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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

Authors

Francesca Citossi

Thomas Smith

Jong Bong Lee

Joel Segal

Pavel Gershkovich

Michael John Stocks

Tracey D. Bradshaw

Barrie Kellam

Maria Marlow



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.

Journal Article Type Article
Journal Molecular Pharmaceutics
Print ISSN 1543-8384
Electronic ISSN 1543-8392
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 15
Issue 4
APA6 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), doi:10.1021/acs.molpharmaceut.7b01106
DOI https://doi.org/10.1021/acs.molpharmaceut.7b01106
Keywords benzothiazole derivatives, low molecular weight gelators, CYP1A1 induction, in vitro antitumour activity
Publisher URL https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.7b01106
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information Copyright © 2018 American Chemical Society

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf







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