An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors

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.

Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review

“…Interestingly, enhanced NP functioning has been reported through co-modification with Angiopep-2 and other cell-penetrating peptides. It is worth noting, however, that functionalization of the chemo-therapeutic agent, PAPTP, with either Angiopep-2 or the TAT 48-61 peptide, permitted similar delivery to the brain in mice [157].…”

Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges

“…114 Conjugation to the peptide, a first for TPPdecorated molecules, allowed brain delivery. 115 Transferrin receptors are abundant in brain capillary endothelial cells and in rapidly dividing cells and immature erythroid cells. 116 They are however scarce in other vasculature and tissues, and this provides a built-in selectivity which has made this system a popular target for receptor-mediated delivery attempts 89,90 (see Table 1).…”

“…TAT-PAPTP toxicity may be attributed, at least in part, to its hemolytic action. 115 The ability to cause lysis can be put to good use, at least in principle, not only against noxious microorganisms but also against cancer, since cancer cells appear to be more sensitive to them than normal ones, probably due to differences in lipid composition. 442,443 For example, breast and prostate cancers and their metastases have been attacked with lytic peptides conjugated to ligands of hormone receptors.…”

“…Indeed, an An2-paclitaxel conjugate (ANG1005) , has reached the clinical trials stage. − Our group has recently produced a conjugate of An2 with PAPTP, a triphenylphosphonium (TPP)-containing mitochondriotropic psoralene derivative which shows powerful anticancer activity but cannot cross the BBB . Conjugation to the peptide, a first for TPP-decorated molecules, allowed brain delivery …”

“…However, the severe toxicity observed in the case of TAT-PAPTP forced us to focus the study on Angiopep2-PAPTP. TAT-PAPTP toxicity may be attributed, at least in part, to its hemolytic action …”