Cathepsin nanofiber substrates as potential agents for targeted drug delivery

Yael Ben-Nun, Galit Fichman, Lihi Adler-Abramovich, Boris Turk, Ehud Gazit, Galia Blum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageAmerican English
Pages (from-to)60-67
Number of pages8
JournalJournal of Controlled Release
StatePublished - 10 Jul 2017

Bibliographical note

Publisher Copyright:
© 2016 Elsevier B.V.


  • Cathepsins
  • Diphenylalanine
  • Nanofibers
  • Self-assembly
  • Targeted drug delivery


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