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Citossi, Francesca and Smith, Thomas and Lee, Jong Bong and Segal, Joel and Gershkovich, Pavel and Stocks, Michael John and Bradshaw, Tracey D. and Kellam, Barrie and Marlow, Maria (2018) Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation. Molecular Pharmaceutics, 15 (4). pp. 1578-1586. ISSN 1543-8392

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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.

Item Type:	Article
Additional Information:	Copyright © 2018 American Chemical Society
Keywords:	benzothiazole derivatives, low molecular weight gelators, CYP1A1 induction, in vitro antitumour activity
Schools/Departments:	University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number:	https://doi.org/10.1021/acs.molpharmaceut.7b01106
Depositing User:	Eprints, Support
Date Deposited:	07 Mar 2018 15:36
Last Modified:	24 Apr 2018 14:56
URI:	http://eprints.nottingham.ac.uk/id/eprint/50299

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