the involvement of endothelial adhesion molecules in atherogenesis, an overview of current advances in the development of adhesion molecule blocking agents, as well as an insight into the potential of these molecules in cardiovascular therapy.

Recent Findings: As endothelial adhesion molecules are deemed to play an important role in the development and progression of atherosclerotic lesions, they are interesting targets for therapeutic intervention in this process. In particular, P-selectin and vascular cell adhesion molecule 1 are widely considered to hold promise in this regard.

P-selectin as a candidate target in atherosclerosis.

P-selectin is of critical importance in early atherogenesis by initiating leukocyte rolling at the site of endothelial injury. In order to validate P-selectin as a candidate target for the development of anti-atherogenic strategies, we wanted to obtain quantitative information on P-selectin expression, and identify novel peptide-based lead structures that interact with P-selectin. P-selectin mRNA expression in the aortic arch and in other tissues of apoE-deficient (apoE-/-) mice was determined by real-time PCR technology.

Rational optimization of a short human P-selectin-binding peptide leads to nanomolar affinity antagonists.

P-selectin plays an important role in the development of various diseases, including atherosclerosis and thrombosis. In our laboratory we recently identified a number of specific human P-selectin-binding peptides containing a Glu-Trp-Val-Asp-Val consensus motif, displaying a low micromolar affinity for P-selectin (IC(50) = 2 microm). In search of more potent antagonists for P-selectin, we have optimized the EWVDV pentapeptide core motif via a two-step combinatorial chemistry approach.

Specific inhibition of P-selectin-mediated cell adhesion by phage display-derived peptide antagonists.

P-selectin is a leukocyte adhesion receptor expressed on activated vascular endothelium and platelets that mediates leukocyte rolling and attachment. Because P-selectin is critically involved in inflammation, we used phage display libraries to identify P-selectin-specific peptides that might interfere with its proinflammatory function. Isolated phage contained a highly conserved amino acid motif.

Targeting of peptides to restenotic vascular smooth muscle cells using phage display in vitro and in vivo.

Restenosis after angioplasty occurs in 30-40% of the treated patients. To develop a strategy to deliver drugs to restenotic lesions, we selected phages that bind to proliferating vascular smooth muscle cells (VSMC), from a random constraint 15-mer peptide phage display library. Phages were selected for binding to cultured primary aortic VSMC (in vitro biopanning) and selected for binding to denudated carotid arteries in mice (in vivo biopanning).

The effect of TGF-beta receptor binding peptides on smooth muscle cells.

TGF-beta1 is a potent regulator of vascular smooth muscle cell (VSMC) proliferation, migration, and extracellular matrix (ECM) synthesis. In this study, we selected two peptides, IM-1 and IM-2, that bind to the TGF-beta type II receptor (TGF-beta RII) using phage display. IM-1 and IM-2 bind to the TGF-beta RII, with a K(d) of 1 microM.

Uptake and processing of modified bacteriophage M13 in mice: implications for phage display.

Internalization and degradation of filamentous bacteriophage M13 by a specific target cell may have major consequences for the recovery of phage in in vivo biopanning of phage libraries. Therefore, we investigated the pharmacokinetics and processing of native and receptor-targeted phage in mice. (35)S-radiolabeled M13 was chemically modified by conjugation of either galactose (lacM13) or succinic acid groups (sucM13) to the coat protein of the phage to stimulate uptake by galactose recognizing hepatic receptors and scavenger receptors, respectively.