Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells
| Autor: | Jose Carlos Quilles Junior, Andrei Leitão, Fernanda dos Reis Rocho Carlos, Tracey D. Bradshaw, Viviane W. Mignone, Lyudmila Turyanska, A. Montanari, Maria Augusta Arruda |
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| Rok vydání: | 2019 |
| Předmět: |
Proteases
biology Chemistry General Chemical Engineering Transferrin receptor 02 engineering and technology General Chemistry Protein degradation 010402 general chemistry 021001 nanoscience & nanotechnology 01 natural sciences Molecular biology Cytostasis Cysteine protease 0104 chemical sciences Cathepsin L Cancer cell biology.protein 0210 nano-technology Clonogenic assay |
| Zdroj: | RSC Advances. 9:36699-36706 |
| ISSN: | 2046-2069 |
| DOI: | 10.1039/c9ra07161j |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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