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.

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., Turyanska, L., & 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
• Acceptance Date: Sep 30, 2019
• Online Publication Date: Dec 5, 2019
• Publication Date: Dec 5, 2019
• Deposit Date: Oct 10, 2019
• Publicly Available Date: Dec 5, 2019
• Print ISSN: 1176-9114
• Electronic ISSN: 1178-2013
• Publisher: Dove 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
• Contract Date: Oct 10, 2019