No abstract

Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using -(2-F-fluoroethyl)-l-tyrosine (F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and F-FET uptake in a human xenograft model. Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment ( = 8). Time-activity curves, slope, and tumor-to-brain ratios of F-FET uptake (18-61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration ( = 0.055) and long-term therapy resulted in a significant decrease ( = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of F-FET uptake were observed in PET and autoradiography ( > 0.05). F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.

Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer’s disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely -enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the -peptides’ potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three -peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all--peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides’ potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.