Alastair F. Breen
Protein Encapsulation of Experimental Anticancer Agents 5F 203 and Phortress: Towards Precision Drug Delivery
Breen, Alastair F.; Scurr, David; Cassioli, Maria Letizia; Wells, Geoffrey; Thomas, Neil R.; Zhang, Jihong; Turyanska, Lyudmila; Bradshaw, Tracey D.
Authors
DAVID SCURR DAVID.SCURR@NOTTINGHAM.AC.UK
Principal Research Fellow
Maria Letizia Cassioli
Geoffrey Wells
NEIL THOMAS neil.thomas@nottingham.ac.uk
Professor of Medicinal and Biological Chemistry
Jihong Zhang
Dr LYUDMILA TURYANSKA LYUDMILA.TURYANSKA@NOTTINGHAM.AC.UK
Associate Professor
Dr TRACEY BRADSHAW tracey.bradshaw@nottingham.ac.uk
Associate Professor
Abstract
Introduction: Advancment of novel anticancer drugs into clinic is frequently halted by their lack of solubility, reduced stability under physiological conditions, and non-specific uptake by normal tissues, causing systemic toxicity. Their progress to clinic could be accelerated by development of new formulations employing suitable and complementary drug delivery vehicles.
Methods: A robust method for apoferritin (AFt)-encapsulation of antitumour benzothiazoles has been developed for enhanced activity against and drug delivery to benzothiazole-sensitive cancers.
Results: More than 70 molecules of benzothiazole 5F 203 were encapsulated per AFt cage. Post-encapsulation, the size and integrity of the protein cages were retained as evidenced by dynamic light scattering. ToF-SIMS depth profiling using an argon cluster beam confirmed 5F 203 exclusively within the AFt cavity. Improved encapsulation of benzothiazole lysyl-amide prodrugs was achieved (~130 molecules of Phortress per AFt cage). Transferrin receptor 1, TfR1, was detected in lysates prepared from most cancer cell lines studied, contributing to enhanced anticancer potency of the AFt-encapsulated benzothiazoles (5F 203, Phortress, GW 610, GW 608-Lys). Nanomolar activity was demonstrated by AFt-formulations in breast, ovarian, renal and gastric carcinoma cell lines, whereas GI50 >50 µM was observed in non-tumourigenic MRC-5 fibroblasts. Intracellular 5F 203, a potent arylhydrocarbon receptor (AhR) ligand, and inducible expression of cytochrome P450 (CYP) 1A1 were detected following exposure of sensitive cells to AFt-5F 203, confirming that the activity of benzothiazoles was not compromised following encapsulation.
Conclusions: Our results show enhanced potency and selectivity of AFt-encapsulated 5F 203 against carcinomas derived from breast, ovarian, renal, colorectal as well as gastric cancer models, and offer realistic prospects for potential refinement of tumour-targeting and treatment, and merit further in vivo investigations.
Citation
Breen, A. F., Scurr, D., Cassioli, M. L., Wells, G., Thomas, N. R., Zhang, J., …Bradshaw, T. D. (2019). Protein Encapsulation of Experimental Anticancer Agents 5F 203 and Phortress: Towards Precision Drug Delivery. International Journal of Nanomedicine, 14, 9525-9534. https://doi.org/10.2147/IJN.S226293
Journal Article Type | Article |
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Acceptance Date | Sep 30, 2019 |
Online Publication Date | Dec 5, 2019 |
Publication Date | Dec 5, 2019 |
Deposit Date | Oct 10, 2019 |
Publicly Available Date | Oct 10, 2019 |
Print ISSN | 1176-9114 |
Electronic ISSN | 1178-2013 |
Publisher | Dove Medical Press |
Peer Reviewed | Peer Reviewed |
Volume | 14 |
Pages | 9525-9534 |
DOI | https://doi.org/10.2147/IJN.S226293 |
Keywords | Benzothiazole, Apoferritin, Transferrin receptor, Anticancer activity, Drug delivery |
Public URL | https://nottingham-repository.worktribe.com/output/2795787 |
Publisher URL | https://www.dovepress.com/protein-encapsulation-of-experimental-anticancer-agents-5f-203-and-pho-peer-reviewed-article-IJN |
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https://creativecommons.org/licenses/by-nc/3.0/