An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors
A developing family of chemotherapeutics—derived from 5-(4-phenoxybutoxy)psoralen (PAP-1)—target mitochondrial potassium channel mtKv1.3 to selectively induce oxidative stress and death of diseased cells. The key to their effectiveness is the presence of a positively charged triphenylphosphonium gro...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/2/129 |
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| author | Sofia Parrasia Andrea Rossa Tatiana Varanita Vanessa Checchetto Riccardo De Lorenzi Mario Zoratti Cristina Paradisi Paolo Ruzza Andrea Mattarei Ildikò Szabò Lucia Biasutto |
| author_facet | Sofia Parrasia Andrea Rossa Tatiana Varanita Vanessa Checchetto Riccardo De Lorenzi Mario Zoratti Cristina Paradisi Paolo Ruzza Andrea Mattarei Ildikò Szabò Lucia Biasutto |
| author_sort | Sofia Parrasia |
| collection | DOAJ |
| description | A developing family of chemotherapeutics—derived from 5-(4-phenoxybutoxy)psoralen (PAP-1)—target mitochondrial potassium channel mtKv1.3 to selectively induce oxidative stress and death of diseased cells. The key to their effectiveness is the presence of a positively charged triphenylphosphonium group which drives their accumulation in the organelles. These compounds have proven their preclinical worth in murine models of cancers such as melanoma and pancreatic adenocarcinoma. In in vitro experiments they also efficiently killed glioblastoma cells, but in vivo they were powerless against orthotopic glioma because they were completely unable to overcome the blood-brain barrier. In an effort to improve brain delivery we have now coupled one of these promising compounds, PAPTP, to well-known cell-penetrating and brain-targeting peptides TAT<sub>48–61</sub> and Angiopep-2. Coupling has been obtained by linking one of the phenyl groups of the triphenylphosphonium to the first amino acid of the peptide via a reversible carbamate ester bond. Both TAT<sub>48–61</sub> and Angiopep-2 allowed the delivery of 0.3–0.4 nmoles of construct per gram of brain tissue upon intravenous (i.v.) injection of 5 µmoles/kg bw to mice. This is the first evidence of PAPTP delivery to the brain; the chemical strategy described here opens the possibility to conjugate PAPTP to small peptides in order to fine-tune tissue distribution of this interesting compound. |
| first_indexed | 2024-03-09T05:19:07Z |
| format | Article |
| id | doaj.art-626110aa0ab94bc1b185777c2fbdf1c5 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T05:19:07Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-626110aa0ab94bc1b185777c2fbdf1c52023-12-03T12:41:55ZengMDPI AGPharmaceuticals1424-82472021-02-0114212910.3390/ph14020129An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain TumorsSofia Parrasia0Andrea Rossa1Tatiana Varanita2Vanessa Checchetto3Riccardo De Lorenzi4Mario Zoratti5Cristina Paradisi6Paolo Ruzza7Andrea Mattarei8Ildikò Szabò9Lucia Biasutto10Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35131 Padova, ItalyDepartment of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, ItalyDepartment of Biology, University of Padova, Viale G. Colombo 3, 35131 Padova, ItalyDepartment of Biology, University of Padova, Viale G. Colombo 3, 35131 Padova, ItalyDepartment of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35131 Padova, ItalyDepartment of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, ItalyDepartment of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, ItalyDepartment of Biology, University of Padova, Viale G. Colombo 3, 35131 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35131 Padova, ItalyA developing family of chemotherapeutics—derived from 5-(4-phenoxybutoxy)psoralen (PAP-1)—target mitochondrial potassium channel mtKv1.3 to selectively induce oxidative stress and death of diseased cells. The key to their effectiveness is the presence of a positively charged triphenylphosphonium group which drives their accumulation in the organelles. These compounds have proven their preclinical worth in murine models of cancers such as melanoma and pancreatic adenocarcinoma. In in vitro experiments they also efficiently killed glioblastoma cells, but in vivo they were powerless against orthotopic glioma because they were completely unable to overcome the blood-brain barrier. In an effort to improve brain delivery we have now coupled one of these promising compounds, PAPTP, to well-known cell-penetrating and brain-targeting peptides TAT<sub>48–61</sub> and Angiopep-2. Coupling has been obtained by linking one of the phenyl groups of the triphenylphosphonium to the first amino acid of the peptide via a reversible carbamate ester bond. Both TAT<sub>48–61</sub> and Angiopep-2 allowed the delivery of 0.3–0.4 nmoles of construct per gram of brain tissue upon intravenous (i.v.) injection of 5 µmoles/kg bw to mice. This is the first evidence of PAPTP delivery to the brain; the chemical strategy described here opens the possibility to conjugate PAPTP to small peptides in order to fine-tune tissue distribution of this interesting compound.https://www.mdpi.com/1424-8247/14/2/129PAPTPAngiopep-2blood-brain barrierbrain deliveryglioma |
| spellingShingle | Sofia Parrasia Andrea Rossa Tatiana Varanita Vanessa Checchetto Riccardo De Lorenzi Mario Zoratti Cristina Paradisi Paolo Ruzza Andrea Mattarei Ildikò Szabò Lucia Biasutto An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors Pharmaceuticals PAPTP Angiopep-2 blood-brain barrier brain delivery glioma |
| title | An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors |
| title_full | An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors |
| title_fullStr | An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors |
| title_full_unstemmed | An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors |
| title_short | An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors |
| title_sort | angiopep2 paptp construct overcomes the blood brain barrier new perspectives against brain tumors |
| topic | PAPTP Angiopep-2 blood-brain barrier brain delivery glioma |
| url | https://www.mdpi.com/1424-8247/14/2/129 |
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