Alastair F Breen1, Geoffrey Wells2, Lyudmila Turyanska3,4, Tracey D Bradshaw1. 1. Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK. 2. School of Pharmacy, University College London, London, UK. 3. School of Physics and Astronomy, University of Nottingham, Nottingham, UK. 4. School of Chemistry, University of Lincoln, Lincoln, UK.
Abstract
BACKGROUND: The benzothiazole structure is important in medicinal chemistry, and 5-fluoro-2-(3,4-dimethoxyphenyl) benzothiazole (GW 610) is of particular interest as it shows outstanding anticancer activity in sensitive breast and colorectal carcinoma cell lines via generation of lethal DNA adducts in sensitive cancer cells. Despite promising activity, poor water solubility limits its applications. The apoferritin (AFt) protein cage has been proposed as a robust and biocompatible drug delivery vehicle. AIMS: Here, we aim to enhance solubility of GW 610 by developing amino acid prodrug conjugates and utilizing the AFt capsule as drug delivery vessel. METHODS AND RESULTS: The potent experimental antitumour agent, GW 610, has been successfully encapsulated within AFt with more than 190 molecules per AFt cage. The AFt-GW 610 complex exhibits dose-dependent growth inhibition and is more potent than GW 610 alone in 5/7 cancer cell lines. To enhance both aqueous solubility and encapsulation efficiency, a series of amino acid esters of GW 608 prodrug were synthesized via N,N'-dicyclohexylcarbodiimide ester coupling to produce molecules with different polarity. A dramatic increase in encapsulation efficiency was achieved, with more than 380 molecules of GW 608-Lys molecules per AFt cage. Release studies show sustained release of the cargo over 12 hours at physiologically relevant pH. The AFt-encapsulated amino acid modified GW 608 complexes are sequestered more rapidly and exhibit more potent anticancer activity than unencapsulated agent. CONCLUSION: These results indicate that AFt-encapsulation of GW 610 prodrug provides a biocompatible delivery option for this potent, selective experimental antitumour agent and for amino acid-modified GW 608. Of particular interest is the encapsulation efficiency and in vitro antitumour activity of AFt-GW 608-Lys, which warrants further preclinical evaluation.
BACKGROUND: The benzothiazole structure is important in medicinal chemistry, and 5-fluoro-2-(3,4-dimethoxyphenyl) benzothiazole (GW 610) is of particular interest as it shows outstanding anticancer activity in sensitive breast and colorectal carcinoma cell lines via generation of lethal DNA adducts in sensitive cancer cells. Despite promising activity, poor water solubility limits its applications. The apoferritin (AFt) protein cage has been proposed as a robust and biocompatible drug delivery vehicle. AIMS: Here, we aim to enhance solubility of GW 610 by developing amino acid prodrug conjugates and utilizing the AFt capsule as drug delivery vessel. METHODS AND RESULTS: The potent experimental antitumour agent, GW 610, has been successfully encapsulated within AFt with more than 190 molecules per AFt cage. The AFt-GW 610 complex exhibits dose-dependent growth inhibition and is more potent than GW 610 alone in 5/7 cancer cell lines. To enhance both aqueous solubility and encapsulation efficiency, a series of amino acid esters of GW 608 prodrug were synthesized via N,N'-dicyclohexylcarbodiimide ester coupling to produce molecules with different polarity. A dramatic increase in encapsulation efficiency was achieved, with more than 380 molecules of GW 608-Lys molecules per AFt cage. Release studies show sustained release of the cargo over 12 hours at physiologically relevant pH. The AFt-encapsulated amino acid modified GW 608 complexes are sequestered more rapidly and exhibit more potent anticancer activity than unencapsulated agent. CONCLUSION: These results indicate that AFt-encapsulation of GW 610 prodrug provides a biocompatible delivery option for this potent, selective experimental antitumour agent and for amino acid-modified GW 608. Of particular interest is the encapsulation efficiency and in vitro antitumour activity of AFt-GW 608-Lys, which warrants further preclinical evaluation.
Authors: Tracy R Daniels; Ezequiel Bernabeu; José A Rodríguez; Shabnum Patel; Maggie Kozman; Diego A Chiappetta; Eggehard Holler; Julia Y Ljubimova; Gustavo Helguera; Manuel L Penichet Journal: Biochim Biophys Acta Date: 2011-08-05
Authors: Kaouthar Bouzinab; Helen Summers; Jihong Zhang; Malcolm F G Stevens; Christopher J Moody; Lyudmila Turyanska; Neil R Thomas; Pavel Gershkovich; Marianne B Ashford; Emily Vitterso; Lisa C D Storer; Richard Grundy; Tracey D Bradshaw Journal: Cancer Drug Resist Date: 2019-12-19