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

Authors
Shim, NayeonJeon, Seong IkYang, SuahPark, Jung YeonJo, MiheeKim, JinseongChoi, JiwoongYun, Wan SuKim, JeongraeLee, YoungjooShim, Man KyuKim, YongjuKim, Kwangmeyung
Issue Date
10월-2022
Publisher
ELSEVIER SCI LTD
Keywords
Prodrug; Nanomedicine; Carrier -free nanoparticle; Cancer-targeting therapy; Cathepsin B -sensitive linker
Citation
BIOMATERIALS, v.289
Indexed
SCIE
SCOPUS
Journal Title
BIOMATERIALS
Volume
289
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/145501
DOI
10.1016/j.biomaterials.2022.121806
ISSN
0142-9612
Abstract
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 spontane-ously assemble into nanoparticles via their intermolecular hydrophobic and 7C-7C 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) nano-particle 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.
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