TY - JOUR
T1 - Cathepsin nanofiber substrates as potential agents for targeted drug delivery
AU - Ben-Nun, Yael
AU - Fichman, Galit
AU - Adler-Abramovich, Lihi
AU - Turk, Boris
AU - Gazit, Ehud
AU - Blum, Galia
N1 - Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2017/7/10
Y1 - 2017/7/10
N2 - The development of reactive drug carriers that could actively respond to biological signals is a challenging task. Different peptides can self-assemble into biocompatible nanostructures of various functionalities, including drugs carriers. Minimal building blocks, such as diphenylalanine, readily form ordered nanostructures. Here we present the development of self-assembled tetra-peptides that include the diphenylalanine motif, serving as substrates of the cathepsin proteases. This is of great clinical importance as cathepsins, whose activity and expression are highly elevated in cancer and other pathologies, have been shown to serve as efficient enzymes for therapeutic release. Based on the cathepsins affinity around the active site, we generated a library of Phe-Phe-Lys-Phe (FFKF) tetra-peptide substrates (TPSs). We inserted various N-termini capping groups with different chemical properties to investigate the effect on protease affinity and self-assembly. All nine TPSs were cleaved by their targets, cathepsins B and L. However, solvent switching led to nanofibers self-assembly of only seven of them. Due to its rapid self-assembly and complete degradation by cathepsin B, we focused on TPS4, Cbz-FFKF-OH. Degradation of TPS4 nanofibers by cathepsin B led to the release of 91.8 ± 0.3% of the incorporated anti-cancerous drug Doxorubicin from the nanofibers within 8 h while only 55 ± 0.2% was released without enzyme treatment. Finally, we demonstrated that tumor lysates fully degraded TPS4 nanofibers. Collectively, these results suggest that tetra-peptide substrates that form nanostructures could serve as a promising platform for targeted drug delivery to pathologies in which protease activity is highly elevated.
AB - The development of reactive drug carriers that could actively respond to biological signals is a challenging task. Different peptides can self-assemble into biocompatible nanostructures of various functionalities, including drugs carriers. Minimal building blocks, such as diphenylalanine, readily form ordered nanostructures. Here we present the development of self-assembled tetra-peptides that include the diphenylalanine motif, serving as substrates of the cathepsin proteases. This is of great clinical importance as cathepsins, whose activity and expression are highly elevated in cancer and other pathologies, have been shown to serve as efficient enzymes for therapeutic release. Based on the cathepsins affinity around the active site, we generated a library of Phe-Phe-Lys-Phe (FFKF) tetra-peptide substrates (TPSs). We inserted various N-termini capping groups with different chemical properties to investigate the effect on protease affinity and self-assembly. All nine TPSs were cleaved by their targets, cathepsins B and L. However, solvent switching led to nanofibers self-assembly of only seven of them. Due to its rapid self-assembly and complete degradation by cathepsin B, we focused on TPS4, Cbz-FFKF-OH. Degradation of TPS4 nanofibers by cathepsin B led to the release of 91.8 ± 0.3% of the incorporated anti-cancerous drug Doxorubicin from the nanofibers within 8 h while only 55 ± 0.2% was released without enzyme treatment. Finally, we demonstrated that tumor lysates fully degraded TPS4 nanofibers. Collectively, these results suggest that tetra-peptide substrates that form nanostructures could serve as a promising platform for targeted drug delivery to pathologies in which protease activity is highly elevated.
KW - Cathepsins
KW - Diphenylalanine
KW - Nanofibers
KW - Self-assembly
KW - Targeted drug delivery
UR - http://www.scopus.com/inward/record.url?scp=85007607290&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2016.11.028
DO - 10.1016/j.jconrel.2016.11.028
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 27908759
AN - SCOPUS:85007607290
SN - 0168-3659
VL - 257
SP - 60
EP - 67
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -