Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells

Quilles Junior, Jos� C.; Bradshaw, Tracey D; Turyanska, Lyudmila; Carlos, Fernanda dos Reis Rocho; Montanari, A.; Leit�o, Andrei; Mignone, Viviane W.; Arruda, Maria Augusta; Turyanska, Lyudmila; Bradshaw, Tracey D.

Abstract

Cysteine proteases play a key role in tumorigenesis causing protein degradation and promoting invasive tumour growth. Cathepsin L is overexpressed in cancer cells and could provide a specific target for delivery of anticancer agents. We encapsulated novel dipeptidyl nitrile based cysteine protease inhibitors (Neq0551, Neq0554 and Neq0568) into biocompatible apoferritin (AFt) protein nanocages to achieve specific delivery to tumours and pH-induced drug release. AFt-encapsulated Neq0554 demonstrated $3-fold enhanced in vitro activity (GI 50 ¼ 79 mM) compared to naked agent against MiaPaCa-2 pancreatic carcinoma cells. Selectivity for cancer cells was confirmed by comparing their activity to non-tumourigenic human fibroblasts (GI 50 > 200 mM). Transferrin receptor (TfR-1) expression, detected only in lysates prepared from carcinoma cells, may contribute to the cancer-selectivity. The G 1 cell cycle arrest caused by AFt-Neq0554 resulting in cytostasis was corroborated by clonogenic assays. Superior and more persistent inhibition of cathepsin L up to 80% was achieved with AFt-encapsulated agent in HCT-116 cells following 6 h exposure to 50 mM agent. The selective anticancer activity of AFt-encapsulated cysteine protease inhibitor Neq0554 reported here warrants further preclinical in vivo evaluation.

Citation

Quilles Junior, J. C., Bradshaw, T. D., Turyanska, L., Carlos, F. D. R. R., Montanari, A., Leitão, A., …Bradshaw, T. D. (2019). Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells. RSC Advances, 9(63), 36699-36706. https://doi.org/10.1039/c9ra07161j

• Journal Article Type: Article
• Acceptance Date: Nov 4, 2019
• Online Publication Date: Nov 11, 2019
• Publication Date: Nov 11, 2019
• Deposit Date: Nov 18, 2019
• Publicly Available Date: Nov 18, 2019
• Journal: RSC Advances
• Electronic ISSN: 2046-2069
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 63
• Pages: 36699-36706
• DOI: https://doi.org/10.1039/c9ra07161j
• Keywords: General Chemistry; General Chemical Engineering
• Public URL: https://nottingham-repository.worktribe.com/output/3308395
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2019/RA/C9RA07161J#!divAbstract
• Contract Date: Nov 18, 2019