International Journal of Nanomedicine (Dec 2019)
Protein Encapsulation of Experimental Anticancer Agents 5F 203 and Phortress: Towards Precision Drug Delivery
Abstract
Alastair F Breen,1 David Scurr,1 Maria Letizia Cassioli,1 Geoffrey Wells,2 Neil R Thomas,3 Jihong Zhang,4 Lyudmila Turyanska,5 Tracey D Bradshaw1 1Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK; 2UCL School of Pharmacy, University College London, London, UK; 3Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK; 4Medical School, Kunming University of Science and Technology, Kunming, People’s Republic of China; 5Faculty of Engineering, University of Nottingham, Nottingham NG7 2RD, UKCorrespondences: Tracey D BradshawCentre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UKTel +44 115 9515033Email [email protected] TuryanskaFaculty of Engineering, University of Nottingham, Nottingham NG7 2RD, UKTel +44 115 9515151Email [email protected]: Advancement of novel anticancer drugs into clinical use 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 use in the clinic could be accelerated by the 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 aryl hydrocarbon 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.Conclusion: 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.Keywords: benzothiazole, apoferritin, transferrin receptor, anticancer activity, drug delivery
