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Published on: April 16, 2019
An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors
Sofia Parrasia1, Andrea Rossa2, Tatiana Varanita3
1Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35131 Padova, Italy.
Abstract:
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 TAT48-61 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 TAT48-61 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.
Insights
New chemotherapy drugs targeting mitochondrial potassium channels show promise for cancer treatment. Researchers successfully delivered these drugs to the brain by linking them to peptides, overcoming a major delivery challenge.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- 5-(4-phenoxybutoxy)psoralen (PAP-1) derivatives are novel chemotherapeutics targeting mitochondrial potassium channel mtKv1.3.
- These compounds induce selective oxidative stress and cell death in cancerous cells, with preclinical success in melanoma and pancreatic cancer models.
- While effective in vitro against glioblastoma, in vivo brain delivery was hindered by the blood-brain barrier.
Purpose of the Study:
- To enhance brain delivery of PAP-1 derivatives, specifically PAPTP, for potential glioma treatment.
- To conjugate PAPTP to cell-penetrating and brain-targeting peptides (TAT48-61 and Angiopep-2).
- To evaluate the feasibility and efficacy of peptide-mediated brain delivery of PAPTP.
Main Methods:
- PAPTP was chemically linked to TAT48-61 and Angiopep-2 peptides via a reversible carbamate ester bond.
- The constructs were administered intravenously to mice at a dose of 5 µmoles/kg bw.
- Brain tissue concentration of the PAPTP-peptide constructs was quantified.
Main Results:
- Successful conjugation of PAPTP to both TAT48-61 and Angiopep-2 peptides was achieved.
- Intravenous administration resulted in the delivery of 0.3-0.4 nmoles of construct per gram of brain tissue.
- This study provides the first evidence of PAPTP delivery to the brain.
Conclusions:
- Peptide conjugation is a viable strategy to overcome the blood-brain barrier for PAPTP delivery.
- This approach opens avenues for fine-tuning the tissue distribution of PAPTP and similar compounds.
- Further research may lead to effective brain-targeted therapies for central nervous system cancers.
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