Comparative study of cathepsin B-cleavable linkers for the optimal design of cathepsin B-specific doxorubicin prodrug nanoparticles for targeted cancer therapy

Nayeon Shim, Seong Ik Jeon, Suah Yang, Jung Yeon Park, Mihee Jo, Jinseong Kim, Jiwoong Choi, Wan Su Yun, Jeongrae Kim, Youngjoo Lee, Man Kyu Shim, Yongju Kim, Kwangmeyung Kim

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10 Scopus citations


A carrier-free prodrug nanoparticle has emerged as a potential approach to cancer therapy. It plays a vital role in enhancing the tumor targeting and therapeutic efficacy of the anticancer agent at sites of intention wherein the prodrug nanoparticle is potentially activated. Herein, five derivatives of cathepsin B-cleavable prodrugs are synthesized via chemically conjugating different cathepsin B-cleavable peptides (Phe-Arg-Arg-Gly, Phe-Arg-Arg-Leu, Phe-Arg-Arg-Leu-Gly, Phe-Leu-Arg-Arg-Gly) to doxorubicin (DOX). The peptide-DOX prodrugs can spontaneously assemble into nanoparticles via their intermolecular hydrophobic and π-π stacking interactions. The resulting cathepsin B-cleavable prodrugs nanoparticles formed different nanoparticle structures according to the amphiphilicity and flexibility of different peptides and their particle stability and cellular uptake mechanism are carefully evaluated in vitro. Among five prodrug nanoparticles, the Phe-Arg-Arg-Leu-DOX (FRRL-DOX) nanoparticle was formed to a size of 167.5 ± 12.4 nm and stably maintains its nanoparticle structure in saline media for 3 days. The FRRL-DOX nanoparticle is well taken up by tumoral nuclei and effectively induces cancer cell death with minimal toxicity to normal cells. In addition, the FRRL-DOX nanoparticle shows 2.3–16.3-fold greater tumor-specific accumulation in vivo than other prodrug nanoparticles and free DOX. The therapeutic effect of FRRL-DOX is finally examined, demonstrating 2.1-fold better anticancer efficacy compared to that of free DOX. Notably, the FRRL-DOX nanoparticle does not exert serious toxicity in its repeated intravenous administration at a high dose of up to 10 mg/kg (equiv. to DOX). In conclusion, the peptide sequence for cathepsin B-cleavable prodrug nanoparticle is determined to be successfully optimized in a way of increasing its tumor selectivity and lowering toxicity to normal tissues.

Original languageEnglish
Article number121806
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government ( NRF-2019R1A2C3006283 ).

Publisher Copyright:
© 2022 Elsevier Ltd


  • Cancer-targeting therapy
  • Carrier-free nanoparticle
  • Cathepsin B-sensitive linker
  • Nanomedicine
  • Prodrug


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