In Vitro and Initial In Vivo Evaluation of 68Ga-Labeled Transferrin Receptor (TfR) Binding Peptides as Potential Carriers for Enhanced Drug Transport into TfR Expres
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- 作者：Carmen W?ngler (1) (2)
Dina Nada (1) (2)
Georg H?fner (3)
Simone Maschauer (4)
Bj?rn W?ngler (5)
Stephan Schneider (6)
Esther Schirrmacher (1)
Klaus T. Wanner (3)
Ralf Schirrmacher (1) (2)
Olaf Prante (4) - 关键词：Blood brain barrier (BBB) ; Active drug transport ; Transferrin receptor (TfR)
- 刊名：Molecular Imaging and Biology
- 出版年：2011
- 出版时间：April 2011
- 年：2011
- 卷：13
- 期：2
- 页码：332-341
- 全文大小：254KB
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Dina Nada (1) (2)
Georg H?fner (3)
Simone Maschauer (4)
Bj?rn W?ngler (5)
Stephan Schneider (6)
Esther Schirrmacher (1)
Klaus T. Wanner (3)
Ralf Schirrmacher (1) (2)
Olaf Prante (4)
1. McConnell Brain Imaging Centre, McGill University, Montreal, Canada
2. Lady Davis Institute for Medical Research, McGill University, Montreal, Canada
3. Pharmaceutical Chemistry, Ludwig-Maximilians-University Munich, Munich, Germany
4. Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Erlangen, Germany
5. Department of Nuclear Medicine, University Hospital Munich, Ludwig-Maximilians University Munich, Munich, Germany
6. Department of Internal Medicine I, Division of Endocrinology and Metabolism, Berufsgenossenschaftliches University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
文摘
Purpose The transferrin receptor (TfR) is one of the most attractive targets to overcome the blood–brain barrier (BBB). It has recently been shown that THRPPMWSPVWP binds to the TfR and is subsequently internalized into TfR-expressing cells. Here, we evaluated the ability of THRPPMWSPVWP to become internalized into human TfR-expressing cells via endocytosis to determine its potential to act as a carrier system for the transport of small molecules across the BBB. Procedures To validate the underlying concept of a conjugate consisting of a small brain imaging tracer and a large peptidic carrier molecule, a conjugate of the high affinity D2 receptor ligand fallypride and the TfR targeting peptide THRPPMWSPVWP has been synthesized. Furthermore, two derivatives of THRPPMWSPVWP were labeled with 68Ga in high radiochemical yields (>96%) and a radiochemical purity of 96-8% and evaluated in vitro and in vivo. Results The fallypride–THRPPMWSPVWP conjugate still displayed a K i of 27?nM. The uptake of the 68Ga-labeled peptides into TfR-bearing cells was investigated using U87MG and HT-29 cells to assess the capability of the peptide to act as a carrier molecule targeting the TfR. The in vitro binding studies revealed negligible uptake of the tested 68Ga-labeled conjugates ranging from 0.08% to 0.66% after 60?min incubation at 37°C. Initial in vivo experiments with 68Ga-DOTA-S-maleimido–THRPPMWSPVWP in two healthy rats showed a mean brain uptake of 0.037% injected dose per gram, confirming the results obtained in vitro. Conclusion These results suggest that the accumulation of the 68Ga-radiolabeled conjugates of the TfR-binding peptide THRPPMWSPVWP into TFR expressing human cell lines is nonspecific and too low to render this peptide suitable as a possible carrier molecule for a receptor-mediated transport of compounds across the BBB.