Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells. Issue 63 (11th November 2019)

• Record Type: Journal Article
• Authors: Quilles Junior, José C.; Carlos, Fernanda dos Reis Rocho; Montanari, A.; Leitão, Andrei; Mignone, Viviane W.; Arruda, Maria Augusta; Turyanska, Lyudmila; Bradshaw, Tracey D.
• Is Part Of: RSC advances. Volume 9:Issue 63(2019)
• Page Start: 36699
• Page End: 36706
• Publication Date: 2019-11-11
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c9ra07161j
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Novel apoferritin encapsulated cysteine protease inhibitors are developed with enhanced and selective uptake by cancer cells, and sustained pH-induced release of the agent. The persistent inhibition of cathepsin L is demonstrated in vitro . 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 (GI50 = 79 μM) 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 (GI50 > 200 μM). Transferrin receptor (TfR-1) expression, detected only in lysates prepared from carcinoma cells, may contribute to the cancer-selectivity. The G1 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 μM agent. The selective anticancer activity of AFt-encapsulated cysteine protease inhibitor Neq0554 reported here warrants further preclinical in vivo evaluation.