Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation

Citossi, Francesca; Smith, Thomas; Lee, Jong Bong; Segal, Joel; Gershkovich, Pavel; Stocks, Michael John; Bradshaw, Tracey D.; Kellam, Barrie; Marlow, Maria

Abstract

Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing poly-mer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumour benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro anti-tumour activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells. In contrast, MRC-5 fibroblasts were inherently resistant to the above derivatives (GI50>10 μM), thus revealing stark selectivity against the malignant cell lines over the non-transformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its deriva-tives only in sensitive malignant cells (MCF-7), corroborating conservation of CYP1A1-mediated mechanism of action. The ability to form stable gels under relatively high strains was supported by rheological tests; in addition, their inner morphology was characterized as possessing a crossed-linked nanostructure, with formation of thick aggregates with variable widths between 1100 nm and 400 nm and lengths from 8 μm to 32 μm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 hours, therefore demonstrating its ability to act as a plat-form for localized delivery.

Citation

Citossi, F., Smith, T., Lee, J. B., Segal, J., Gershkovich, P., Stocks, M. J., …Marlow, M. (in press). Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation. Molecular Pharmaceutics, 15(4), https://doi.org/10.1021/acs.molpharmaceut.7b01106

• Journal Article Type: Article
• Acceptance Date: Mar 5, 2018
• Online Publication Date: Mar 5, 2018
• Deposit Date: Mar 7, 2018
• Publicly Available Date: Mar 6, 2019
• Journal: Molecular Pharmaceutics
• Print ISSN: 1543-8384
• Electronic ISSN: 1543-8392
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 4
• DOI: https://doi.org/10.1021/acs.molpharmaceut.7b01106
• Keywords: benzothiazole derivatives, low molecular weight gelators, CYP1A1 induction, in vitro antitumour activity
• Public URL: https://nottingham-repository.worktribe.com/output/918946
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.7b01106
• Additional Information: Copyright © 2018 American Chemical Society