Development of novel apoferritin formulations for antitumour benzothiazoles

• Main Author: Breen, Alastair F
• Format: Dissertation
• Language: English
• Published: University of Nottingham 2019
• Subjects: RC 254 Neoplasms. Tumors. Oncology (including Cancer)

The antitumour effects of benzothiazoles are well documented, but they suffer from poor aqueous solubility and lipophilicity. Apoferritin (AFt) has been identified as a potential drug delivery vehicle due to its uniform size, biocompatibility, nontoxicity and its ability to load both hydrophobic and hydrophilic agents. Both 5F 203 and GW 610 were successfully encapsulated within AFt via the nanoreactor route, with 71 and 191 molecules per AFt, respectively. The encapsulation efficiency and drug loading of GW 610 are far superior to those of 5F 203. Encapsulation enhanced the potency of 5F 203 and GW 610 in the majority of sensitive cell lines tested, while retaining their selectivity. To improve solubility and increase encapsulation efficiency of GW 610, a series of GW 608 amino acid esters were synthesised. All GW 608-AAs showed enhanced encapsulation compared to GW 610. Increased polarity appeared to hinder encapsulation while a net positive charge increased encapsulation, with > 380 molecules of GW 608-Lys molecules per AFt cage. AFt-GW 608-Lys was found to more potent than AFt-GW 610 in 4/6 sensitive cell lines tested, and up to >3x more potent. The lysyl-amide conjugate of 5F 203, Phortress, was also encapsulated within AFt, with 130 molecules per AFt cage. This increased number of molecules per AFt cage led AFt-Phortress being more potent than AFt-5F 203 in 3/4 sensitive cell lines tested. Steady release of benzothiazoles from within AFt occurs over 12 hr at physiologically relevant pH, and is controlled by electrostatic interactions between the benzothiazole and the Aft. The formulations, AFt-Phortress and AFt-GW 608-Lys, which combine the potent and selective antitumour activity of parent benzothiazoles with biocompatibility of AFt delivery vehicle, present a viable putative anticancer therapy worthy of further preclinical development.