Advanced search
Start date
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Quilles Junior, Jose C. [1, 2] ; Rocho Carlos, Fernanda dos Reis [2] ; Montanari, A. [2] ; Leitao, Andrei [2] ; Mignone, Viviane W. [3] ; Arruda, Maria Augusta [3] ; Turyanska, Lyudmila [4] ; Bradshaw, Tracey D. [1]
Total Authors: 8
[1] Univ Nottingham, Sch Pharm, Ctr Biomol Sci, Nottingham NG7 2RD - England
[2] Univ Sao Paulo, Sao Carlos Inst Chem IQSC, Med Chem Grp NEQUIMED, Av Trabalhador Sao Carlense 400, BR-13566590 Sao Carlos, SP - Brazil
[3] Univ Nottingham, Sch Life Sci, Queens Med Ctr, Nottingham NG7 2RD - England
[4] Univ Nottingham, Sch Phys & Astron, Nottingham NG7 2RD - England
Total Affiliations: 4
Document type: Journal article
Source: RSC ADVANCES; v. 9, n. 63, p. 36699-36706, NOV 11 2019.
Web of Science Citations: 0

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 similar to 3-fold enhanced in vitro activity (GI(50) = 79 mu M) 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 mu M). 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 mu M agent. The selective anticancer activity of AFt-encapsulated cysteine protease inhibitor Neq0554 reported here warrants further preclinical in vivo evaluation. (AU)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support type: Research Projects - Thematic Grants
FAPESP's process: 14/07292-0 - Molecular design, trypanocidal and anticancer activities of covalent reversible inhibitors of cysteine proteases
Grantee:José Carlos Quilles Junior
Support type: Scholarships in Brazil - Doctorate